Overground Walking to Improve BDNF, IL-6, hs-CRP, Cognitive Function, Functional Capacity, and Quality of Life in Older Adults with Mild Cognitive Impairment: A Pilot Study in a Developing Country

Overground Walking to Improve BDNF, IL-6, hs-CRP, Cognitive Function, Functional Capacity, and Quality of Life in Older Adults with Mild Cognitive Impairment: A Pilot Study in a Developing Country | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Overground Walking to Improve BDNF, IL-6, hs-CRP, Cognitive Function, Functional Capacity, and Quality of Life in Older Adults with Mild Cognitive Impairment: A Pilot Study in a Developing Country Irma Ruslina Defi, Andry Setiawan Lim, Ildzamar Haifa, Novitri Novitri, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7485672/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Backgrounds Mild cognitive impairment (MCI) is associated with cognitive decline which impact performing instrumental activities of daily living (IADL) that depend on memory and frontal/executive functions. Physical exercise has protective effect toward cognitive function and is suspected to influence inflammatory biomarkers. This study aims to evaluate the improvement in BDNF, IL-6, and hs-CRP levels, as well as cognitive function, functional capacity, and quality of life, and to examine the association between these parameters in older adults with mild cognitive impairment following eight weeks of overground walking exercises. Methods This study utilized a quasi-experimental approach. Thirteen participants were included based on inclusion and exclusion criteria. The intervention is an aerobic exercise program using overground walking (trained with the moderate-intensity interval training [MIIT]) method for 8 weeks. It lasted 20 minutes, and each week they added another five minutes. Cognitive function, serum BDNF, inflammatory biomarkers such as Interleukin-6 (IL-6) and High Sensitivity C-Reactive Protein (hs-CRP), quality of life with the Quality of Life Alzheimer’s Disease (QoL-AD) instrument, and functional capacity by The 6-Minute Walking Test (METs) were measured before and after intervention. Results BDNF was increased significantly after intervention (p = 0.038). IL-6 (pre 6.32; post 2.86; p = 0.002) and hs-CRP (pre 2.50; post 1.30; p = 0.0027) levels were significantly decreased, MoCA-Ina total score was increased after intervention (p = 0.09). After 8 weeks of intervention, a notable rise was observed in METs (pre 3,4; post 4.0;p = 0.001) and the QoL-AD scores (pre 27.5; post 34.8; p = 0.001). The parameters were not significantly correlated. Conclusion This study showed that 8-week overground walking with MIIT improves the body’s response to aerobic exercise by producing more anti-inflammatory cytokines and less pro-inflammatory cytokines. It helps to reduce levels of systemic IL-6, and hs-CRP, and increase BDNF and cognitive function as well as functional capacity and QoL. Lower levels of hs-CRP and IL-6 may result from this general reduction in inflammation. The absence of relationships among the parameters in this study, may be attributed to the small sample size. When aerobic exercise equipment is unavailable, overground walking can be an alternative option. Trial registration number NCT06029920 (registration date: 01/09/2023) BDNF Interleukin-6 moderate-intensity interval training mild cognitive impairments overground walking quality of life Figures Figure 1 Introduction Mild Neurocognitive Disorder, also referred to as Mild Cognitive Impairment (MCI), is characterized by noticeable cognitive decline with little to no interference in performing instrumental activities of daily living (IADLs). While it may represent an early manifestation of Alzheimer’s Disease (AD), it can also result from various other underlying medical conditions. 1 IADLs that depend on memory and frontal/executive functions are especially impacted in individuals with MCI. 2 The incidence of MCI is increasingly becoming a significant public health challenge that increases with age. According to a meta-analysis, the prevalence of MCI was 12.2% in the population over 55 years old. 3 This condition generally causes a decrease in the Quality of Life (QoL) and is an early sign of dementia even though the patient can still adequately perform daily activities. 4 The risk of dementia is not only caused by MCI but also by the interaction of genetic and environmental factors. 5 The dementia process is irreversible, while MCI can be reversed to normal when early and appropriate intervention is carried out. Furthermore, the mechanism that explains the protective effect of physical exercise on cognitive function is the Brain-Derived Neurotrophic Factor (BDNF) pathway. 6 , 7 , 8 , 9 BDNF is a vital protein that supports neural plasticity, brain health, and the survival of neurons and synapses. 10 , 11 It plays a critical role in the formation of long-term potentiation (LTP), a fundamental process involved in learning and memory. 9 Several studies have indicated the involvement of inflammatory factors in cognitive decline and dementia. 12 Overexpression of Interleukin-6 (IL-6) may contribute to cognitive impairment by disrupting neural signaling in brain areas responsible for cognitive functions, including the hippocampus and prefrontal cortex. 13 Research has also linked elevated levels of inflammatory markers such as C-reactive protein (CRP) and high-sensitivity C-reactive protein (Hs-CRP) to cognitive decline in older adults. Physical activity is suspected to influence both of these inflammatory biomarkers. A previous study explored the effects of regular physical exercise on cognitive function in individuals with schizophrenia, with particular emphasis on the involvement of the IL-6 signaling pathway. Frequent exercise has an impact on IL-6 by lowering baseline levels and diminishing the transient rise that occurs in response to exercise (an anti-inflammatory reaction to physical effort). 14 Similar findings were also observed for Hs-CRP levels, where 12 weeks of moderate aerobic exercise resulted in a significant reduction in Hs-CRP levels in the obese population. 15 According to the American College of Sports Medicine (ACSM), aerobic exercise refers to sustained, rhythmic movements that involve large muscle groups. These exercises depend on aerobic metabolic processes, where the body produces energy in the form of Adenosine Triphosphate (ATP) by utilizing carbohydrates, fats, and amino acids. Typical forms of aerobic exercise include activities such as cycling, swimming, hiking, dancing, long-distance running or jogging, and overground walking. 16 The exercise is often performed on a treadmill or bicycle ergometer in research examining cognitive rehabilitation. 16 , 17 , 18 Overground walking is the easiest and cheap physical activity and is closely related to the ability to do daily activities, specifically in the older adult population. A popular instrument in the field of medical rehabilitation to measure an individual's functional capacity is The Six Minute Walk Test (6MWT). Overground walking has been found to enhance functional capacity and walking performance—measured by speed and Metabolic Equivalents (METs) for energy expenditure—more effectively than treadmill walking. 19 Moreover, in the context of developing countries, overground walking is considerably more beneficial as it represents a low-cost and easily accessible form of exercise. Populations, particularly those from lower socioeconomic backgrounds, often face difficulties in affording technologically advanced equipment such as treadmills. The Quality of Life in Alzheimer’s Disease (QoL-AD) scale, originally developed to assess the subjective well-being of individuals with Alzheimer’s disease, is also applicable for evaluating quality of life in patients with Mild Cognitive Impairment (MCI). 20 , 21 To strengthen the explanation of the effects of overground walking on the aforementioned parameters, it is necessary to conduct an analysis of the relationships among these parameters. The objectives of this study are to elucidate the improvement in cognitive function, functional capacity, BDNF, IL-6, and hs-CRP levels, as well as the relation between these parameters, in older adults in nursing homes with mild cognitive MCI and QoL after eight weeks of overground walking exercises. Methods Study Design and Participants This was a pre-post intervention study with one-group pretest-posttest design that was conducted from September 2023 to October 2023. Participants were individuals aged 60–85 years residing in nursing home with MCI (Montreal Cognitive Assessment Indonesian Version (MoCA-Ina) Score 18–25 out of 30, Barthel Index Score 20, Geriatric Depression Scale ≤ 5, Timed Up and Go Test < 15 seconds) who walked without aids as well as understand oral and written instructions. Exclusion criteria include individuals with a hearing impairment that could prevent the receipt of instructions, as well as others with uncorrected visual impairment and musculoskeletal disorder preventing the performance of exercise or the measurement procedure for the research variables. In addition, those on other rehabilitation programs had a disease that caused cognitive impairment such as Alzheimer's disease, traumatic head injury, and Parkinson's disease; severe joint diseases capable of worsening during exercise (including osteoarthritis and rheumatoid arthritis), were excluded. Individuals who had severe cardiovascular disease diagnosed by a cardiologist were also excluded. The specific exclusion criteria included participants who did not exercise three times in a row or more than five times, or if targeted heart rate 40–59% of reserved heart rate were not obtained ≥ 50% duration for every exercise, two times in a row. Data Collection Participants who met inclusion and exclusion criteria were continuously assessed. MoCA-Ina, QoL-AD, BDNF, IL-6, METs, and hs-CRP levels were measured prior and after the intervention. All participants underwent the same intervention, a program which include overground walking on a flat surface, and the outcomes were subsequently analyzed using statistical methods.. The basic characteristics of the subjects were examined using the Geriatric Depression Scale (GDS), the Timed Up and Go (TUG) test, as well as the Barthel Index in the sample group with an age range of 60 years to 85 years. BDNF levels were assessed during both the pre- and post-intervention phases using the Quantikine Human Total BDNF Immunoassay (R&D Systems®) and expressed in ng/mL. IL-6 levels were quantified using the Electrochemiluminescence Immunoassay (ECLIA®) and reported in pg/mL. Furthermore, hs-CRP levels were measured using Immunoturbidimetry, reported in ng/mL. As, BDNF value rise acutely after exercise, to obtain the peak level of BDNF post-intervention (Knaepen et al, 2010), the blood sample for BDNF were taken as soon as the subjects finished their last exercise. On the other hand, blood sample for IL-6 and Hs-CRP were taken 48 hours after the last exrecise as the circulating level of those parameters as the effect of the exercise reached aftfer 48 hours. 22 MoCA-Ina, METs, and QoL-AD. The QoL-AD scale assesses multiple aspects of quality of life, including areas such as physical well-being, energy levels, emotional state, living conditions, memory, relationships with family, spouse, and friends, self-perception, ability to perform household tasks and engage in enjoyable activities, financial status, and overall life satisfaction. The QoL-AD is administered by how they rate those different items in (1), fair (2), good (3), or excellent (4). "Living situation" refers to how the individual feels about their current place of residence. The "family" item assesses the respondent's relationship with family members; if they report having no immediate family, inquire about siblings, children, nieces, or nephews. The "marriage" item evaluates the relationship with their spouse; if the respondent is single, widowed, or divorced, ask about the person with whom they have the closest emotional connection. If none appropriate score as missing. Friend is anyone beside family whom they close to. If they say there is no friend then how do they feel about having no friends. Both patients (self-assessed) and their caregivers (proxy-assessed) completed the QoL-AD questionnaire. To obtain a more balanced assessment than relying on either the patient’s or caregiver’s rating alone, a weighted total score was computed using the following formula: [(patient-assessed total score × 2 + caregiver-assessed total score) / 3] . This combined score, along with additional measures, was used to assess cognitive function, functional capacity, and quality of life 20 , 23 , 24 Sample size This study was designed as a pilot study to assess the feasibility and preliminary effects of overground walking in a small cohort. Due to the study's exploratory design, a minimum of 12 participants was considered adequate to offer preliminary insights into the effects of the intervention, while also enabling refinement of the study design and procedures. As pilot studies are not primarily powered for hypothesis testing, the focus was on estimating effect sizes and variability to inform future larger-scale trials. The findings from this study will serve as a foundation for subsequent research with a larger sample to validate these preliminary observations. Small sample size also justified to assess feasibility, safety and adherence before scaling up, particularly in this study to a group of older adult that prone to adverse event of intervention. Intervention The type of intervention is 8-week interval training program, with overground walking exercise on a flat surface, three times per week. The exercise protocol was taken from previous study by Abba et al. 25 The exercise duration starts with 15 minutes of walking and 4 minutes of rest, with a progressive increase of 5 minutes of walking each week and an adjustable rest duration. The exercise was performed at a moderate intensity, targeting heart rate of 40–59% of the heart rate reserve (HRR). This exercise was supervised by a general practitioner and patients caregiver to ensure the safety and standard. Statistical Analysis A quasi-experimental design method was used with a pretest-posttest group approach. The pre-post test design was carried out by assessing the research variables before and after treatment in the group and between groups. Paired t -tests and Wilcoxon tests were used to compare participants before and after the intervention. The effect size was also calculated by figuring out each variable's Cohen's d value. Five percent was the threshold for statistical significance. The correlations between MoCA and clinical parameters were determined using Pearson's correlation and linear regression analyses. Statistical analyses were conducted using IBM Corp.'s SPSS 20.0 program, and a difference was deemed statistically significant if it was P < 0.05. Results Subjects characteristics A total of 22 older adults initally assessed for eligibility, due to the criterias and conditions during study, 13 subjects were included in the final analysis (Fig. 1 ). The mean age of the subjects was 72.31 ± 9.205 years (range, 60‑85 years), and most of the subjects (69.2%) were female. The mean GDS score was 2.69 ± 1.377, TUG test score was 10.17 ± 2.351, and Barthel Index was 20 (Table 1 ). Table 1 Subject Characteristics Variable N = 13 Age Mean ± SD 72.31 ± 9.205 Median 72.00 Range (min-max) 60.00–85.00 Gender Male 4 (30.8%) Female 9 (69.2%) Geriatric Depression Scale (GDS) Mean ± SD 2.69 ± 1.377 Median 3.00 Range (min-max) 1.00–5.00 Time Up and Go (TUG) Test Mean ± SD 10.17 ± 2.351 Median 11.00 Range (min-max) 6.00–14.00 Barthel Index Mean ± SD 20.00 Median 20.00 Range (min-max) 20.00 SD: Standard Deviation.Categorical data were presented with the number/frequency and percentage, while numerical data were presented with the mean, median, standard deviation, and range. Changes in blood biomarker parameters After 8 weeks of overground walking exercise, there was a significant increase in BDNF level from 41,273.23 ± 6,713.68 to 45,460.00 ± 7,954.73 (P = 0.038, Cohen’s d = 0.646 [0.034, 1.236]) indicating medium effect size (Table 2 ). IL-6 and Hs-CRP plasma levels found to be significantly decrease from 7.07 ± 4.877 to 3.53 ± 2.262 (P = 0.002, Cohen’s d = -0.797 [-0.157, -1.413]) and 2.67 ± 2.243 to 1.88 ± 1.453 (P = 0.027, Cohen’s d = -0.608 [-0.003, -1.192]), respectively, both indicating medium effect size (Table 2 ). Table 2 Comparison of Variables Pre- and Post-Intervention Variable p -Value Pre n = 13 Post n = 13 Blood parameter BDNF ( ng/mL ) 0.038* Mean ± SD 41.273 ± 6.713 45.460 ± 7.954 Median 42.161 45.755 Range (min-max) 27.747–56.465 33.955–62.276 IL-6 (p g/mL ) 0.002* Mean ± SD 7.07 ± 4.877 3.53 ± 2.262 Median 6.32 2.86 Range (min-max) 1.86–19.36 1.50–8.90 Hs-CRP ( ng/mL ) 0.027* Mean ± SD 2.67 ± 2.243 1.88 ± 1.453 Median 2.50 1.30 Range (min-max) 0.30–8.90 0.10–4.40 Cognitive Function Total MoCA-Ina 0.009* Mean ± SD 21.62 ± 2.364 24.08 ± 3.523 Median 21.00 25.00 Range (min-max) 19.00–25.00 19.00–29.00 Alzheimer’s Disease Quality of Life Physical Health 0.004* Mean ± SD 2.25 ± 0.394 2.81 ± 0.365 Median 2.00 3.00 Range (min-max) 2.00–3.00 2.00–3.00 Energy 0.0001** Mean ± SD 2.21 ± 0.319 3.00 ± 0.211 Median 2.00 3.00 Range (min-max) 2.00–3.00 2.67–3.67 Mood 0.003* Mean ± SD 2.06 ± 0.304 2.73 ± 0.574 Median 2.00 3.00 Range (min-max) 1.67-3.00 2.00–4.00 Life Situation 0.001* Mean ± SD 2.06 ± 0.278 2.81 ± 0.344 Median 2.00 3.00 Range (min-max) 1.67-3.00 2.00–3.00 Memory 0.002* Mean ± SD 2.06 ± 0.327 2.60 ± 0.490 Median 2.00 2.83 Range (min-max) 2.67-3.00 1.67-3.00 Family 0.001* Mean ± SD 2.02 ± 0.537 2.71 ± 0.419 Median 2.00 3.00 Range (min-max) 1.00–3.00 2.00-3.33 Marriage 0.026* Mean ± SD 1.71 ± 0.698 1.90 ± 0.696 Median 1.83 2.00 Range (min-max) 1.00–3.00 1.00–3.00 Friends 0.001* Mean ± SD 2.06 ± 0.459 2.94 ± 0.278 Median 2.00 3.00 Range (min-max) 1.00–3.00 2.00-3.33 Overall Personal 0.0001** Mean ± SD 2.15 ± 0.344 2.92 ± 0.228 Median 2.00 3.00 Range (min-max) 2.00–3.00 2.33-3.00 Ability to do work at home 0.001* Mean ± SD 2.19 ± 0.403 2.94 ± 0.181 Median 2.00 3.00 Range (min-max) 2.00–3.00 2.33-3.00 Financial 0.013* Mean ± SD 2.04 ± 0.295 2.31 ± 0.564 Median 2.00 2.33 Range (min-max) 1.33–2.67 1.00-3.33 Life Overall 0.001* Mean ± SD 2.15 ± 0.344 2.85 ± 0.321 Median 2.00 3.00 Range (min-max) 2.00–3.00 2.00–3.00 QoL-AD Total Composite 0.0001** Mean ± SD 27.02 ± 4.029 32.25 ± 2.665 Median 25.33 35.00 Range (min-max) 23.00-38.67 230.67–41.33 BDNF: Brain-Derived Neurotrophic Factor. IL-6: Interleukin-6. Hs-CRP: High Sensitivity C-Reactive Protein. MoCA-Ina, Montreal Cognitive Assessment Indonesian Version. QoL-AD: Alzheimer’s Disease Quality of Life. SD: Standard Deviation. IL-6 unit in pg/mL. Hs-CRP in ng/mL. BDNF unit in ng/mL The p-value is tested using a paired T-test. (*) indicates a significant result at the 5% level (p < 0.05). (**) suggest stronger significance at the 1% level (p < 0.01) Changes in cognitive function, functional capacity, and quality of life After the intervention, cognitive function – assessed through MoCA-Ina score – was significantly increased from 21.62 ± 2.364 to 24.08 ± 3.523 (P = 0.009, Cohen’s d = 0.830 [0.182, 1.453]), indicating large effect size (Table 2 ). Similar result found in QoL-AD score that showed significant increase in all domains then collectively in the total composite score from 27.02 ± 4.029 to 32.25 ± 2.665 (P = 0.0001, Cohen’s d = 2.584 [1.417, 3.729]), indicating large effect size (Table 2 ). Likewise the other, functional capacity, represent by 6-MWT or METs, showed notable increase from 3.4 ± 0.8 to 4.0 ± 1.2 (P = 0.001) (Table 3 ). Table 3 Comparison of The 6-Minute Walking Test Pre and Post-Intervention Variable Group p -Value Pre n = 13 Post n = 13 6MWT (METs) 0.001* Mean ± SD 3.4 ± 0.8 4.0 ± 1.2 6MWT (METs): The 6-Minute Walking Test (Metabolic Equivalents). SD: Standard Deviation. The p-value is tested using a paired T-test. (*) indicates a significant result at the 5% level (p < 0.05). Factors associated with the cognitive function and QoL-AD Pearson's correlation analysis was performed. Result showed that the increase in BDNF, reduction of IL-6, reduction of Hs-CRP, and increase in METs was not significantly correlated in MoCA-Ina and QoL-AD score improvement in this study (P > 0.05 in all parameters) (Table 4 ). Table 4 Correlation between change in blood biomarker parameters and functional capacity with cognitive function assessed through change in MoCA-INA and QoL-AD total composite score according to Pearson’s correlation analysis MoCA-INA Bivariate Correlation QoL-AD Total Bivariate Correlation r p -Value r p -Value Increase in BDNF 0,462 0,056 -0,271 0,185 Reduction of IL-6 0,115 0,354 -0,021 0,473 Reduction of Hs-CRP -0,249 0,206 0,263 0,192 Increase in METs 0,146 0,316 0,031 0,461 MoCA-Ina: Montreal Cognitive Assessment Indonesian Version; QoL-AD: Quality of Life Alzheimer's Disease; BDNF: Brain-Derived Neurotrophic Factor; IL-6: Interleukin-6; Hs-CRP: High Sensitivity C-Reactive Protein; METs: Metabolic Equivalent Linear regression analysis also showed that parameters in this study were not factors that associated with cognitive function improvement and QoL with and without the consideration of functional capacity (METs) as confounding factor (P > 0.05 in all parameters) (Table 5 ). Table 5 Linear regression analysis on relationship between blood biomarker parameters wtih cognitive function parameter and Alzheimer’s disease quality of life with and without METs as confouding variable Multiple linear regression MoCA-INA Multiple linear regression QoL-AD total Without confoundersadjustment With confoundersadjustment Without confoundersadjustment With confoundersadjustment β p -Value β p -Value β p -Value β p -Value BDNF 0,225 0,157 0.218 0,187 -0,105 0,591 -0,103 0,621 IL-6 0,171 0,439 0,065 0,819 -0,053 0,848 -0,020 0,957 Hs-CRP 0,021 0,973 -0,154 0,829 0,344 0,672 0,399 0,672 METs - - 1,370 0,541 - - -0,429 0,883 MoCA-Ina: Montreal Cognitive Assessment Indonesian Version; QoL-AD: Quality of Life Alzheimer's disease; BDNF: Brain-Derived Neurotrophic Factor; IL-6: Interleukin-6; Hs-CRP: High Sensitivity C-Reactive Protein; METs: Metabolic Equivalent. Discussion According to previous research, aerobic exercise induces BDNF release, which then acts as a mediating variable in the relationship with cognition. 26 BDNF mediates the effects on the brain by enhancing neuroplasticity through different pathways, namely neurogenesis, synaptic formation, and long-term potential. 27 Higher levels due to aerobic exercise are associated with improved cognitive and memory abilities. Furthermore, among various exercise-related factors, intensity has shown the most consistent influence on acute BDNF release, surpassing other elements like type, duration, and frequency. High-intensity interval aerobic exercise has been associated with elevated serum BDNF levels, likely due to increased synthesis within the brain. 27 , 28 Characteristics of Research Samples The mean age of patients in this research was 72.31 ± 9.205 years, consisting of males less than females. This was contrary to research data from Assaf et al., stating that 50 out of 337 people (14.8%) were 60 years of age or older, with a mean age of 70.38 ± 7.4 years, and 58% were female. 29 Previous research showed that the older adults (≥ 60 years) often experience cognitive dysfunction. 30 The prevalence of MCI also rose with age in the Chinese community-dwelling population, according to Yuan Lu et al., with the prevalence being 7.6% for those aged 55–59, 9.5% for those aged 60–69, 14.6% for those aged 70–79, and 23.6% for those aged 80 and above. 3 Older adults residing in nursing homes are at a higher risk of cognitive decline compared to those living in the community. While the exact causes remain uncertain, this decline may be linked to the physical and psychological effects associated with institutional living. Cognitive decline occurs as part of the aging process in the older adults across various countries identified sociodemographic characteristics including living arrangements as risk factors related to aging. 32 Place of residence is associated with health status, well-being, and quality of life 10–12 years into the future. Most older adult people in Indonesia live in homes (communities), and only a small proportion live in institutional settings. 33 Furthermore, the research of older adult’s cognitive function, specifically in institutional settings, such as nursing homes, are not fully elucidated. The Effect of Aerobic Exercise on BDNF The p -value for the BDNF variable was 0.038 ( p -value < 0.05), indicating a statistically significant difference in the BDNF variable pre- and post-aerobic exercise intervention with MIIT for 8 weeks. The findings were consistent with Zhang et al., who found that aged rats given 45 minutes of MIIT aerobic exercise daily, five days a week, for eight weeks showed better expression of the proteins cAMP, PKA, p-CREB, and BDNF. Additionally, the treatment enhanced memory and spatial learning skills and boosted the synaptic structure of the CA1 hippocampus area. 32 Another research by Afzalpour et al., found that high-intensity interval training (HIIT) and high-intensity continuous training (HICT) raised BDNF concentrations, but higher increases were found in the HICT group. 33 Kim et al., found a significant increase in basal serum BDNF along with a decrease in serum levels of sVCAM-1 and TNF-α, indicating that the training program reduced inflammation in Parkinson’s Disease patients. 34 This research used aerobic exercise with MIIT defined by ACSM as a moderate-intensity activity that applied THR of 40–59% HRR. Meanwhile, interval training is broadly defined as periods of intermittent intensive exercise interspersed with recovery periods. Currently, there are no specific guidelines regarding intensity for the older adult, but more caution is needed. 16 Older adults often exhibit changes in their gait, commonly adopting a "cautious" walking pattern marked by slower pace, shorter stride length, and greater variability in step timing. These gait adaptations become more pronounced on uneven terrain compared to flat surfaces and may serve to enhance head and pelvic stability. These gait alterations are influenced by several factors, such as reduced peak hip extension, increased forward tilt of the pelvis, and diminished ankle plantarflexion, which are commonly linked to hip flexion contractures and decreased concentric strength of the ankle plantar flexors. In older adults, gait stability is a key marker, with dynamic stability recognized as a strong predictor of fall risk. Studies indicate that gait instability tends to increase starting in the fourth to fifth decades of life. While mediolateral stability decreases with age, anteroposterior and vertical stability tend to remain relatively stable across age groups. Additionally, treadmill walking imposes timing constraints that may mask age-related gait differences typically seen during overground walking. 35 Overground walking has been shown to be more effective than treadmill walking in enhancing postural stability in older adults. A study by Hirjakova et al. comparing postural stability in young and older adult individuals after both treadmill and overground walking found that treadmill walking significantly impaired postural stability in older adults, particularly under conditions involving sensory conflict. With aging, the ability to maintain balance and perform postural compensatory responses—critical for stability and fall prevention when body posture is disrupted—tends to decline. 36 Studies have demonstrated that physical activity alters acetylation and methylation, two epigenetic changes linked to synaptic plasticity, learning, and memory, which in turn impacts BDNF levels. By activating N-methyl-D-aspartate receptors (NMDA-Rs), which phosphorylate the nuclear transcription factor cAMP response element-binding protein (CREB), physical activity promotes BDNF production and LTP. The efficacy of CREB in regulating BDNF transcription is dependent on the activation of transcriptional coactivators CREB-binding protein (CBP) and Histone acetyltransferases (HAT). Exercise promotes the acetylation of histones H4K8 and H3 in BDNF and raises the expression of CBP in the hippocampus. 37 For those with neurological problems, aerobic exercise is a physical activity intervention that has shown a number of beneficial effects. Szuhany et al.'s meta-analysis of 29 studies offered solid proof that both acute and consistent exercise significantly impacted BDNF levels.. The research also showed that BDNF levels significantly increased after moderate-intensity aerobic exercise. 38 , 39 Silva et al.,showed that there was an increase in BDNF after continuous and interval aerobic exercise in patients with Parkinson's disease. Research on individuals with multiple sclerosis also reported that aerobic exercise could enhance serum BDNF levels. 40 Individuals with neurological disorders may potentially benefit from neuroplasticity to facilitate motor performance. As observed in a rat cerebral embolism model, aerobic exercise increased BDNF levels with parallel improvements in sensorimotor learning, skill acquisition, and memory. 41 Human studies have primarily aimed to characterize changes in serum BDNF (sBDNF) levels following a single session of exercise and to determine how exercise intensity influences these changes. 40 Both short-term high-intensity and moderate-intensity aerobic exercise can increase BDNF levels. In some literature, high-interval intensity exercise (HIIE) aerobic exercise had positive effects on BDNF as a protein needed for the survival and growth of nerve cells in the brain. 42 Research has shown that HIIE can increase BDNF levels in the brain, ultimately improving cognitive function, and mood, as well as reducing the risk of neurological disorders. 31 Vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF) production can be stimulated by HIIE, which is responsible for the functions. 43 It has been demonstrated that these growth factors encourage the development of new neurons and blood vessels in the brain, enhancing cognitive performance and lowering the risk of neurological diseases. Furthermore, HIIE has been shown to increase the production of hormones such as cortisol 33 and adrenaline, 44 known to stimulate BDNF production. This contributes to the explanation of the potent effect of HIIE treatments on raising BDNF levels. 34 According to recent research, transient increases can be further elevated in response to prolonged aerobic exercise. Sustained resistance training in humans has also been shown to result in long-term elevations of resting serum BDNF levels. 35 In contrast, other research found that the duration of aerobic exercise had no significant effect on resting serum BDNF levels. IGF-1 plays a crucial in neurogenesis and BDNF gene regulation as well as neuronal development and differentiation. IGF-1 levels rise in both the brain and the peripheral tissues in response to exercise, which improves neurotransmission via the blood vessel wall. 39 Fernandez et al. showed the idea that high-intensity exercise (HIE) increased serum BDNF levels compared to no aerobic activity and low-intensity exercise (LIE) groups. However, no significant difference was observed when HIE was compared to LIE. There was also no significant association between HIE and plasma BDNF. 45 Another research reported an increase in circulating BDNF after aerobic exercise in healthy subjects. 46 Several mechanisms have been proposed to explain the acute increase in BDNF levels in response to exercise intensity, including (1) platelet-mediated BDNF release, driven by elevated catecholamines and increased sympathetic nervous system activity during physical exertion; 45 (2) the lactate pathway, which is associated with exercise intensity and contributes to brain metabolism; 47 (3) cerebral hypoxia and muscle damage induced by high-intensity exercise (HIE), which may directly stimulate BDNF release into circulation; and (4) exercise-induced hyperthermia, which enhances blood-brain barrier permeability, thereby facilitating neuronal BDNF transport. 48 The Effect of Aerobic Exercise on Cognitive Function Our study results showed that the p -value for the total MoCA-Ina variable was less than 0.05 ( p -value < 0.05), indicating statistical significance. Amjad I et al. also carried out aerobic exercise given to the older adult using treadmills and stationary bicycles for 6 weeks, 3 times a week, for 20–40 minutes with an intensity of 60–80% of maximum heart rate. The results showed improvements in global cognitive function based on examinations by MoCA-Ina. 49 According to a meta-analysis, aerobic dance was very useful for improving global cognitive function, memory, and executive function (Ross et al., 2019). This was supported by a meta-analysis of 15 prospective research showing a decrease in the risk of cognition by 38%. 50 Based on a statistical analysis of MoCA scores, cognitive function was found to be significantly higher in individuals with consistent aerobic exercise. The research observed significant differences in visuospatial abilities through the initial MoCA test but there were no significant differences in memory abilities influenced by exercise. 51 The results showed that there were two research samples with decreased scores post-intervention. This may be due to several factors, as well as physical and mental health conditions that were not re-assessed post-intervention. MoCA-Ina examination in the research was carried out using similar environmental conditions between pre-intervention and post-intervention to eliminate factors known to cause bias. Atsushi Motohiro et al. stated that environmental factors including housing density, narrow living space, air pollution, occupational exposure, as well as personal factors namely stress or depression can affect a person's level of cognition, both in the short and long term. 52 Another research on the Influence of ICU and the Official Environment on the reliability of the MoCA-Ina examination conducted by Martin Nikolaus Stienen et all showed that there was no "location effect" on the results. Therefore, the reliability of MoCA can be considered very good and the difference between the two locations was small. 53 The relationship between aerobic exercise and improved cognition can be explained by several mechanisms. Direct mechanisms include improvements in brain circulation, increased growth factors (eg BDNF, VEGF, and IGF), decreased inflammation, and reduced HPA axis. On the other hand, indirect mechanisms include improved cardiovascular and cerebrovascular health, decreased LDL and triglycerides in blood plasma as well as inhibition of platelet aggregation. 50 , 54 The white and gray matter structures of the brain start to atrophy, specifically in the prefrontal cortex and hippocampus with age. There is a 1–2% volume decrease per year in the hippocampus, and it is even greater in individuals with Alzheimer's disease. Generally, increasing age affects the decline in BDNF levels. Neuroplasticity, namely the brain's ability to form and reorganize synaptic connections, is an important mechanism for cognitive improvement due to exercise in old age. 50 Aerobic exercise is known to increase oxygen and glucose transport to the brain, thereby improving cognitive efficiency. 50 , 54 Other research has shown an increase in the density of blood vessels leading to the cerebral cortex in rats given exercise intervention, in addition to maintaining blood vessel integrity, preventing a decrease in cerebral circulation, as well as increasing capillarity and the number of inter-dendritic connections. 55 Furthermore, Alfini et.al showed that a 12-week aerobic exercise intervention improved working and verbal memory in individuals with cognitive impairment. 51 Aerobic exercise significantly helped verbal fluency performance through increased cerebral blood flow and decreased cerebrovascular resistance index (CVRi), however, additional studies are required to validate this observation. 52 Moderate to high-intensity aerobic exercise has a significant impact on cognition compared to low-intensity. 53 One of the earliest cognitive domains to decline with age is episodic memory. This memory decline is associated with decreased ability to perform daily activities and increased social isolation. Larger hippocampal volume is important because decreased levels are associated with memory and cognitive decline, as well as dementia. 56 Hippocampal gray matter volume, blood volume, and hippocampus functional connectivity have all been found to increase with aerobic exercise in older adults, according to cross-sectional, longitudinal, and randomized controlled studies. 57 It improves the functional connection between the hippocampus and the cortical brain network, which consists of the medial and lateral surfaces of the temporal, parietal, and prefrontal cortices. Decreased functional connectivity with age is associated with cognitive impairment. Aerobic exercise has been proposed as a low-cost, scalable, and widely accessible therapy option to enhance hippocampus-related functions or to prevent or postpone the danger of aging-related degeneration and the early stages of pathological cognitive decline. 58 Meta-analysis research conducted by Ieraci A et al., proved the relationship between cognitive performance and the nervous system. This system plays an important role in polypeptide growth factors, which affect brain development, neuronal differentiation, and viability, as well as synaptic plasticity and connectivity. The neuron group includes neuron growth factor (NGF) derived from BDNF, neurotrophin-3 (NT-3), and neurotropic 4/5 (NT4/5). 59 According to Chumakov et al., current data and results cannot determine the role of BDNF as a biomarker. The results regarding plasma BDNF concentrations after training and learning suggest the role of a mechanism related to performance during cognitive training. 60 Based on the results, aerobic exercise has been shown as an effective method to increase brain BDNF levels. The Effect of Aerobic Exercise on IL-6 and hs-CRP Increased levels of IL-6 and CRP make you more likely to develop chronic conditions such as diabetes mellitus, cardiovascular problems, and Alzheimer's. Higher levels of the inflammatory markers IL-6 and CRP have been linked to functional decline, frailty, and a lower quality of life. 61 Physical activity and systemic IL-6 Increased physical activity is an effective approach to reducing systemic IL-6 levels among the older adults, which seems even more evident in very old, disability-prone individuals with high baseline levels. 62 Another meta-analysis of 16 studies on the influence of physical activity on lowering inflammatory biomarkers showed similar results, with a major decrease in all GWG measures, especially CRP and IL-6, following aerobic exercise without resistance training. 63 As for the IL-6 variable in the present study, the p -value was 0.002 (< In a study conducted by Custodero et al., a reduction in IL-6 levels was also found after aerobic exercise without any weight loss. 64 A p -value of 0.027 was less than the threshold for significance difference ( p < 0.05) obtained in our study on the hs-CRP variable, which implies a statistically significant difference between mean levels of hs-CRP pre and post-intervention. The findings are consistent with those reported by Alghadir et al. 65 After 12 weeks of moderate aerobic activity, the findings showed a significant improvement in all bone metabolism markers, including serum osteocalcin, serum-free calcium, serum bone-specific alkaline phosphatase, and bone mineral density across all patients. Aerobic Exercise Effect on Quality of Life All QoL domains had non-negligible baseline values in this study. Impaired cognitive function contributes to a lower quality of life. The QoL values were moderately high, possibly explaining why MCI did not significantly negatively impact quality of life. The baseline quality of life values was reasonable at the start, but we can always benefit from exercise methods. This aligns with the findings of a meta-analysis conducted by Roberts et al., which reported moderate effect sizes when analyzing quality-of-life outcomes before and after exercise interventions. Their study highlights the significant role of physical activity and exercise in enhancing the overall well-being of older adults. Perceived physical fitness, improved general positive affect, and reduced depressive symptoms are among the factors related to this influence. 66 Increased levels of inflammatory markers such as IL-6 and hs-CRP are closely associated with the onset of sarcopenia and frailty. These conditions, marked by the decline of muscle mass, strength, and physical activity in older adults, significantly affect their quality of life. 67 , 68 Penzes et al. conducted a study in which they investigated the effects of cannabinoids on different immune cell types, including myeloid-derived cells like dendritic and macrophage cells. They found that higher serum CRP levels were associated with low scores in the physical health-related quality of life domain. Engaging with the older adult in exercises performed at adequate frequency, duration, and intensity leads to the prevention of diseases and the preservation of physical fitness, as well as preventing fatigue during activities, which therefore provides a better quality of life. 69 Different studies assessed the relationship of inflammatory factors to QoL, showing that IL-6 was negatively correlated with QoL as well because inflammatory cytokines cause other symptoms (e.g., fatigue, muscle aches, and loss of appetite). 70 The 6-Minute Walking Test The 6MWT assesses energy expenditure during physical activity, expressed as METs, relative to resting metabolic rate. The 6MWT serves as a validated predictor for evaluating functional capacity, particularly in assessing endurance and overall physical performance. Overground walking significantly improves both METs by increasing energy expenditure and enhancing cardiovascular endurance. Regular overground walking also improves functional capacity, which makes it possible for individuals to go further since their muscles work more efficiently and consume less oxygen. Walking is a convenient and efficient workout for enhancing general fitness. 71 , 72 Relationship of Paramaters to Cognitive Function and to Alzheimer’s Disease Quality of Life Even though our study showed no correlation between BDNF, IL-6, and Hs-CRP to MoCA-Ina score in this study, multiple previous studies have shown that those parameters have significant effects on cognitive function. The results of a population-based cohort study, IL-6 levels raise the risk of dementia from all causes over an extended period of time, and they are inversely correlated with cognitive performance on a number of tests. 73 Previous cross-sectional studies to the older adults in Japan also showed that elevated hs-CRP levels were linked to reduced cognitive function among 70 to 80-year-old older adults living in the community, indicating a potential impact on Hs-CRP levels on cognitive function. 74 As for BDNF, a previous study showed that higher brain BDNF expression was linked to a significantly slower rate of cognitive decline. 75 Moreover, in our study, no association was found between BDNF, IL-6, and Hs-CRP and QoL-AD. These results are similar with a study by Jamie et al. that found that neurological and biomarker markers were not always linked to QoL dimensions. This study demonstrates that there was no correlation between any measure of well-being or quality of life and the levels of neurological and inflammatory markers in the blood. This implies that these biomarkers may not serve as reliable substitutes for assessing subjective well-being in relatively healthy older adults. 76 Earlier research only reported the relationship between BDNF and cognitive function and the association between cognitive function and QoL-AD. 77 , 78 This relationship might be due to that BDNF can act as a buffer against stress that may impair cognitive function and decline of cognitive function can impair an individual's ability to work, socialize, or manage personal needs, which directly impacts their quality of life. Study limitation Different findings of correlation showed in this study compared to previous studies are most likely due to the small sample size. Because of this, our findings might underrepresent the true effects. But, consistent significant findings in post-intervention differences for each parameter suggest a strong likelihood of identifying significant correlations if the study were conducted on a larger population. Moreover, we were unable to statistically control for all potential confounding variables, including the limitation of conducting the study at a single site. Consequently, the generalizability of our findings to populations with differing characteristics may be limited. Given these limitations, our results still provide valuable insights and serves as pilot investigation that could inform the design of future studies with a larger and more diverse sample, aimed at testing the generalizability and causal nature of the relationships identified in this research. A more extensive study is warranted to further confirm these findings and strengthen the evidence base for their potential clinical application. Conclusion Overground walking exercise can increase BDNF levels, reduce IL-6 and hs-CRP levels, also can improve the QoL, cognitive function, and functional capacity in older adult individuals with MCI. This finding also provides insight that overground walking exercise can have beneficial effects, making it as an alternative for exercise training in the older adult population. Even though, there is no correlation between blood biomarker parameters, the findings of significant differences post-intervention across all variables strengthen the possibility of relationships among the variables. However, this should be supported by a larger sample size. This paper is important because it contributes to identifying a more affordable and feasible method of aerobic exercise that can be implemented by older adults in nursing homes in Indonesia, to improve cognitive function in patients with MCI. Overground walking, which involves natural walking on uneven surfaces, provides the body’s visual system with information regarding head movement and body position, with visual surroundings moving in the opposite direction. This optic visual stream is obtained during overground walking but is not present when walking on a treadmill. Declarations Statement of Ethics This research was carried out in alignment with the ethical standards set by the Declaration of Helsinki and received approval from the Research Ethics Committee of Padjadjaran University (approval No. 143/UN6.KEP/EC/2023). The clinical trial was registered on ClinicalTrials.gov on September 1, 2023, under the registration number NCT06029920. All older adult participants provided with written informed consent prior to their participation in the study. Conflict of Interest Statement The authors declare that there are no conflicts of interest related to this study. Data Availability The data supporting the findings of this study are not publicly available due to privacy considerations but can be obtained from the corresponding author upon reasonable request. Funding This study was supported by the Hibah Riset Padjadjaran University (1549/UN6.3.1/PT.00/2023). Author Contributions I.R.D: conceptualization, funding acqualization, project administration, writing-review&editing. A.S.L: data curation, investigation, software, visualization, writing-original draft. I.H: formal analysis, methodology, resource. N.N: supervision, validation, writing-review&editing. I.D: data curation, supervision, writing-review, and editing. Acknowledgements The authors extend their sincere gratitude to the residents of Nasution Nursing Home for their valuable participation and contributions to this research. References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association; 2013. Lauren L, Mc Ardle R, Wilson S, Beswick E, Karimi R, Slight SP. Digital Endpoints for Assessing Instrumental Activities of Daily Living in Mild Cognitive Impairement: Systematic Review. J Med Internet Res. 2023;25:e45658. doi: 10.2196/45658. Lu Y, Liu C, Yu D, Fawkes S, Ma J, Zhang M, et al. Prevalence of mild cognitive impairment in community-dwelling Chinese populations aged over 55 years: a meta-analysis and systematic review. BMC Geriatr. 2021;21(1):10. doi: 10.1186/s12877-020-01948-3. Pottie K, Rahal R, Jaramillo A, Birtwhistle R, Thombs BD, Singh H, et al. Recommendations on screening for cognitive impairment in older adults. CMAJ. 2016;188(1):37-46. doi: 10.1503/cmaj.141165. Radler KH, Zdrodowska MA, Dowd H, Cersonsky TE, Huey ED, Cosentino S, et al. Rate of progression from mild cognitive impairment to dementia in an essential tremor cohort: a prospective, longitudinal study. Parkinsonism Relat Disord. 2020;74:38-42. doi: 10.1016/j.parkreldis.2020.04.008. McCraw A, Sullivan J, Lowery K, Eddings R, Heim HR, Buss AT. Dynamic field theory of executive function: identifying early neurocognitive markers. Monogr Soc Res Child Dev. 2024;89(3):7-109. doi: 10.1111/mono.12478. Moon HY, Lee M. Exercise-induced expression of genes associated with aging in the hippocampus of rats. Neurosci Lett. 2024;823:1376646. doi: 10.1016/j.neulet.2024.137646. Behrendt T, Quisilima JI, Bielitzki R, Behrens M, Glazachev OS, Brigadski T, et al. Brain-derived neurotrophic factor and inflammatory biomarkers are unaffected by acute and chronic intermittent hypoxic-hyperoxic exposure in geriatric patients: a randomized controlled trial. Ann Med. 2024;56(1): 2304650. doi: 10.1080/07853890.2024.2304650. Ieraci A, Beggiato S, Ferraro L, Barbieri SS, Popoli M. Kynurenine pathway is altered in BDNF Val66Met knock-in mice: effect of physical exercise. Brain Behav Immun. 2020;89:440-450. doi: 10.1016/j.bbi.2020.07.031. Trzesicki M, Bialon N, Kuzma D, Gorka D. Bcl-2-proteins and neurotrophins as important factors for the survival of peripheral neurons in transgenic animals. Postepy Biochem. 2022;68(4):381-386. doi: 10.18388/pb.2021_460. Kutsarova E, Schohl A, Munz M, Wang A, Zhang YY, Bilash OM, et al. BDNF signaling in correlation-dependent structural plasticity in the developing visual system. Plos Biol. 2023;21(4):e3002070. doi: 10.1371/journal.pbio.3002070. Perrin RJ, Franklin EE, Bernhardt H, Burns A, Schwetye KE, Cairns NJ, et al. The alzheimer’s disease neuroimaging initiative neuropathology core: an update. Alzheimers Dement. 2024;20(11):7859-7870. doi: 10.1002/alz.14253. Palta P, Xue QL, Deal JA, Fried LP, Walston JD, Carlson MC. Interleukin-6 and C-Reactive Protein Levels and 9-Year Cognitive Decline in Community-Dwelling Older Women: The Women's Health and Aging Study II. J Gerontol A Biol Sci Med Sci. 2015;70(7):873-8. doi: 10.1093/gerona/glu132. Gómez-Rubio P, Trapero I. The Effects of Exercise on IL-6 Levels and Cognitive Performance in Patients with Schizophrenia. Diseases. 2019;7(1):11. Published 2019 Jan 22. doi:10.3390/diseases7010011. Kargarfard M, Nobari H, Kamyar K, Zadeh AK, Oliveira R. Effects of 12-week moderate aerobic exercise on ROCK2 activity, hs-CRP and glycemic index in obese patients with impaired glucose tolerance. Physiol Behav. 2022 Dec 1;257:113976. doi: 10.1016/j.physbeh.2022.113976. Palfi V, Kovacsik R, Szabo A. Symptoms of exercise addiction in aerobic and anaerobic exercises: beyond the components model of addiction. Addict Behav Rep. 2021;14:100369. doi: 10.1016/j.abrep.2021.100369. Koch S, Tiozzo E, Simonetto M, Loewenstein D, Wright CB, Dong C, et al. Randomized trial of combined aerobic, resistance, and cognitive training to improve recovery from stroke: feasibility and safety. J Am Heart Assoc. 2020;9(10):e015377. doi: 10.1161/JAHA.119.015377. Kimhy D, Vakhrusheva J, Bartels MN, Armstrong HF, Ballon JS, Khan S, et al. The Impact of Aerobic Exercise on Brain-Derived Neurotrophic Factor and Neurocognition in Individuals With Schizophrenia: A Single-Blind, Randomized Clinical Trial. Schizophr Bull. 2015;41(4):859-68. doi: 10.1093/schbul/sbv022. Bangsbo J, Blackwell J, Boraxbekk CJ, Caserotti P, Dela F, Evans AB, et al. Copenhagen consensus statement 2019: physical activity and ageing. Br J Sports Med. 2019;53(14):856-858. doi: 10.1136/bjsports-2018-100451. Christiansen L, Berglund JS, Anderbeg P, Cellek S, Zhang J, Lemmens E, et al. Associations between mobile health technology use and self-rated quality of life: a cross-sectional study on older adults with cognitive impairement. Gerontol Geriatr Med. 2021;7:23337214211018924. doi: 10.1177/23337214211018924. Hunter SW. Opportunities for falls prevention in older adults with mild cognitive impairment. Int Psychogeriatr. 2024;36(4):235-237. doi: 10.1017/S1041610223000649. Cerqueira E, Marinho DA, Neiva HP, Lourenco O. Inflammatory Effects of High and Moderate Intensity Exercise—A Systematic Review. Front Physiol. 2020;10:1550. doi: 10.3389/fphys.2019.01550 Kahle-Wrobleski K, Ye W, Henley D, Hake AM, Siemers E, Chen YF, et al. Assessing quality of life in Alzheimer's disease: Implications for clinical trials. Alzheimers Dement (Amst). 2016;13(6):82-90. doi: 10.1016/j.dadm.2016.11.004. Torisson G, Stavenow L, Minthon L, Londos E. Reliability, validity and clinical correlates of the Quality of Life in Alzheimer’s disease (QoL-AD) scale in medical inpatients. Health Qual Life Outcomes. 2016;14:90. doi: 10.1186/s12955-016-0493-8. Abba MA, Olaleye OA, Hamzat TK. Effects of over-ground walking and cognitive rehabilitation on cognition, brain-derived neurotrophic factor, participation and quality of life among stroke survivors: a study protocol. European Journal of Physiotherapy. 2020;24(3), 144–150. https://doi.org/10.1080/21679169.2020.1808056. Wu Y, Deng F, Wang J, Liu Y, Zhou W, Qu L, et al. Intensity-dependent effects of consecutive treadmill exercise on spatial learning and memory through the p-CREB/ BDNF /NMDAR signaling in hippocampus. Behav Brain Research. 2020:386:112599. doi: 10.1016/j.bbr.2020.112599. Wang YH, Zhou HH, Luo Q, Cui S. The effect of physical exercise on circulating brain-derived neurotrophic factor in healthy subjects: a meta-analysis of randomized controlled trials. Brain Behav. 2022;12(4):e2544. doi: 10.1002/brb3.2544. Renteria I, Garcia-Suarez PC, Martinez-Corona DO, Moncada-Jimenez J, Plaisance EP, Jimenez-Maldonado A. Short-term high-intensity interval training increases systemic brain-derived neurotrophic factor (BDNF) in healthy women. Eur J Sport Sci. 2020;20(4):516-524. doi: 10.1080/17461391.2019.1650120. Assaf G, Khoury JE, Jawhar S, Rahme D. Mild cognitive Impairment and modifiable risk factors among Lebanese older adults in primary care. Asian J Psychiatr. 2021;65:102828. 10.1016/j.ajp.2021.102828. Thomas N, Gardiner JD, Crompton RH, Lawson R. Keep your head down:maintaining gait stability in challenging conditions. Hum Mov Sci. 2020;73:102676. doi: 10.1016/j.humov.2020.102676. Badan Pusat Statistik Indonesia. Statistik Penduduk Lanjut Usia. 2014. Zhang J, Gao Q, Gao J, Lv L, Liu R, Wu Y, et al. Moderate-Intensity Intermittent Training Alters the DNA Methylation Pattern of PDE4D Gene in Hippocampus to Improve the Ability of Spatial Learning and Memory in Aging Rats Reduced by D-Galactose. Brain Sci. 2023;13(3):422. doi: 10.3390/brainsci13030422. Afzalpour ME, Chadorneshin HT, Foadoddini M, Eivari HA, et al. Comparing interval and continuous exercise training regimens on neurotrophic factors in rat brain. Physiol Behav. 2015;147:78-83. doi: 10.1016/j.physbeh.2015.04.012. Kim HJ, Lee DJ, Lee YS. The effect of aerobic exercise on brain-derived neurotrophic factor ( BDNF ) in individuals with mild cognitive impairment: A systematic review and meta-analysis of a randomized controlled trials. Phys Ther Rehabil Sci. 2022;11:304-10. doi:10.14474/ptrs.2022.11.3.304. Osoba MY, Rao AK, Agrawal SK, Lalwani AK. Balance and gait in the elderly: A contemporary review. Laryngoscope Investig Otolaryngolog. 2019;4(1):143-153. doi: 10.1002/lio2.252. Hirjakova Z, Bizovska L, Bzuduskova D, Hlavacka F. Postural stability after treadmill and overground walking in young and elderly. Gait Posture. 2020;80:84-89. doi: 10.1016/j.gaitpost.2020.05.014. Ward S, Orme M, Zatloukal J, Singh S. Adherence to walking exercise prescription during pulmonary rehabilitation in COPD with a commercial activity monitor: a feasibility trial. BMC Pulm Med. 2021;21(1):30. doi: 10.1186/s12890-021-01406-9. Szuhany KL, Matteo B, Otto MW. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. J Psychiatr Research. 2015;60:56-64. doi: 10.1016/j.jpsychires.2014.10.003. Shobeiri P, Karimi A, Momtazmanesh S, Teixeira AL, Teunissen CE, Van Weden EE, et al. Exercise-induced increase in blood-based brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis: a systematic review and meta analysis of exercise intervention trials. Plos One. 2022;17(3):e0264557. Silva ML, Carvalho de Morais VA, Santos RM, Rocha NP, Christo PP, Fuscaldi LT, et al. No change in brain-derived neurotrophic factor levels following a single session of light to-moderate intensity walk in chronic stroke patients. J Neurol Disord. 2017;5:2. doi: 10.4172/2329-6895.1000334. Mojtabavi H, Shaka Z, Momtazmanesh S, Ajdari A, Rezaei N. Circulationg brain-derived neurotrophic factor as a potential biomarker in stroke: a systematic review and meta-analysis. J Transl Med. 2022;20(1):126. doi: 10.1186/s12967-022-03312-y. Ren L, Zheng Y, Wu L, Gu Y, He Y, Jiang B, et al. Investigation of the prevalence of cognitive impairment and its risk factors within the elderly population in Shanghai, China. Sci Rep. 2018;8(1):3575. doi: 10.1038/s41598-018-21983-w. Jin Y, Li X, Wei C, Yuan Q. Effect of exercise-targeted hippocampal PDE-4 methylation on synaptic plasticity and spatial learning/memory impairments in D-galactose-induced aging rats. Exp Brain Res. 2024;242(2):309-320. doi: 10.1007/s00221-023-06749-9. Malczynska-Sims P, Chalimoniuk M, Wronski Z, Marusiak J, Sulek A. High-intensity interval training modulates inflammatory response in parkinson’s disease. Aging Clin Exp Res. 2022;34(9):2165-2176. doi: 10.1007/s40520-022-02153-5. Fernandez-Rodriguez R, Alvarez-Bueno C, Martinez-Ortega IA, Martinez-Vizcaino V, Mesas AE, Notario-Pacheco B. Immediate effect of high-intensity exercise on brain-derived neurotrophic factor in healthy young adults: A systematic review and meta-analysis. J Sport Health Sci. 2022;11(3):367-375. doi: 10.1016/j.jshs.2021.08.004. Bjornestad A, Tysnes OB, Larsen JP, Alves G. Reliability of Three Disability Scales for Detection of Independence Loss in Parkinson’s Disease. Parkinsons Dis. 2016;2016:1941034. doi: 10.1155/2016/1941034. Feter N, Alt R, Dias MG, Rombaldi AJ. How do different physical exercise parameters modulate brain-derived neurotrophic factor in healthy and nonhealthy adults? A systematic review, meta-analysis and meta-regression. Sci Sport. 2019;34(5):293-304. doi: 10.1016/j.scispo.2019.02.001. Ross RE, Saladin ME, George MS, Gregory CM. High-intensity aerobik exercise acutely increases brain-derived neurotrophic factor. Med Sci Sports Exerc. 2019;51(8):1698-1709. doi: 10.1249/MSS.0000000000001969. Amjad I, Toor H, Niazi IK, Afzal H, Jochumsen M, Shafique M et al. Therapeutic effects of aerobic exercise on EEG parameters and higher cognitive functions in mild cognitive impairment patients. Int J Neurosci.2019;129(6):551-562. Coeberg J, Zimianiti I, Ellmers TJ, Kaski D. Response to geroin et al.: tapping into the mechanisms of abnormal functional postural control. Eur J Neurol. 2022;29(12):3748-3749. doi: 10.1111/ene.15578. Alfini AJ, Weiss LR, Nielson KA, Verber MD, Smith JC, et al. Resting cerebral blood flow after exercise training in mild cognitive impairment. J Alzheimers Dis. 2019;67(2):671-684. doi: 10.3233/JAD-180728. Motohiro A, Abe T, Okuyama K, Onoda K, Ito T, Isomura M, et al. Environmental factors affecting cognitive function among community-dwelling older adults: a longitudinal research. Int J Environ Res Public Health. 2021;18(16):8528. doi: 10.3390/ijerph18168528. Stienen MN, Geisseler O, Velz J, Maldaner N, Sebok M, Dannecker N, et al. Influence of the intensive care unit environment on the reliability of the Montreal cognitive assessment. Front Neurol. 2019;10:734. doi: 10.3389/fneur.2019.00734. Fernandes J, Arida RM, Gomez-Pinilla F. Physical exercise as an epigenetic modulator of brain plasticity and cognition. Neurosci Biobehav Rev. 2017;80:443–456. doi: 10.1016/j.neubiorev.2017.06.012. Morimoto SS, Kanellopoulos D, Manning KJ, Alexopoulos GS. Diagnosis and treatment of depression and cognitive impairment in late life. Ann N Y Acad Sci. 2015;1345(1):36-46. doi: 10.1111/nyas.12669. Aghjayan SL, Bournias T, Kang C, Zhou X, Stillman CM, Donofry SD, et al. Aerobik exercise improves episodic memory in late adulthood: a systematic review and meta-analysis. Commun Med (Lond). 2022;2:15. doi: 10.1038/s43856-022-00079-7. Palmer JA, Morris JK, Billinger SA, Lepping RJ, Martin L, Green Z, et al. Hippocampal blood flow rapidly and preferentially increases after a bout of moderate-intensity exercise in older adults with poor cerebrovascular health. Cereb Cortex. 2023;33(9):5297-5306. doi: 10.1093/cercor/bhac418. Walsh JJ, Tschakovsky ME. Exercise and circulating BDNF: Mechanisms of release and implications for the design of exercise interventions. Appl Physiol Nutr Metab. 2018;43(11):1095-1104. doi: 10.1139/apnm-2018-0192. Ieraci A, Madaio AI, Mallei A, Lee FS, Popoli M. Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice. Neuropsychopharmacology. 2016;41(13):3070-3079. doi: 10.1038/npp.2016.120. Chumakov E, Dorofeikova M, Tsyrenova K, Petrova N. A Cross-Sectional Study on Associations Between BDNF, CRP, IL-6 and Clinical Symptoms, Cognitive and Personal Performance in Patients With Paranoid Schizophrenia. Front Psychiatry. 2022;13:943869. doi: 10.3389/fpsyt.2022.943869. Monteiro-Junior RS, De Tarso Maciel-Pinheiro P, Da Matta Mello Portugal E, Da Silva Figueiredo LF, Terra R, Carneiro LSFF, et al. Effect of exercise on inflammatory profile of older persons: Systematic review and meta-analyses. J Physical Act and Health. 2018;15(1):64–71. doi: 10.1123/jpah.2016-0735. Panza F, Custodero C, Solfrizzi V. Physical activity, interleukin-6 change, and gait speed. Aging. 2023;15(11):4568-4570. doi: 10.18632/aging.204797. Chen X, Sun X, Wang C, He H. Effects of Exercise on Inflammatory Cytokines in Patients with Type 2 Diabetes: A Meta-analysis of Randomized Controlled Trials. Oxid Med Cell Longev. 2020;2020:6660557. doi: 10.1155/2020/6660557. Custodero C, Pahor M, Mazzoccoli C, Manini TM, Anton SD, Mazzocca A,et al. Effect of change of interleukin-6 over time on gait speed response: Results from the lifestyle interventions and independence for elders study. Mech Ageing Dev. 2023;210:111763. doi: 10.1016/j.mad.2022.111763. Alghadir AH, Gabr SA, Al-Eisa ES. Effects of Moderate Aerobic Exercise on Cognitive Abilities and Redox State Biomarkers in Older Adults. Oxid Med Cell Longev. 2016;2545168. doi: 10.1155/2016/2545168. Roberts CE, Phillips LH, Cooper CL, Gray S, Allan JL. Effect of Different Types of Physical Activity on Activities of Daily Living in Older Adults: Systematic Review and Meta-Analysis. J Aging Phys Act. 2017;25(4):653-670. doi: 10.1123/japa.2016-0201. Bourdel-Marchasson I, Laksir H, Puget E. Interpreting routine biochemistry in those aged over 65 years: a time for change. Maturitas. 2010;66(1):39–45. doi: 10.1016/j.maturitas.2010.02.004. Rong YD, Bian AL, Hu HY, Ma Y, Zhou XZ. Study on relationship between elderly sarcopenia and inflammatory cytokine IL-6, anti-inflammatory cytokine IL-10. BMC Geriatr. 2018;18(1):308. doi: 10.1186/s12877-018-1007-9. Penzes Z, Alimohammadi S, Horvath D, Olah A, Toth BI, Bacsi A, et al. The dual of cannabidiol on monocyte-derived dendritic cell differentiation and maturation. Front Immunol. 2023;14:1240800. doi: 10.3389/fimmu.2023.1240800. Krapic M, Kavazovic I, Wensveen FM. Immunological mechanisms of sickness behavior in viral infection. Viruses. 2021;13(11):2245. doi: 10.3390/v13112245. Makino A, Yamaguchi K, Sumi D, Ichikawa M, Ohno M, Goto K. Comparison of energy expenditure and substrate oxidation between walking and running in men and women. Phys Act Nutr. 2022;26(1):8-13. doi: 10.20463/pan.2022.0002. Duddy D, Doherty R, Connolly J, McNally S, Loughrey J, Faulkner M. The Effects of Powered Exoskeleton Gait Training on Cardiovascular Function and Gait Performance: A Systematic Review. Sensors. 2021;21(9):3207. doi: 10.3390/s21093207 Zhao Z, Zhang J, Wu Y, Xie M, Tao S, Lv Q, et al. Plasma IL-6 levels and their association with brain health and dementia risk: A population-based cohort study. Brain Behavior and Immunity. 2024;120:430–438. doi: 10.1016/j.bbi.2024.06.014. Hosokawa M, Kabayama M, Godai K, Akagi Y, Tachibana Y, Gondo Y, et al. Cross-sectional association between high-sensitivity C-reactive protein and cognitive function in community-dwelling older adults: the SONIC study. BMC Geriatr. 2024;24(1):756. doi:10.1186/s12877-024-05354-x. Buchman AS, Yu L, Boyle PA, Schneider JA, De Jager PL, Bennett DA. Higher brain BDNF gene expression is associated with slower cognitive decline in older adults. Neurology. 2016;86(8):735–741. doi: 10.1212/WNL.0000000000002387. Tait JL, Duckham RL, Milte CM, Main LC, Daly RM. Associations between inflammatory and neurological markers with quality of life and well-being in older adults. Experimental Gerontology. 2019;125:1100662. doi: 10.1016/j.exger.2019.110662. Gao L, Zhang Y, Sterling K, Song W. Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential. Transl Neurodegener. 2022;11(1):4. doi: 10.1186/s40035-022-00279-0. Stites SD, Harkins K, Rubright JD, Karlawish J. Relationships Between Cognitive Complaints and Quality of Life in Older Adults With Mild Cognitive Impairment, Mild Alzheimer Disease Dementia, and Normal Cognition. Alzheimer Dis Assoc Disord. 2018;32(4):276-283. doi: 10.1097/WAD.0000000000000262. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7485672","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":516763009,"identity":"d090e0eb-fdfb-489a-9313-8794c080297e","order_by":0,"name":"Irma Ruslina 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10:00:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1724353,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7485672/v1/5b870827-1e75-44f5-8af6-d8ce6137edae.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Overground Walking to Improve BDNF, IL-6, hs-CRP, Cognitive Function, Functional Capacity, and Quality of Life in Older Adults with Mild Cognitive Impairment: A Pilot Study in a Developing Country","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMild Neurocognitive Disorder, also referred to as Mild Cognitive Impairment (MCI), is characterized by noticeable cognitive decline with little to no interference in performing instrumental activities of daily living (IADLs). While it may represent an early manifestation of Alzheimer\u0026rsquo;s Disease (AD), it can also result from various other underlying medical conditions.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e IADLs that depend on memory and frontal/executive functions are especially impacted in individuals with MCI.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e The incidence of MCI is increasingly becoming a significant public health challenge that increases with age. According to a meta-analysis, the prevalence of MCI was 12.2% in the population over 55 years old.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e This condition generally causes a decrease in the Quality of Life (QoL) and is an early sign of dementia even though the patient can still adequately perform daily activities.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The risk of dementia is not only caused by MCI but also by the interaction of genetic and environmental factors.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e The dementia process is irreversible, while MCI can be reversed to normal when early and appropriate intervention is carried out. Furthermore, the mechanism that explains the protective effect of physical exercise on cognitive function is the Brain-Derived Neurotrophic Factor (BDNF) pathway.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e BDNF is a vital protein that supports neural plasticity, brain health, and the survival of neurons and synapses.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e It plays a critical role in the formation of long-term potentiation (LTP), a fundamental process involved in learning and memory.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eSeveral studies have indicated the involvement of inflammatory factors in cognitive decline and dementia.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Overexpression of Interleukin-6 (IL-6) may contribute to cognitive impairment by disrupting neural signaling in brain areas responsible for cognitive functions, including the hippocampus and prefrontal cortex.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Research has also linked elevated levels of inflammatory markers such as C-reactive protein (CRP) and high-sensitivity C-reactive protein (Hs-CRP) to cognitive decline in older adults. Physical activity is suspected to influence both of these inflammatory biomarkers. A previous study explored the effects of regular physical exercise on cognitive function in individuals with schizophrenia, with particular emphasis on the involvement of the IL-6 signaling pathway. Frequent exercise has an impact on IL-6 by lowering baseline levels and diminishing the transient rise that occurs in response to exercise (an anti-inflammatory reaction to physical effort).\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Similar findings were also observed for Hs-CRP levels, where 12 weeks of moderate aerobic exercise resulted in a significant reduction in Hs-CRP levels in the obese population.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAccording to the American College of Sports Medicine (ACSM), aerobic exercise refers to sustained, rhythmic movements that involve large muscle groups. These exercises depend on aerobic metabolic processes, where the body produces energy in the form of Adenosine Triphosphate (ATP) by utilizing carbohydrates, fats, and amino acids. Typical forms of aerobic exercise include activities such as cycling, swimming, hiking, dancing, long-distance running or jogging, and overground walking.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e The exercise is often performed on a treadmill or bicycle ergometer in research examining cognitive rehabilitation.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Overground walking is the easiest and cheap physical activity and is closely related to the ability to do daily activities, specifically in the older adult population. A popular instrument in the field of medical rehabilitation to measure an individual's functional capacity is The Six Minute Walk Test (6MWT). Overground walking has been found to enhance functional capacity and walking performance\u0026mdash;measured by speed and Metabolic Equivalents (METs) for energy expenditure\u0026mdash;more effectively than treadmill walking.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Moreover, in the context of developing countries, overground walking is considerably more beneficial as it represents a low-cost and easily accessible form of exercise. Populations, particularly those from lower socioeconomic backgrounds, often face difficulties in affording technologically advanced equipment such as treadmills. The Quality of Life in Alzheimer\u0026rsquo;s Disease (QoL-AD) scale, originally developed to assess the subjective well-being of individuals with Alzheimer\u0026rsquo;s disease, is also applicable for evaluating quality of life in patients with Mild Cognitive Impairment (MCI).\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e To strengthen the explanation of the effects of overground walking on the aforementioned parameters, it is necessary to conduct an analysis of the relationships among these parameters.\u003c/p\u003e\u003cp\u003eThe objectives of this study are to elucidate the improvement in cognitive function, functional capacity, BDNF, IL-6, and hs-CRP levels, as well as the relation between these parameters, in older adults in nursing homes with mild cognitive MCI and QoL after eight weeks of overground walking exercises.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design and Participants\u003c/h2\u003e\u003cp\u003eThis was a pre-post intervention study with one-group pretest-posttest design that was conducted from September 2023 to October 2023. Participants were individuals aged 60\u0026ndash;85 years residing in nursing home with MCI (Montreal Cognitive Assessment Indonesian Version (MoCA-Ina) Score 18\u0026ndash;25 out of 30, Barthel Index Score 20, Geriatric Depression Scale\u0026thinsp;\u0026le;\u0026thinsp;5, Timed Up and Go Test\u0026thinsp;\u0026lt;\u0026thinsp;15 seconds) who walked without aids as well as understand oral and written instructions. Exclusion criteria include individuals with a hearing impairment that could prevent the receipt of instructions, as well as others with uncorrected visual impairment and musculoskeletal disorder preventing the performance of exercise or the measurement procedure for the research variables. In addition, those on other rehabilitation programs had a disease that caused cognitive impairment such as Alzheimer's disease, traumatic head injury, and Parkinson's disease; severe joint diseases capable of worsening during exercise (including osteoarthritis and rheumatoid arthritis), were excluded. Individuals who had severe cardiovascular disease diagnosed by a cardiologist were also excluded. The specific exclusion criteria included participants who did not exercise three times in a row or more than five times, or if targeted heart rate 40\u0026ndash;59% of reserved heart rate were not obtained \u0026ge; 50% duration for every exercise, two times in a row.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eParticipants who met inclusion and exclusion criteria were continuously assessed. MoCA-Ina, QoL-AD, BDNF, IL-6, METs, and hs-CRP levels were measured prior and after the intervention. All participants underwent the same intervention, a program which include overground walking on a flat surface, and the outcomes were subsequently analyzed using statistical methods.. The basic characteristics of the subjects were examined using the Geriatric Depression Scale (GDS), the Timed Up and Go (TUG) test, as well as the Barthel Index in the sample group with an age range of 60 years to 85 years. BDNF levels were assessed during both the pre- and post-intervention phases using the Quantikine Human Total BDNF Immunoassay (R\u0026amp;D Systems\u0026reg;) and expressed in ng/mL. IL-6 levels were quantified using the Electrochemiluminescence Immunoassay (ECLIA\u0026reg;) and reported in pg/mL. Furthermore, hs-CRP levels were measured using Immunoturbidimetry, reported in ng/mL. As, BDNF value rise acutely after exercise, to obtain the peak level of BDNF post-intervention (Knaepen et al, 2010), the blood sample for BDNF were taken as soon as the subjects finished their last exercise. On the other hand, blood sample for IL-6 and Hs-CRP were taken 48 hours after the last exrecise as the circulating level of those parameters as the effect of the exercise reached aftfer 48 hours.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e MoCA-Ina, METs, and QoL-AD. The QoL-AD scale assesses multiple aspects of quality of life, including areas such as physical well-being, energy levels, emotional state, living conditions, memory, relationships with family, spouse, and friends, self-perception, ability to perform household tasks and engage in enjoyable activities, financial status, and overall life satisfaction. The QoL-AD is administered by how they rate those different items in (1), fair (2), good (3), or excellent (4). \"Living situation\" refers to how the individual feels about their current place of residence. The \"family\" item assesses the respondent's relationship with family members; if they report having no immediate family, inquire about siblings, children, nieces, or nephews. The \"marriage\" item evaluates the relationship with their spouse; if the respondent is single, widowed, or divorced, ask about the person with whom they have the closest emotional connection. If none appropriate score as missing. Friend is anyone beside family whom they close to. If they say there is no friend then how do they feel about having no friends. Both patients (self-assessed) and their caregivers (proxy-assessed) completed the QoL-AD questionnaire. To obtain a more balanced assessment than relying on either the patient\u0026rsquo;s or caregiver\u0026rsquo;s rating alone, a weighted total score was computed using the following formula:\u003c/p\u003e\u003cp\u003e\u003cem\u003e[(patient-assessed total score \u0026times; 2\u0026thinsp;+\u0026thinsp;caregiver-assessed total score) / 3]\u003c/em\u003e.\u003c/p\u003e\u003cp\u003eThis combined score, along with additional measures, was used to assess cognitive function, functional capacity, and quality of life\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eSample size\u003c/h3\u003e\n\u003cp\u003eThis study was designed as a pilot study to assess the feasibility and preliminary effects of overground walking in a small cohort. Due to the study's exploratory design, a minimum of 12 participants was considered adequate to offer preliminary insights into the effects of the intervention, while also enabling refinement of the study design and procedures. As pilot studies are not primarily powered for hypothesis testing, the focus was on estimating effect sizes and variability to inform future larger-scale trials. The findings from this study will serve as a foundation for subsequent research with a larger sample to validate these preliminary observations. Small sample size also justified to assess feasibility, safety and adherence before scaling up, particularly in this study to a group of older adult that prone to adverse event of intervention.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003eThe type of intervention is 8-week interval training program, with overground walking exercise on a flat surface, three times per week. The exercise protocol was taken from previous study by Abba et al.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e The exercise duration starts with 15 minutes of walking and 4 minutes of rest, with a progressive increase of 5 minutes of walking each week and an adjustable rest duration. The exercise was performed at a moderate intensity, targeting heart rate of 40\u0026ndash;59% of the heart rate reserve (HRR). This exercise was supervised by a general practitioner and patients caregiver to ensure the safety and standard.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eA quasi-experimental design method was used with a pretest-posttest group approach. The pre-post test design was carried out by assessing the research variables before and after treatment in the group and between groups. Paired \u003cem\u003et\u003c/em\u003e-tests and Wilcoxon tests were used to compare participants before and after the intervention. The effect size was also calculated by figuring out each variable's Cohen's d value. Five percent was the threshold for statistical significance. The correlations between MoCA and clinical parameters were determined using Pearson's correlation and linear regression analyses. Statistical analyses were conducted using IBM Corp.'s SPSS 20.0 program, and a difference was deemed statistically significant if it was P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eSubjects characteristics\u003c/h2\u003e\u003cp\u003eA total of 22 older adults initally assessed for eligibility, due to the criterias and conditions during study, 13 subjects were included in the final analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The mean age of the subjects was 72.31\u0026thinsp;\u0026plusmn;\u0026thinsp;9.205 years (range, 60‑85 years), and most of the subjects (69.2%) were female. The mean GDS score was 2.69\u0026thinsp;\u0026plusmn;\u0026thinsp;1.377, TUG test score was 10.17\u0026thinsp;\u0026plusmn;\u0026thinsp;2.351, and Barthel Index was 20 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eSubject Characteristics\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eN\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72.31\u0026thinsp;\u0026plusmn;\u0026thinsp;9.205\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60.00\u0026ndash;85.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (30.8%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (69.2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGeriatric Depression Scale (GDS)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.69\u0026thinsp;\u0026plusmn;\u0026thinsp;1.377\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u0026ndash;5.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTime Up and Go (TUG) Test\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.17\u0026thinsp;\u0026plusmn;\u0026thinsp;2.351\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.00\u0026ndash;14.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBarthel Index\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eSD: Standard Deviation.Categorical data were presented with the number/frequency and percentage, while numerical data were presented with the mean, median, standard deviation, and range.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eChanges in blood biomarker parameters\u003c/h3\u003e\n\u003cp\u003eAfter 8 weeks of overground walking exercise, there was a significant increase in BDNF level from 41,273.23\u0026thinsp;\u0026plusmn;\u0026thinsp;6,713.68 to 45,460.00\u0026thinsp;\u0026plusmn;\u0026thinsp;7,954.73 (P\u0026thinsp;=\u0026thinsp;0.038, Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.646 [0.034, 1.236]) indicating medium effect size (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). IL-6 and Hs-CRP plasma levels found to be significantly decrease from 7.07\u0026thinsp;\u0026plusmn;\u0026thinsp;4.877 to 3.53\u0026thinsp;\u0026plusmn;\u0026thinsp;2.262 (P\u0026thinsp;=\u0026thinsp;0.002, Cohen\u0026rsquo;s d = -0.797 [-0.157, -1.413]) and 2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.243 to 1.88\u0026thinsp;\u0026plusmn;\u0026thinsp;1.453 (P\u0026thinsp;=\u0026thinsp;0.027, Cohen\u0026rsquo;s d = -0.608 [-0.003, -1.192]), respectively, both indicating medium effect size (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eComparison of Variables Pre- and Post-Intervention\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePre\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePost\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood parameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBDNF (\u003c/b\u003e\u003cb\u003eng/mL\u003c/b\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.038*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41.273\u0026thinsp;\u0026plusmn;\u0026thinsp;6.713\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45.460\u0026thinsp;\u0026plusmn;\u0026thinsp;7.954\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42.161\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e45.755\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.747\u0026ndash;56.465\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33.955\u0026ndash;62.276\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIL-6 (p\u003c/b\u003e\u003cb\u003eg/mL\u003c/b\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.002*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.07\u0026thinsp;\u0026plusmn;\u0026thinsp;4.877\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.53\u0026thinsp;\u0026plusmn;\u0026thinsp;2.262\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.86\u0026ndash;19.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.50\u0026ndash;8.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eHs-CRP (\u003c/b\u003e\u003cb\u003eng/mL\u003c/b\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.027*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.243\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.88\u0026thinsp;\u0026plusmn;\u0026thinsp;1.453\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.30\u0026ndash;8.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.10\u0026ndash;4.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCognitive Function\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTotal MoCA-Ina\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.009*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21.62\u0026thinsp;\u0026plusmn;\u0026thinsp;2.364\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.523\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19.00\u0026ndash;25.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19.00\u0026ndash;29.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAlzheimer\u0026rsquo;s Disease Quality of Life\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePhysical Health\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.004*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.394\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.365\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eEnergy\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.0001**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.319\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.211\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.67\u0026ndash;3.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMood\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.003*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.304\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.574\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.67-3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.00\u0026ndash;4.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLife Situation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.278\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.344\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.67-3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMemory\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.002*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.327\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.490\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.67-3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.67-3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFamily\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.537\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.419\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.00-3.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMarriage\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.026*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.71\u0026thinsp;\u0026plusmn;\u0026thinsp;0.698\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.696\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFriends\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.459\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.94\u0026thinsp;\u0026plusmn;\u0026thinsp;0.278\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.00-3.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eOverall Personal\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.0001**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.344\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.228\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.33-3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAbility to do work at home\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.403\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.94\u0026thinsp;\u0026plusmn;\u0026thinsp;0.181\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.33-3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFinancial\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.013*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.295\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.564\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.33\u0026ndash;2.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.00-3.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLife Overall\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.344\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.321\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.00\u0026ndash;3.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eQoL-AD Total Composite\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.0001**\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.02\u0026thinsp;\u0026plusmn;\u0026thinsp;4.029\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.665\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRange (min-max)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.00-38.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e230.67\u0026ndash;41.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eBDNF: Brain-Derived Neurotrophic Factor. IL-6: Interleukin-6. Hs-CRP: High Sensitivity C-Reactive Protein. MoCA-Ina, Montreal Cognitive Assessment Indonesian Version. QoL-AD: Alzheimer\u0026rsquo;s Disease Quality of Life. SD: Standard Deviation. IL-6 unit in pg/mL. Hs-CRP in ng/mL. BDNF unit in ng/mL\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eThe p-value is tested using a paired T-test. (*) indicates a significant result at the 5% level (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e(**) suggest stronger significance at the 1% level (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01)\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eChanges in cognitive function, functional capacity, and quality of life\u003c/h2\u003e\u003cp\u003eAfter the intervention, cognitive function \u0026ndash; assessed through MoCA-Ina score \u0026ndash; was significantly increased from 21.62\u0026thinsp;\u0026plusmn;\u0026thinsp;2.364 to 24.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.523 (P\u0026thinsp;=\u0026thinsp;0.009, Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.830 [0.182, 1.453]), indicating large effect size (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Similar result found in QoL-AD score that showed significant increase in all domains then collectively in the total composite score from 27.02\u0026thinsp;\u0026plusmn;\u0026thinsp;4.029 to 32.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.665 (P\u0026thinsp;=\u0026thinsp;0.0001, Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;2.584 [1.417, 3.729]), indicating large effect size (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Likewise the other, functional capacity, represent by 6-MWT or METs, showed notable increase from 3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8 to 4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2 (P\u0026thinsp;=\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eComparison of The 6-Minute Walking Test Pre and Post-Intervention\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGroup\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePre\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePost\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6MWT (METs)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.001*\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e6MWT (METs): The 6-Minute Walking Test (Metabolic Equivalents). SD: Standard Deviation.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eThe p-value is tested using a paired T-test. (*) indicates a significant result at the 5% level (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eFactors associated with the cognitive function and QoL-AD\u003c/h2\u003e\u003cp\u003ePearson's correlation analysis was performed. Result showed that the increase in BDNF, reduction of IL-6, reduction of Hs-CRP, and increase in METs was not significantly correlated in MoCA-Ina and QoL-AD score improvement in this study (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05 in all parameters) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eCorrelation between change in blood biomarker parameters and functional capacity with cognitive function assessed through change in MoCA-INA and QoL-AD total composite score according to Pearson\u0026rsquo;s correlation analysis\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eMoCA-INA Bivariate Correlation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eQoL-AD Total\u003c/p\u003e\u003cp\u003eBivariate Correlation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003er\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003ep\u003c/b\u003e\u003cb\u003e-Value\u003c/b\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003er\u003c/b\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003ep\u003c/b\u003e\u003cb\u003e-Value\u003c/b\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIncrease in BDNF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,462\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0,056\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0,271\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,185\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReduction of IL-6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,115\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0,354\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0,021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,473\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReduction of Hs-CRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0,249\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0,206\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0,263\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,192\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIncrease in METs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,146\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0,316\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0,031\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,461\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eMoCA-Ina: Montreal Cognitive Assessment Indonesian Version; QoL-AD: Quality of Life Alzheimer's Disease; BDNF: Brain-Derived Neurotrophic Factor; IL-6: Interleukin-6; Hs-CRP: High Sensitivity C-Reactive Protein; METs: Metabolic Equivalent\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eLinear regression analysis also showed that parameters in this study were not factors that associated with cognitive function improvement and QoL with and without the consideration of functional capacity (METs) as confounding factor (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05 in all parameters) (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eLinear regression analysis on relationship between blood biomarker parameters wtih cognitive function parameter and Alzheimer\u0026rsquo;s disease quality of life with and without METs as confouding variable\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003eMultiple linear regression MoCA-INA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003eMultiple linear regression QoL-AD total\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eWithout confoundersadjustment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eWith confoundersadjustment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eWithout confoundersadjustment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003eWith confoundersadjustment\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-Value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-Value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBDNF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,225\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0,157\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.218\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,187\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0,105\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0,591\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-0,103\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0,621\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIL-6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0,439\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0,065\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,819\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0,053\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0,848\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-0,020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0,957\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHs-CRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0,021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0,973\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0,154\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,829\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0,344\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0,672\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0,399\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0,672\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMETs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,370\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0,541\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-0,429\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0,883\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eMoCA-Ina: Montreal Cognitive Assessment Indonesian Version; QoL-AD: Quality of Life Alzheimer's disease; BDNF: Brain-Derived Neurotrophic Factor; IL-6: Interleukin-6; Hs-CRP: High Sensitivity C-Reactive Protein; METs: Metabolic Equivalent.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eAccording to previous research, aerobic exercise induces BDNF release, which then acts as a mediating variable in the relationship with cognition.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e BDNF mediates the effects on the brain by enhancing neuroplasticity through different pathways, namely neurogenesis, synaptic formation, and long-term potential.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Higher levels due to aerobic exercise are associated with improved cognitive and memory abilities. Furthermore, among various exercise-related factors, intensity has shown the most consistent influence on acute BDNF release, surpassing other elements like type, duration, and frequency. High-intensity interval aerobic exercise has been associated with elevated serum BDNF levels, likely due to increased synthesis within the brain.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eCharacteristics of Research Samples\u003c/h2\u003e\u003cp\u003eThe mean age of patients in this research was 72.31\u0026thinsp;\u0026plusmn;\u0026thinsp;9.205 years, consisting of males less than females. This was contrary to research data from Assaf et al., stating that 50 out of 337 people (14.8%) were 60 years of age or older, with a mean age of 70.38\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4 years, and 58% were female.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Previous research showed that the older adults (\u0026ge;\u0026thinsp;60 years) often experience cognitive dysfunction.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e The prevalence of MCI also rose with age in the Chinese community-dwelling population, according to Yuan Lu et al., with the prevalence being 7.6% for those aged 55\u0026ndash;59, 9.5% for those aged 60\u0026ndash;69, 14.6% for those aged 70\u0026ndash;79, and 23.6% for those aged 80 and above.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Older adults residing in nursing homes are at a higher risk of cognitive decline compared to those living in the community. While the exact causes remain uncertain, this decline may be linked to the physical and psychological effects associated with institutional living. Cognitive decline occurs as part of the aging process in the older adults across various countries identified sociodemographic characteristics including living arrangements as risk factors related to aging.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Place of residence is associated with health status, well-being, and quality of life 10\u0026ndash;12 years into the future. Most older adult people in Indonesia live in homes (communities), and only a small proportion live in institutional settings.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Furthermore, the research of older adult\u0026rsquo;s cognitive function, specifically in institutional settings, such as nursing homes, are not fully elucidated.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eThe Effect of Aerobic Exercise on BDNF\u003c/h2\u003e\u003cp\u003eThe \u003cem\u003ep\u003c/em\u003e-value for the BDNF variable was 0.038 (\u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating a statistically significant difference in the BDNF variable pre- and post-aerobic exercise intervention with MIIT for 8 weeks. The findings were consistent with Zhang et al., who found that aged rats given 45 minutes of MIIT aerobic exercise daily, five days a week, for eight weeks showed better expression of the proteins cAMP, PKA, p-CREB, and BDNF. Additionally, the treatment enhanced memory and spatial learning skills and boosted the synaptic structure of the CA1 hippocampus area.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Another research by Afzalpour et al., found that high-intensity interval training (HIIT) and high-intensity continuous training (HICT) raised BDNF concentrations, but higher increases were found in the HICT group.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Kim et al., found a significant increase in basal serum BDNF along with a decrease in serum levels of sVCAM-1 and TNF-α, indicating that the training program reduced inflammation in Parkinson\u0026rsquo;s Disease patients.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThis research used aerobic exercise with MIIT defined by ACSM as a moderate-intensity activity that applied THR of 40\u0026ndash;59% HRR. Meanwhile, interval training is broadly defined as periods of intermittent intensive exercise interspersed with recovery periods. Currently, there are no specific guidelines regarding intensity for the older adult, but more caution is needed.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Older adults often exhibit changes in their gait, commonly adopting a \"cautious\" walking pattern marked by slower pace, shorter stride length, and greater variability in step timing. These gait adaptations become more pronounced on uneven terrain compared to flat surfaces and may serve to enhance head and pelvic stability. These gait alterations are influenced by several factors, such as reduced peak hip extension, increased forward tilt of the pelvis, and diminished ankle plantarflexion, which are commonly linked to hip flexion contractures and decreased concentric strength of the ankle plantar flexors. In older adults, gait stability is a key marker, with dynamic stability recognized as a strong predictor of fall risk. Studies indicate that gait instability tends to increase starting in the fourth to fifth decades of life. While mediolateral stability decreases with age, anteroposterior and vertical stability tend to remain relatively stable across age groups. Additionally, treadmill walking imposes timing constraints that may mask age-related gait differences typically seen during overground walking.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eOverground walking has been shown to be more effective than treadmill walking in enhancing postural stability in older adults. A study by Hirjakova et al. comparing postural stability in young and older adult individuals after both treadmill and overground walking found that treadmill walking significantly impaired postural stability in older adults, particularly under conditions involving sensory conflict. With aging, the ability to maintain balance and perform postural compensatory responses\u0026mdash;critical for stability and fall prevention when body posture is disrupted\u0026mdash;tends to decline.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e Studies have demonstrated that physical activity alters acetylation and methylation, two epigenetic changes linked to synaptic plasticity, learning, and memory, which in turn impacts BDNF levels. By activating N-methyl-D-aspartate receptors (NMDA-Rs), which phosphorylate the nuclear transcription factor cAMP response element-binding protein (CREB), physical activity promotes BDNF production and LTP. The efficacy of CREB in regulating BDNF transcription is dependent on the activation of transcriptional coactivators CREB-binding protein (CBP) and Histone acetyltransferases (HAT). Exercise promotes the acetylation of histones H4K8 and H3 in BDNF and raises the expression of CBP in the hippocampus.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eFor those with neurological problems, aerobic exercise is a physical activity intervention that has shown a number of beneficial effects. Szuhany et al.'s meta-analysis of 29 studies offered solid proof that both acute and consistent exercise significantly impacted BDNF levels.. The research also showed that BDNF levels significantly increased after moderate-intensity aerobic exercise.\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eSilva et al.,showed that there was an increase in BDNF after continuous and interval aerobic exercise in patients with Parkinson's disease. Research on individuals with multiple sclerosis also reported that aerobic exercise could enhance serum BDNF levels.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eIndividuals with neurological disorders may potentially benefit from neuroplasticity to facilitate motor performance. As observed in a rat cerebral embolism model, aerobic exercise increased BDNF levels with parallel improvements in sensorimotor learning, skill acquisition, and memory.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e Human studies have primarily aimed to characterize changes in serum BDNF (sBDNF) levels following a single session of exercise and to determine how exercise intensity influences these changes.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e Both short-term high-intensity and moderate-intensity aerobic exercise can increase BDNF levels.\u003c/p\u003e\u003cp\u003eIn some literature, high-interval intensity exercise (HIIE) aerobic exercise had positive effects on BDNF as a protein needed for the survival and growth of nerve cells in the brain.\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e Research has shown that HIIE can increase BDNF levels in the brain, ultimately improving cognitive function, and mood, as well as reducing the risk of neurological disorders.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF) production can be stimulated by HIIE, which is responsible for the functions.\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e It has been demonstrated that these growth factors encourage the development of new neurons and blood vessels in the brain, enhancing cognitive performance and lowering the risk of neurological diseases. Furthermore, HIIE has been shown to increase the production of hormones such as cortisol\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e and adrenaline,\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e known to stimulate BDNF production. This contributes to the explanation of the potent effect of HIIE treatments on raising BDNF levels.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAccording to recent research, transient increases can be further elevated in response to prolonged aerobic exercise. Sustained resistance training in humans has also been shown to result in long-term elevations of resting serum BDNF levels.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e In contrast, other research found that the duration of aerobic exercise had no significant effect on resting serum BDNF levels. IGF-1 plays a crucial in neurogenesis and BDNF gene regulation as well as neuronal development and differentiation. IGF-1 levels rise in both the brain and the peripheral tissues in response to exercise, which improves neurotransmission via the blood vessel wall.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e Fernandez et al. showed the idea that high-intensity exercise (HIE) increased serum BDNF levels compared to no aerobic activity and low-intensity exercise (LIE) groups. However, no significant difference was observed when HIE was compared to LIE. There was also no significant association between HIE and plasma BDNF.\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAnother research reported an increase in circulating BDNF after aerobic exercise in healthy subjects.\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e Several mechanisms have been proposed to explain the acute increase in BDNF levels in response to exercise intensity, including (1) platelet-mediated BDNF release, driven by elevated catecholamines and increased sympathetic nervous system activity during physical exertion;\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e (2) the lactate pathway, which is associated with exercise intensity and contributes to brain metabolism;\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e (3) cerebral hypoxia and muscle damage induced by high-intensity exercise (HIE), which may directly stimulate BDNF release into circulation; and (4) exercise-induced hyperthermia, which enhances blood-brain barrier permeability, thereby facilitating neuronal BDNF transport.\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eThe Effect of Aerobic Exercise on Cognitive Function\u003c/h2\u003e\u003cp\u003eOur study results showed that the \u003cem\u003ep\u003c/em\u003e-value for the total MoCA-Ina variable was less than 0.05 (\u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05), indicating statistical significance. Amjad I et al. also carried out aerobic exercise given to the older adult using treadmills and stationary bicycles for 6 weeks, 3 times a week, for 20\u0026ndash;40 minutes with an intensity of 60\u0026ndash;80% of maximum heart rate. The results showed improvements in global cognitive function based on examinations by MoCA-Ina.\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAccording to a meta-analysis, aerobic dance was very useful for improving global cognitive function, memory, and executive function (Ross et al., 2019). This was supported by a meta-analysis of 15 prospective research showing a decrease in the risk of cognition by 38%.\u003csup\u003e50\u003c/sup\u003e Based on a statistical analysis of MoCA scores, cognitive function was found to be significantly higher in individuals with consistent aerobic exercise. The research observed significant differences in visuospatial abilities through the initial MoCA test but there were no significant differences in memory abilities influenced by exercise.\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e The results showed that there were two research samples with decreased scores post-intervention. This may be due to several factors, as well as physical and mental health conditions that were not re-assessed post-intervention.\u003c/p\u003e\u003cp\u003eMoCA-Ina examination in the research was carried out using similar environmental conditions between pre-intervention and post-intervention to eliminate factors known to cause bias. Atsushi Motohiro et al. stated that environmental factors including housing density, narrow living space, air pollution, occupational exposure, as well as personal factors namely stress or depression can affect a person's level of cognition, both in the short and long term.\u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e Another research on the Influence of ICU and the Official Environment on the reliability of the MoCA-Ina examination conducted by Martin Nikolaus Stienen et all showed that there was no \"location effect\" on the results. Therefore, the reliability of MoCA can be considered very good and the difference between the two locations was small.\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e The relationship between aerobic exercise and improved cognition can be explained by several mechanisms. Direct mechanisms include improvements in brain circulation, increased growth factors (eg BDNF, VEGF, and IGF), decreased inflammation, and reduced HPA axis. On the other hand, indirect mechanisms include improved cardiovascular and cerebrovascular health, decreased LDL and triglycerides in blood plasma as well as inhibition of platelet aggregation.\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe white and gray matter structures of the brain start to atrophy, specifically in the prefrontal cortex and hippocampus with age. There is a 1\u0026ndash;2% volume decrease per year in the hippocampus, and it is even greater in individuals with Alzheimer's disease. Generally, increasing age affects the decline in BDNF levels. Neuroplasticity, namely the brain's ability to form and reorganize synaptic connections, is an important mechanism for cognitive improvement due to exercise in old age.\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAerobic exercise is known to increase oxygen and glucose transport to the brain, thereby improving cognitive efficiency.\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e Other research has shown an increase in the density of blood vessels leading to the cerebral cortex in rats given exercise intervention, in addition to maintaining blood vessel integrity, preventing a decrease in cerebral circulation, as well as increasing capillarity and the number of inter-dendritic connections.\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e Furthermore, Alfini et.al showed that a 12-week aerobic exercise intervention improved working and verbal memory in individuals with cognitive impairment.\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e Aerobic exercise significantly helped verbal fluency performance through increased cerebral blood flow and decreased cerebrovascular resistance index (CVRi), however, additional studies are required to validate this observation.\u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eModerate to high-intensity aerobic exercise has a significant impact on cognition compared to low-intensity.\u003csup\u003e\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e One of the earliest cognitive domains to decline with age is episodic memory. This memory decline is associated with decreased ability to perform daily activities and increased social isolation. Larger hippocampal volume is important because decreased levels are associated with memory and cognitive decline, as well as dementia.\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eHippocampal gray matter volume, blood volume, and hippocampus functional connectivity have all been found to increase with aerobic exercise in older adults, according to cross-sectional, longitudinal, and randomized controlled studies.\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e It improves the functional connection between the hippocampus and the cortical brain network, which consists of the medial and lateral surfaces of the temporal, parietal, and prefrontal cortices. Decreased functional connectivity with age is associated with cognitive impairment. Aerobic exercise has been proposed as a low-cost, scalable, and widely accessible therapy option to enhance hippocampus-related functions or to prevent or postpone the danger of aging-related degeneration and the early stages of pathological cognitive decline.\u003csup\u003e\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eMeta-analysis research conducted by Ieraci A et al., proved the relationship between cognitive performance and the nervous system. This system plays an important role in polypeptide growth factors, which affect brain development, neuronal differentiation, and viability, as well as synaptic plasticity and connectivity. The neuron group includes neuron growth factor (NGF) derived from BDNF, neurotrophin-3 (NT-3), and neurotropic 4/5 (NT4/5).\u003csup\u003e59\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAccording to Chumakov et al., current data and results cannot determine the role of BDNF as a biomarker. The results regarding plasma BDNF concentrations after training and learning suggest the role of a mechanism related to performance during cognitive training.\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e Based on the results, aerobic exercise has been shown as an effective method to increase brain BDNF levels.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eThe Effect of Aerobic Exercise on IL-6 and hs-CRP\u003c/h2\u003e\u003cp\u003eIncreased levels of IL-6 and CRP make you more likely to develop chronic conditions such as diabetes mellitus, cardiovascular problems, and Alzheimer's. Higher levels of the inflammatory markers IL-6 and CRP have been linked to functional decline, frailty, and a lower quality of life.\u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e Physical activity and systemic IL-6 Increased physical activity is an effective approach to reducing systemic IL-6 levels among the older adults, which seems even more evident in very old, disability-prone individuals with high baseline levels.\u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e Another meta-analysis of 16 studies on the influence of physical activity on lowering inflammatory biomarkers showed similar results, with a major decrease in all GWG measures, especially CRP and IL-6, following aerobic exercise without resistance training.\u003csup\u003e\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e As for the IL-6 variable in the present study, the \u003cem\u003ep\u003c/em\u003e-value was 0.002 (\u0026lt;\u0026thinsp;In a study conducted by Custodero et al., a reduction in IL-6 levels was also found after aerobic exercise without any weight loss.\u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e A \u003cem\u003ep\u003c/em\u003e-value of 0.027 was less than the threshold for significance difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) obtained in our study on the hs-CRP variable, which implies a statistically significant difference between mean levels of hs-CRP pre and post-intervention. The findings are consistent with those reported by Alghadir et al.\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e After 12 weeks of moderate aerobic activity, the findings showed a significant improvement in all bone metabolism markers, including serum osteocalcin, serum-free calcium, serum bone-specific alkaline phosphatase, and bone mineral density across all patients.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eAerobic Exercise Effect on Quality of Life\u003c/h2\u003e\u003cp\u003eAll QoL domains had non-negligible baseline values in this study. Impaired cognitive function contributes to a lower quality of life. The QoL values were moderately high, possibly explaining why MCI did not significantly negatively impact quality of life. The baseline quality of life values was reasonable at the start, but we can always benefit from exercise methods. This aligns with the findings of a meta-analysis conducted by Roberts et al., which reported moderate effect sizes when analyzing quality-of-life outcomes before and after exercise interventions. Their study highlights the significant role of physical activity and exercise in enhancing the overall well-being of older adults. Perceived physical fitness, improved general positive affect, and reduced depressive symptoms are among the factors related to this influence.\u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e Increased levels of inflammatory markers such as IL-6 and hs-CRP are closely associated with the onset of sarcopenia and frailty. These conditions, marked by the decline of muscle mass, strength, and physical activity in older adults, significantly affect their quality of life.\u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e,\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e Penzes et al. conducted a study in which they investigated the effects of cannabinoids on different immune cell types, including myeloid-derived cells like dendritic and macrophage cells. They found that higher serum CRP levels were associated with low scores in the physical health-related quality of life domain. Engaging with the older adult in exercises performed at adequate frequency, duration, and intensity leads to the prevention of diseases and the preservation of physical fitness, as well as preventing fatigue during activities, which therefore provides a better quality of life.\u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e Different studies assessed the relationship of inflammatory factors to QoL, showing that IL-6 was negatively correlated with QoL as well because inflammatory cytokines cause other symptoms (e.g., fatigue, muscle aches, and loss of appetite).\u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eThe 6-Minute Walking Test\u003c/h2\u003e\u003cp\u003eThe 6MWT assesses energy expenditure during physical activity, expressed as METs, relative to resting metabolic rate. The 6MWT serves as a validated predictor for evaluating functional capacity, particularly in assessing endurance and overall physical performance. Overground walking significantly improves both METs by increasing energy expenditure and enhancing cardiovascular endurance. Regular overground walking also improves functional capacity, which makes it possible for individuals to go further since their muscles work more efficiently and consume less oxygen. Walking is a convenient and efficient workout for enhancing general fitness.\u003csup\u003e\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e,\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eRelationship of Paramaters to Cognitive Function and to Alzheimer\u0026rsquo;s Disease Quality of Life\u003c/h2\u003e\u003cp\u003eEven though our study showed no correlation between BDNF, IL-6, and Hs-CRP to MoCA-Ina score in this study, multiple previous studies have shown that those parameters have significant effects on cognitive function. The results of a population-based cohort study, IL-6 levels raise the risk of dementia from all causes over an extended period of time, and they are inversely correlated with cognitive performance on a number of tests.\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u003c/sup\u003e Previous cross-sectional studies to the older adults in Japan also showed that elevated hs-CRP levels were linked to reduced cognitive function among 70 to 80-year-old older adults living in the community, indicating a potential impact on Hs-CRP levels on cognitive function.\u003csup\u003e\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e As for BDNF, a previous study showed that higher brain BDNF expression was linked to a significantly slower rate of cognitive decline.\u003csup\u003e\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e Moreover, in our study, no association was found between BDNF, IL-6, and Hs-CRP and QoL-AD. These results are similar with a study by Jamie et al. that found that neurological and biomarker markers were not always linked to QoL dimensions. This study demonstrates that there was no correlation between any measure of well-being or quality of life and the levels of neurological and inflammatory markers in the blood. This implies that these biomarkers may not serve as reliable substitutes for assessing subjective well-being in relatively healthy older adults.\u003csup\u003e\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eEarlier research only reported the relationship between BDNF and cognitive function and the association between cognitive function and QoL-AD.\u003csup\u003e\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e,\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u003c/sup\u003e This relationship might be due to that BDNF can act as a buffer against stress that may impair cognitive function and decline of cognitive function can impair an individual's ability to work, socialize, or manage personal needs, which directly impacts their quality of life.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003eStudy limitation\u003c/h2\u003e\u003cp\u003eDifferent findings of correlation showed in this study compared to previous studies are most likely due to the small sample size. Because of this, our findings might underrepresent the true effects. But, consistent significant findings in post-intervention differences for each parameter suggest a strong likelihood of identifying significant correlations if the study were conducted on a larger population. Moreover, we were unable to statistically control for all potential confounding variables, including the limitation of conducting the study at a single site. Consequently, the generalizability of our findings to populations with differing characteristics may be limited. Given these limitations, our results still provide valuable insights and serves as pilot investigation that could inform the design of future studies with a larger and more diverse sample, aimed at testing the generalizability and causal nature of the relationships identified in this research. A more extensive study is warranted to further confirm these findings and strengthen the evidence base for their potential clinical application.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOverground walking exercise can increase BDNF levels, reduce IL-6 and hs-CRP levels, also can improve the QoL, cognitive function, and functional capacity in older adult individuals with MCI. This finding also provides insight that overground walking exercise can have beneficial effects, making it as an alternative for exercise training in the older adult population. Even though, there is no correlation between blood biomarker parameters, the findings of significant differences post-intervention across all variables strengthen the possibility of relationships among the variables. However, this should be supported by a larger sample size. This paper is important because it contributes to identifying a more affordable and feasible method of aerobic exercise that can be implemented by older adults in nursing homes in Indonesia, to improve cognitive function in patients with MCI. Overground walking, which involves natural walking on uneven surfaces, provides the body\u0026rsquo;s visual system with information regarding head movement and body position, with visual surroundings moving in the opposite direction. This optic visual stream is obtained during overground walking but is not present when walking on a treadmill.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eStatement of Ethics\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis research was carried out in alignment with the ethical standards set by the Declaration of Helsinki and received approval from the Research Ethics Committee of Padjadjaran University (approval No. 143/UN6.KEP/EC/2023). The clinical trial was registered on ClinicalTrials.gov on September 1, 2023, under the registration number NCT06029920. All older adult participants provided with written informed consent prior to their participation in the study.\u003c/p\u003e\n\u003cp\u003eConflict of Interest Statement\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no conflicts of interest related to this study.\u003c/p\u003e\n\u003cp\u003eData Availability\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are not publicly available due to privacy considerations but can be obtained from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eFunding\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Hibah Riset Padjadjaran University (1549/UN6.3.1/PT.00/2023).\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eI.R.D: conceptualization, funding acqualization, project administration, writing-review\u0026amp;editing.\u0026nbsp;A.S.L: data curation, investigation, software, visualization, writing-original draft.\u0026nbsp;I.H: formal analysis, methodology, resource.\u0026nbsp;N.N: supervision, validation, writing-review\u0026amp;editing. I.D: data curation, supervision, writing-review, and editing.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors extend their sincere gratitude to the residents of Nasution Nursing Home for their valuable participation and contributions to this research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAmerican Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association; 2013.\u003c/li\u003e\n\u003cli\u003eLauren L, Mc Ardle R, Wilson S, Beswick E, Karimi R, Slight SP. Digital Endpoints for Assessing Instrumental Activities of Daily Living in Mild Cognitive Impairement: Systematic Review. J Med Internet Res. 2023;25:e45658. doi: 10.2196/45658.\u003c/li\u003e\n\u003cli\u003eLu Y, Liu C, Yu D, Fawkes S, Ma J, Zhang M, et al. Prevalence of mild cognitive impairment in community-dwelling Chinese populations aged over 55 years: a meta-analysis and systematic review. BMC Geriatr. 2021;21(1):10. doi: 10.1186/s12877-020-01948-3.\u003c/li\u003e\n\u003cli\u003ePottie K, Rahal R, Jaramillo A, Birtwhistle R, Thombs BD, Singh H, et al. Recommendations on screening for cognitive impairment in older adults. CMAJ. 2016;188(1):37-46. doi: 10.1503/cmaj.141165.\u003c/li\u003e\n\u003cli\u003eRadler KH, Zdrodowska MA, Dowd H, Cersonsky TE, Huey ED, Cosentino S, et al. Rate of progression from mild cognitive impairment to dementia in an essential tremor cohort: a prospective, longitudinal study. Parkinsonism Relat Disord. 2020;74:38-42. doi: 10.1016/j.parkreldis.2020.04.008.\u003c/li\u003e\n\u003cli\u003eMcCraw A, Sullivan J, Lowery K, Eddings R, Heim HR, Buss AT. Dynamic field theory of executive function: identifying early neurocognitive markers. Monogr Soc Res Child Dev. 2024;89(3):7-109. doi: 10.1111/mono.12478.\u003c/li\u003e\n\u003cli\u003eMoon HY, Lee M. Exercise-induced expression of genes associated with aging in the hippocampus of rats. Neurosci Lett. 2024;823:1376646. doi: 10.1016/j.neulet.2024.137646.\u003c/li\u003e\n\u003cli\u003eBehrendt T, Quisilima JI, Bielitzki R, Behrens M, Glazachev OS, Brigadski T, et al. Brain-derived neurotrophic factor and inflammatory biomarkers are unaffected by acute and chronic intermittent hypoxic-hyperoxic exposure in geriatric patients: a randomized controlled trial. Ann Med. 2024;56(1): 2304650. doi: 10.1080/07853890.2024.2304650.\u003c/li\u003e\n\u003cli\u003eIeraci A, Beggiato S, Ferraro L, Barbieri SS, Popoli M. Kynurenine pathway is altered in BDNF Val66Met knock-in mice: effect of physical exercise. Brain Behav Immun. 2020;89:440-450. doi: 10.1016/j.bbi.2020.07.031.\u003c/li\u003e\n\u003cli\u003eTrzesicki M, Bialon N, Kuzma D, Gorka D. Bcl-2-proteins and neurotrophins as important factors for the survival of peripheral neurons in transgenic animals. Postepy Biochem. 2022;68(4):381-386. doi: 10.18388/pb.2021_460.\u003c/li\u003e\n\u003cli\u003eKutsarova E, Schohl A, Munz M, Wang A, Zhang YY, Bilash OM, et al. BDNF signaling in correlation-dependent structural plasticity in the developing visual system. Plos Biol. 2023;21(4):e3002070. doi: 10.1371/journal.pbio.3002070.\u003c/li\u003e\n\u003cli\u003ePerrin RJ, Franklin EE, Bernhardt H, Burns A, Schwetye KE, Cairns NJ, et al. The alzheimer\u0026rsquo;s disease neuroimaging initiative neuropathology core: an update. Alzheimers Dement. 2024;20(11):7859-7870. doi: 10.1002/alz.14253.\u003c/li\u003e\n\u003cli\u003ePalta P, Xue QL, Deal JA, Fried LP, Walston JD, Carlson MC. Interleukin-6 and C-Reactive Protein Levels and 9-Year Cognitive Decline in Community-Dwelling Older Women: The Women\u0026apos;s Health and Aging Study II. J Gerontol A Biol Sci Med Sci. 2015;70(7):873-8. doi: 10.1093/gerona/glu132. \u003c/li\u003e\n\u003cli\u003eG\u0026oacute;mez-Rubio P, Trapero I. The Effects of Exercise on IL-6 Levels and Cognitive Performance in Patients with Schizophrenia. Diseases. 2019;7(1):11. Published 2019 Jan 22. doi:10.3390/diseases7010011.\u003c/li\u003e\n\u003cli\u003eKargarfard M, Nobari H, Kamyar K, Zadeh AK, Oliveira R. Effects of 12-week moderate aerobic exercise on ROCK2 activity, hs-CRP and glycemic index in obese patients with impaired glucose tolerance. Physiol Behav. 2022 Dec 1;257:113976. doi: 10.1016/j.physbeh.2022.113976. \u003c/li\u003e\n\u003cli\u003ePalfi V, Kovacsik R, Szabo A. Symptoms of exercise addiction in aerobic and anaerobic exercises: beyond the components model of addiction. Addict Behav Rep. 2021;14:100369. doi: 10.1016/j.abrep.2021.100369.\u003c/li\u003e\n\u003cli\u003eKoch S, Tiozzo E, Simonetto M, Loewenstein D, Wright CB, Dong C, et al. Randomized trial of combined aerobic, resistance, and cognitive training to improve recovery from stroke: feasibility and safety. J Am Heart Assoc. 2020;9(10):e015377. doi: 10.1161/JAHA.119.015377.\u003c/li\u003e\n\u003cli\u003eKimhy D, Vakhrusheva J, Bartels MN, Armstrong HF, Ballon JS, Khan S, et al. The Impact of Aerobic Exercise on Brain-Derived Neurotrophic Factor and Neurocognition in Individuals With Schizophrenia: A Single-Blind, Randomized Clinical Trial. Schizophr Bull. 2015;41(4):859-68. doi: 10.1093/schbul/sbv022.\u003c/li\u003e\n\u003cli\u003eBangsbo J, Blackwell J, Boraxbekk CJ, Caserotti P, Dela F, Evans AB, et al. Copenhagen consensus statement 2019: physical activity and ageing. Br J Sports Med. 2019;53(14):856-858. doi: 10.1136/bjsports-2018-100451.\u003c/li\u003e\n\u003cli\u003eChristiansen L, Berglund JS, Anderbeg P, Cellek S, Zhang J, Lemmens E, et al. Associations between mobile health technology use and self-rated quality of life: a cross-sectional study on older adults with cognitive impairement. Gerontol Geriatr Med. 2021;7:23337214211018924. doi: 10.1177/23337214211018924.\u003c/li\u003e\n\u003cli\u003eHunter SW. Opportunities for falls prevention in older adults with mild cognitive impairment. Int Psychogeriatr. 2024;36(4):235-237. doi: 10.1017/S1041610223000649.\u003c/li\u003e\n\u003cli\u003eCerqueira E, Marinho DA, Neiva HP, Lourenco O. Inflammatory Effects of High and Moderate Intensity Exercise\u0026mdash;A Systematic Review. Front Physiol. 2020;10:1550. doi: 10.3389/fphys.2019.01550\u003c/li\u003e\n\u003cli\u003eKahle-Wrobleski K, Ye W, Henley D, Hake AM, Siemers E, Chen YF, et al. Assessing quality of life in Alzheimer\u0026apos;s disease: Implications for clinical trials. Alzheimers Dement (Amst). 2016;13(6):82-90. doi: 10.1016/j.dadm.2016.11.004.\u003c/li\u003e\n\u003cli\u003eTorisson G, Stavenow L, Minthon L, Londos E. Reliability, validity and clinical correlates of the Quality of Life in Alzheimer\u0026rsquo;s disease (QoL-AD) scale in medical inpatients. Health Qual Life Outcomes. 2016;14:90. doi: 10.1186/s12955-016-0493-8.\u003c/li\u003e\n\u003cli\u003eAbba MA, Olaleye OA, Hamzat TK. Effects of over-ground walking and cognitive rehabilitation on cognition, brain-derived neurotrophic factor, participation and quality of life among stroke survivors: a study protocol. European Journal of Physiotherapy. 2020;24(3), 144\u0026ndash;150. https://doi.org/10.1080/21679169.2020.1808056.\u003c/li\u003e\n\u003cli\u003eWu Y, Deng F, Wang J, Liu Y, Zhou W, Qu L, et al. Intensity-dependent effects of consecutive treadmill exercise on spatial learning and memory through the p-CREB/\u003cem\u003eBDNF\u003c/em\u003e/NMDAR signaling in hippocampus. Behav Brain Research. 2020:386:112599. doi: 10.1016/j.bbr.2020.112599.\u003c/li\u003e\n\u003cli\u003eWang YH, Zhou HH, Luo Q, Cui S. The effect of physical exercise on circulating brain-derived neurotrophic factor in healthy subjects: a meta-analysis of randomized controlled trials. Brain Behav. 2022;12(4):e2544. doi: 10.1002/brb3.2544.\u003c/li\u003e\n\u003cli\u003eRenteria I, Garcia-Suarez PC, Martinez-Corona DO, Moncada-Jimenez J, Plaisance EP, Jimenez-Maldonado A. Short-term high-intensity interval training increases systemic brain-derived neurotrophic factor (BDNF) in healthy women. Eur J Sport Sci. 2020;20(4):516-524. doi: 10.1080/17461391.2019.1650120.\u003c/li\u003e\n\u003cli\u003eAssaf G, Khoury JE, Jawhar S, Rahme D. Mild cognitive Impairment and modifiable risk factors among Lebanese older adults in primary care. Asian J Psychiatr. 2021;65:102828. 10.1016/j.ajp.2021.102828.\u003c/li\u003e\n\u003cli\u003eThomas N, Gardiner JD, Crompton RH, Lawson R. Keep your head down:maintaining gait stability in challenging conditions. Hum Mov Sci. 2020;73:102676. doi: 10.1016/j.humov.2020.102676.\u003c/li\u003e\n\u003cli\u003eBadan Pusat Statistik Indonesia. Statistik Penduduk Lanjut Usia. 2014.\u003c/li\u003e\n\u003cli\u003eZhang J, Gao Q, Gao J, Lv L, Liu R, Wu Y, et al. Moderate-Intensity Intermittent Training Alters the DNA Methylation Pattern of PDE4D Gene in Hippocampus to Improve the Ability of Spatial Learning and Memory in Aging Rats Reduced by D-Galactose. Brain Sci. 2023;13(3):422. doi: 10.3390/brainsci13030422.\u003c/li\u003e\n\u003cli\u003eAfzalpour ME, Chadorneshin HT, Foadoddini M, Eivari HA, et al. Comparing interval and continuous exercise training regimens on neurotrophic factors in rat brain. Physiol Behav. 2015;147:78-83. doi: 10.1016/j.physbeh.2015.04.012.\u003c/li\u003e\n\u003cli\u003eKim HJ, Lee DJ, Lee YS. The effect of aerobic exercise on brain-derived neurotrophic factor (\u003cem\u003eBDNF\u003c/em\u003e) in individuals with mild cognitive impairment: A systematic review and meta-analysis of a randomized controlled trials. Phys Ther Rehabil Sci. 2022;11:304-10. doi:10.14474/ptrs.2022.11.3.304.\u003c/li\u003e\n\u003cli\u003eOsoba MY, Rao AK, Agrawal SK, Lalwani AK. Balance and gait in the elderly: A contemporary review. Laryngoscope Investig Otolaryngolog. 2019;4(1):143-153. doi: 10.1002/lio2.252.\u003c/li\u003e\n\u003cli\u003eHirjakova Z, Bizovska L, Bzuduskova D, Hlavacka F. Postural stability after treadmill and overground walking in young and elderly. Gait Posture. 2020;80:84-89. doi: 10.1016/j.gaitpost.2020.05.014.\u003c/li\u003e\n\u003cli\u003eWard S, Orme M, Zatloukal J, Singh S. Adherence to walking exercise prescription during pulmonary rehabilitation in COPD with a commercial activity monitor: a feasibility trial. BMC Pulm Med. 2021;21(1):30. doi: 10.1186/s12890-021-01406-9.\u003c/li\u003e\n\u003cli\u003eSzuhany KL, Matteo B, Otto MW. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. J Psychiatr Research. 2015;60:56-64. doi: 10.1016/j.jpsychires.2014.10.003.\u003c/li\u003e\n\u003cli\u003eShobeiri P, Karimi A, Momtazmanesh S, Teixeira AL, Teunissen CE, Van Weden EE, et al. Exercise-induced increase in blood-based brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis: a systematic review and meta analysis of exercise intervention trials. Plos One. 2022;17(3):e0264557.\u003c/li\u003e\n\u003cli\u003eSilva ML, Carvalho de Morais VA, Santos RM, Rocha NP, Christo PP, Fuscaldi LT, et al. No change in brain-derived neurotrophic factor levels following a single session of light to-moderate intensity walk in chronic stroke patients. J Neurol Disord. 2017;5:2. doi: 10.4172/2329-6895.1000334.\u003c/li\u003e\n\u003cli\u003eMojtabavi H, Shaka Z, Momtazmanesh S, Ajdari A, Rezaei N. Circulationg brain-derived neurotrophic factor as a potential biomarker in stroke: a systematic review and meta-analysis. J Transl Med. 2022;20(1):126. doi: 10.1186/s12967-022-03312-y.\u003c/li\u003e\n\u003cli\u003eRen L, Zheng Y, Wu L, Gu Y, He Y, Jiang B, et al. Investigation of the prevalence of cognitive impairment and its risk factors within the elderly population in Shanghai, China. Sci Rep. 2018;8(1):3575. doi: 10.1038/s41598-018-21983-w.\u003c/li\u003e\n\u003cli\u003eJin Y, Li X, Wei C, Yuan Q. Effect of exercise-targeted hippocampal PDE-4 methylation on synaptic plasticity and spatial learning/memory impairments in D-galactose-induced aging rats. Exp Brain Res. 2024;242(2):309-320. doi: 10.1007/s00221-023-06749-9.\u003c/li\u003e\n\u003cli\u003eMalczynska-Sims P, Chalimoniuk M, Wronski Z, Marusiak J, Sulek A. High-intensity interval training modulates inflammatory response in parkinson\u0026rsquo;s disease. Aging Clin Exp Res. 2022;34(9):2165-2176. doi: 10.1007/s40520-022-02153-5.\u003c/li\u003e\n\u003cli\u003eFernandez-Rodriguez R, Alvarez-Bueno C, Martinez-Ortega IA, Martinez-Vizcaino V, Mesas AE, Notario-Pacheco B. Immediate effect of high-intensity exercise on brain-derived neurotrophic factor in healthy young adults: A systematic review and meta-analysis. J Sport Health Sci. 2022;11(3):367-375. doi: 10.1016/j.jshs.2021.08.004.\u003c/li\u003e\n\u003cli\u003eBjornestad A, Tysnes OB, Larsen JP, Alves G. Reliability of Three Disability Scales for Detection of Independence Loss in Parkinson\u0026rsquo;s Disease. Parkinsons Dis. 2016;2016:1941034. doi: 10.1155/2016/1941034.\u003c/li\u003e\n\u003cli\u003eFeter N, Alt R, Dias MG, Rombaldi AJ. How do different physical exercise parameters modulate brain-derived neurotrophic factor in healthy and nonhealthy adults? A systematic review, meta-analysis and meta-regression. Sci Sport. 2019;34(5):293-304. doi: 10.1016/j.scispo.2019.02.001.\u003c/li\u003e\n\u003cli\u003eRoss RE, Saladin ME, George MS, Gregory CM. High-intensity aerobik exercise acutely increases brain-derived neurotrophic factor. Med Sci Sports Exerc. 2019;51(8):1698-1709. doi: 10.1249/MSS.0000000000001969.\u003c/li\u003e\n\u003cli\u003eAmjad I, Toor H, Niazi IK, Afzal H, Jochumsen M, Shafique M et al. Therapeutic effects of aerobic exercise on EEG parameters and higher cognitive functions in mild cognitive impairment patients. Int J Neurosci.2019;129(6):551-562.\u003c/li\u003e\n\u003cli\u003eCoeberg J, Zimianiti I, Ellmers TJ, Kaski D. Response to geroin et al.: tapping into the mechanisms of abnormal functional postural control. Eur J Neurol. 2022;29(12):3748-3749. doi: 10.1111/ene.15578.\u003c/li\u003e\n\u003cli\u003eAlfini AJ, Weiss LR, Nielson KA, Verber MD, Smith JC, et al. Resting cerebral blood flow after exercise training in mild cognitive impairment. J Alzheimers Dis. 2019;67(2):671-684. doi: 10.3233/JAD-180728.\u003c/li\u003e\n\u003cli\u003eMotohiro A, Abe T, Okuyama K, Onoda K, Ito T, Isomura M, et al. Environmental factors affecting cognitive function among community-dwelling older adults: a longitudinal research. Int J Environ Res Public Health. 2021;18(16):8528. doi: 10.3390/ijerph18168528.\u003c/li\u003e\n\u003cli\u003eStienen MN, Geisseler O, Velz J, Maldaner N, Sebok M, Dannecker N, et al. Influence of the intensive care unit environment on the reliability of the Montreal cognitive assessment. Front Neurol. 2019;10:734. doi: 10.3389/fneur.2019.00734.\u003c/li\u003e\n\u003cli\u003eFernandes J, Arida RM, Gomez-Pinilla F. Physical exercise as an epigenetic modulator of brain plasticity and cognition. Neurosci Biobehav Rev. 2017;80:443\u0026ndash;456. doi: 10.1016/j.neubiorev.2017.06.012.\u003c/li\u003e\n\u003cli\u003eMorimoto SS, Kanellopoulos D, Manning KJ, Alexopoulos GS. Diagnosis and treatment of depression and cognitive impairment in late life. Ann N Y Acad Sci. 2015;1345(1):36-46. doi: 10.1111/nyas.12669.\u003c/li\u003e\n\u003cli\u003eAghjayan SL, Bournias T, Kang C, Zhou X, Stillman CM, Donofry SD, et al. Aerobik exercise improves episodic memory in late adulthood: a systematic review and meta-analysis. Commun Med (Lond). 2022;2:15. doi: 10.1038/s43856-022-00079-7.\u003c/li\u003e\n\u003cli\u003ePalmer JA, Morris JK, Billinger SA, Lepping RJ, Martin L, Green Z, et al. Hippocampal blood flow rapidly and preferentially increases after a bout of moderate-intensity exercise in older adults with poor cerebrovascular health. Cereb Cortex. 2023;33(9):5297-5306. doi: 10.1093/cercor/bhac418.\u003c/li\u003e\n\u003cli\u003eWalsh JJ, Tschakovsky ME. Exercise and circulating BDNF: Mechanisms of release and implications for the design of exercise interventions. Appl Physiol Nutr Metab. 2018;43(11):1095-1104. doi: 10.1139/apnm-2018-0192.\u003c/li\u003e\n\u003cli\u003eIeraci A, Madaio AI, Mallei A, Lee FS, Popoli M. Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice. Neuropsychopharmacology. 2016;41(13):3070-3079. doi: 10.1038/npp.2016.120. \u003c/li\u003e\n\u003cli\u003eChumakov E, Dorofeikova M, Tsyrenova K, Petrova N. A Cross-Sectional Study on Associations Between BDNF, CRP, IL-6 and Clinical Symptoms, Cognitive and Personal Performance in Patients With Paranoid Schizophrenia. Front Psychiatry. 2022;13:943869. doi: 10.3389/fpsyt.2022.943869. \u003c/li\u003e\n\u003cli\u003eMonteiro-Junior RS, De Tarso Maciel-Pinheiro P, Da Matta Mello Portugal E, Da Silva Figueiredo LF, Terra R, Carneiro LSFF, et al. Effect of exercise on inflammatory profile of older persons: Systematic review and meta-analyses. J Physical Act and Health. 2018;15(1):64\u0026ndash;71. doi: 10.1123/jpah.2016-0735.\u003c/li\u003e\n\u003cli\u003ePanza F, Custodero C, Solfrizzi V. Physical activity, interleukin-6 change, and gait speed. Aging. 2023;15(11):4568-4570. doi: 10.18632/aging.204797.\u003c/li\u003e\n\u003cli\u003eChen X, Sun X, Wang C, He H. Effects of Exercise on Inflammatory Cytokines in Patients with Type 2 Diabetes: A Meta-analysis of Randomized Controlled Trials. Oxid Med Cell Longev. 2020;2020:6660557. doi: 10.1155/2020/6660557.\u003c/li\u003e\n\u003cli\u003eCustodero C, Pahor M, Mazzoccoli C, Manini TM, Anton SD, Mazzocca A,et al. Effect of change of interleukin-6 over time on gait speed response: Results from the lifestyle interventions and independence for elders study. Mech Ageing Dev. 2023;210:111763. doi: 10.1016/j.mad.2022.111763. \u003c/li\u003e\n\u003cli\u003eAlghadir AH, Gabr SA, Al-Eisa ES. Effects of Moderate Aerobic Exercise on Cognitive Abilities and Redox State Biomarkers in Older Adults. Oxid Med Cell Longev. 2016;2545168. doi: 10.1155/2016/2545168. \u003c/li\u003e\n\u003cli\u003eRoberts CE, Phillips LH, Cooper CL, Gray S, Allan JL. Effect of Different Types of Physical Activity on Activities of Daily Living in Older Adults: Systematic Review and Meta-Analysis. J Aging Phys Act. 2017;25(4):653-670. doi: 10.1123/japa.2016-0201.\u003c/li\u003e\n\u003cli\u003eBourdel-Marchasson I, Laksir H, Puget E. Interpreting routine biochemistry in those aged over 65 years: a time for change. Maturitas. 2010;66(1):39\u0026ndash;45. doi: 10.1016/j.maturitas.2010.02.004.\u003c/li\u003e\n\u003cli\u003eRong YD, Bian AL, Hu HY, Ma Y, Zhou XZ. Study on relationship between elderly sarcopenia and inflammatory cytokine IL-6, anti-inflammatory cytokine IL-10. BMC Geriatr. 2018;18(1):308. doi: 10.1186/s12877-018-1007-9.\u003c/li\u003e\n\u003cli\u003ePenzes Z, Alimohammadi S, Horvath D, Olah A, Toth BI, Bacsi A, et al. The dual of cannabidiol on monocyte-derived dendritic cell differentiation and maturation. Front Immunol. 2023;14:1240800. doi: 10.3389/fimmu.2023.1240800.\u003c/li\u003e\n\u003cli\u003eKrapic M, Kavazovic I, Wensveen FM. Immunological mechanisms of sickness behavior in viral infection. Viruses. 2021;13(11):2245. doi: 10.3390/v13112245.\u003c/li\u003e\n\u003cli\u003eMakino A, Yamaguchi K, Sumi D, Ichikawa M, Ohno M, Goto K. Comparison of energy expenditure and substrate oxidation between walking and running in men and women. Phys Act Nutr. 2022;26(1):8-13. doi: 10.20463/pan.2022.0002. \u003c/li\u003e\n\u003cli\u003eDuddy D, Doherty R, Connolly J, McNally S, Loughrey J, Faulkner M. The Effects of Powered Exoskeleton Gait Training on Cardiovascular Function and Gait Performance: A Systematic Review. Sensors. 2021;21(9):3207. doi: 10.3390/s21093207\u003c/li\u003e\n\u003cli\u003eZhao Z, Zhang J, Wu Y, Xie M, Tao S, Lv Q, et al. Plasma IL-6 levels and their association with brain health and dementia risk: A population-based cohort study. Brain Behavior and Immunity. 2024;120:430\u0026ndash;438. doi: 10.1016/j.bbi.2024.06.014.\u003c/li\u003e\n\u003cli\u003eHosokawa M, Kabayama M, Godai K, Akagi Y, Tachibana Y, Gondo Y, et al. Cross-sectional association between high-sensitivity C-reactive protein and cognitive function in community-dwelling older adults: the SONIC study. BMC Geriatr. 2024;24(1):756. doi:10.1186/s12877-024-05354-x.\u003c/li\u003e\n\u003cli\u003eBuchman AS, Yu L, Boyle PA, Schneider JA, De Jager PL, Bennett DA. Higher brain BDNF gene expression is associated with slower cognitive decline in older adults. Neurology. 2016;86(8):735\u0026ndash;741. doi: 10.1212/WNL.0000000000002387.\u003c/li\u003e\n\u003cli\u003eTait JL, Duckham RL, Milte CM, Main LC, Daly RM. Associations between inflammatory and neurological markers with quality of life and well-being in older adults. Experimental Gerontology. 2019;125:1100662. doi: 10.1016/j.exger.2019.110662.\u003c/li\u003e\n\u003cli\u003eGao L, Zhang Y, Sterling K, Song W. Brain-derived neurotrophic factor in Alzheimer\u0026rsquo;s disease and its pharmaceutical potential. Transl Neurodegener. 2022;11(1):4. doi: 10.1186/s40035-022-00279-0.\u003c/li\u003e\n\u003cli\u003eStites SD, Harkins K, Rubright JD, Karlawish J. Relationships Between Cognitive Complaints and Quality of Life in Older Adults With Mild Cognitive Impairment, Mild Alzheimer Disease Dementia, and Normal Cognition. Alzheimer Dis Assoc Disord. 2018;32(4):276-283. doi: 10.1097/WAD.0000000000000262.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"BDNF, Interleukin-6, moderate-intensity interval training, mild cognitive impairments, overground walking, quality of life","lastPublishedDoi":"10.21203/rs.3.rs-7485672/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7485672/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackgrounds\u003c/h2\u003e\u003cp\u003eMild cognitive impairment (MCI) is associated with cognitive decline which impact performing instrumental activities of daily living (IADL) that depend on memory and frontal/executive functions. Physical exercise has protective effect toward cognitive function and is suspected to influence inflammatory biomarkers. This study aims to evaluate the improvement in BDNF, IL-6, and hs-CRP levels, as well as cognitive function, functional capacity, and quality of life, and to examine the association between these parameters in older adults with mild cognitive impairment following eight weeks of overground walking exercises.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis study utilized a quasi-experimental approach. Thirteen participants were included based on inclusion and exclusion criteria. The intervention is an aerobic exercise program using overground walking (trained with the moderate-intensity interval training [MIIT]) method for 8 weeks. It lasted 20 minutes, and each week they added another five minutes. Cognitive function, serum BDNF, inflammatory biomarkers such as Interleukin-6 (IL-6) and High Sensitivity C-Reactive Protein (hs-CRP), quality of life with the Quality of Life Alzheimer\u0026rsquo;s Disease (QoL-AD) instrument, and functional capacity by The 6-Minute Walking Test (METs) were measured before and after intervention.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eBDNF was increased significantly after intervention (p\u0026thinsp;=\u0026thinsp;0.038). IL-6 (pre 6.32; post 2.86; p\u0026thinsp;=\u0026thinsp;0.002) and hs-CRP (pre 2.50; post 1.30; p\u0026thinsp;=\u0026thinsp;0.0027) levels were significantly decreased, MoCA-Ina total score was increased after intervention (p\u0026thinsp;=\u0026thinsp;0.09). After 8 weeks of intervention, a notable rise was observed in METs (pre 3,4; post 4.0;p\u0026thinsp;=\u0026thinsp;0.001) and the QoL-AD scores (pre 27.5; post 34.8; p\u0026thinsp;=\u0026thinsp;0.001). The parameters were not significantly correlated.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis study showed that 8-week overground walking with MIIT improves the body\u0026rsquo;s response to aerobic exercise by producing more anti-inflammatory cytokines and less pro-inflammatory cytokines. It helps to reduce levels of systemic IL-6, and hs-CRP, and increase BDNF and cognitive function as well as functional capacity and QoL. Lower levels of hs-CRP and IL-6 may result from this general reduction in inflammation. The absence of relationships among the parameters in this study, may be attributed to the small sample size. When aerobic exercise equipment is unavailable, overground walking can be an alternative option.\u003c/p\u003e\u003ch2\u003eTrial registration number\u003c/h2\u003e\u003cp\u003eNCT06029920 (registration date: 01/09/2023)\u003c/p\u003e","manuscriptTitle":"Overground Walking to Improve BDNF, IL-6, hs-CRP, Cognitive Function, Functional Capacity, and Quality of Life in Older Adults with Mild Cognitive Impairment: A Pilot Study in a Developing Country","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-22 10:14:04","doi":"10.21203/rs.3.rs-7485672/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f952e294-5012-428d-b83a-fd1fb16941f6","owner":[],"postedDate":"September 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T09:54:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-22 10:14:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7485672","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7485672","identity":"rs-7485672","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}