The efficacy of a digital health app Five Lives MED to improve cognitive function in patients with mild cognitive impairment: study protocol for a randomised controlled trial

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Kawadler, Philip Vassilev, Maria Bunyan, Jenny Barnett, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8885992/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Mild cognitive impairment (MCI) is a prevalent neurocognitive disorder associated with an increased risk of progression to dementia. While pharmacological options remain limited and are not universally accessible, non-pharmacological interventions such as cognitive training and lifestyle modification show promise in slowing cognitive decline. Digitally delivered interventions offer advantages in scalability, accessibility, and personalisation, yet there is a lack of rigorously evaluated, multi-domain digital programmes for individuals with MCI. Five Lives MED is a novel digital motor-cognitive intervention combining computerised cognitive training, physical activity habit formation, and psychoeducation, delivered remotely via mobile devices. Methods This study is a single-blind, multicentre, randomised controlled trial conducted in the United Kingdom and France. A total of 170 participants aged 50 years or older with a clinical diagnosis of MCI will be randomised in a 1:1 ratio to either the intervention group or a control group receiving standard lifestyle advice. The intervention consists of a 12-week home-based programme delivered through the Five Lives MED app, incorporating daily motor-cognitive training sessions, goal-oriented physical activity tasks, and optional educational content. Outcome assessments will be conducted at baseline (T0), post-intervention at 12 weeks (T1), and at 6-month follow-up (T2). The primary outcome is change in global cognitive function measured by the Montreal Cognitive Assessment. Secondary outcomes include domain-specific cognitive performance, quality of life, dementia literacy, activities of daily living, behavioural symptoms, physical activity, and exploratory digital cognitive measures. Analyses will be conducted on an intention-to-treat basis, with additional per-protocol analyses where appropriate. Discussion This trial will be the first randomised controlled evaluation of Five Lives MED in individuals with MCI. By integrating cognitive training with physical activity and educational components in a fully remote format, the study aims to address key limitations of existing interventions related to accessibility and scalability. The findings will provide important evidence regarding the efficacy, feasibility, and clinical utility of a digital motor-cognitive intervention for MCI and will inform future implementation and larger-scale trials. Trial registration : ​​ClinicalTrials.gov ID NCT06598163, first submitted on 2024-09-10, https://clinicaltrials.gov/study/NCT06598163?tab=study Mild cognitive impairment Digital health intervention Computerised cognitive training Motor-cognitive training Randomised controlled trial Mobile health application Dementia prevention Cognitive decline Background As population life expectancy increases, research has focused on the differentiation between the cognitive profile of “healthy ageing”, mostly driven by psychomotor slowing, and pathological cognitive dysfunction. Mild cognitive impairment (MCI) is identified by the Diagnostic and Statistical Manual for Mental Disorders as a neurocognitive disorder, defined as “cognitive decline greater than that expected for an individual’s age and education level but that does not interfere notably with activities of daily life” (1). Diagnostic criteria for MCI are determined by abnormal cognitive function in one or more domains: memory, attention, executive functioning, language, and visuospatial processing (2,3). MCI prevalence is reported to range between 6% (4) and 20% (5) in the population from age 65 years onwards, with specific country estimates of 15-18% in the UK (6), 24% in France (7), and 13.11% in Greece (8). This poses a significant public health concern, as 10-15% (9,10) of people with MCI go on to develop dementia each year, with 80% developing dementia within 5 years (10). In some countries, pharmacological interventions (i.e. amyloid clearance therapies) are available to some with early-stage, isolated Alzheimer’s disease (AD) pathology; however, they pose limitations in both supply, patient eligibility, local reimbursement and clinical risks. Non-pharmacological approaches (i.e., cognitive, occupational therapy, and/or lifestyle interventions) intended to curb modifiable risk factors for dementia, and thus slow the progression of cognitive decline are generally accepted as effective alternatives. In 2018, the American Academy of Neurology recommended in their guidelines that cognitive interventions may be effective and that clinicians may recommend them to people with MCI (11). Cognitive training interventions have shown promising results in remediating cognitive function in healthy older individuals (12) and those with MCI (13) through strengthening cognitive abilities using structured tasks. Systematic reviews and meta-analyses have shown CCT can improve both global cognitive functioning (14) with small to moderate effect sizes ( d = 0.37 (15); d = 0.54 (16)), especially when delivered on computers/tablets ( d = 0.61 (16)). Individual studies in MCI have reported effect sizes ranging from small (0.33 (17), 0.38 (18)) to medium (0.56 (19), 0.56 (20)) to large (0.80 (21), 0.88 (22)). Approaches vary widely, with the options of targeting a single cognitive area (e.g., working memory) or multiple cognitive areas (multiple cognitive domains) and with or without other lifestyle interventions (23), in domains such as physical activity or nutrition. A recent Cochrane review found that multi-domain interventions, especially when cognitive training was offered as one of the domains, were effective in improving cognitive function (24). This mirrors findings from the landmark FINGER trial, which was the first to demonstrate the effectiveness of multi-domain lifestyle interventions in improving cognitive performance (23,25) in people at risk for dementia. Results from the FINGER trial showed that the odds of cognitive decline in the control group were estimated to be 31% higher in comparison with the intervention group. Motor-cognitive training (26), where CCT is delivered alongside physical activity interventions, aims to utilise the long-known benefits of physical activity on improving cognition in MCI (27,28). In older adults, motor-cognitive training has been shown to improve postural control (29) and mobility (30). Meta-analyses have shown small-to-moderate effect sizes of motor-cognitive interventions on global cognition in adults with MCI or dementia ( d = 0.32 (31), d = 0.24 (32), g = 0.22 (33)), and some have suggested there may be a synergistic effect on cognition (34–36). Cognitive training administered digitally ( e.g., through smartphones, tablets or computers) has several advantages over traditional in-person/paper-based programmes: a) Specific and personalised. Digital programmes can be directed to specific cognitive domains such as memory or attention and can be personalised and adaptive to the performance of the individual (37,38); b) Accessible and scalable. Digital tools are convenient and overcome accessibility issues (39), such as the expense and physical challenge of travelling to appointments. Remote CCT delivered at home or at community centres may also increase autonomy (40) and independence for living at home as long as possible (41). c) Engagement. Digital programmes can provide immediate feedback and can be designed to be highly immersive and enjoyable (37). Currently, there are not yet any established standards for the design, optimal “dose” or delivery of CCT (42); although retrospective analyses highlight the need for age-specific optimal dosing (43). Commercially-available CCT programmes that claim to have clinical benefits have been scrutinised for lacking appropriate scientific evaluation; a Cochrane review from 2019 found the quality of evidence for CCT was very low and no conclusions were able to be drawn about the outcome (44). A recent review of only commercially available CCT programmes (13) noted a lack of empirical evidence but also that it is a rapidly expanding industry in which substantial evidence may still be gained with appropriate clinical evaluation. Current study This protocol details the first investigation of the Five Lives MED, a 12-week digital motor-cognitive intervention delivered on mobile devices at home, consisting of CCT and physical activity exercises as well as educational articles. The aim of the study is to investigate if 12-weeks of Five Lives MED improves global cognitive function compared to a control group receiving standard health information. As secondary outcomes, this study will also evaluate the effectiveness of the Five Lives MED app on specific cognitive function subtests and also quality of life, dementia literacy, activities of daily living, behavioural symptoms, and physical activity measures. Methods Study design This study is a single-blind, multicentre, randomised controlled trial. Participants will be randomly assigned to the intervention (Five Lives MED) or control group for a 12-week period on a 1:1 allocation ratio. Outcome measures will be conducted at baseline (T 0 ) study exit (T 1 , 12 weeks). A follow-up visit (T 2 ) will be conducted 6 months after study exit. The intervention group will be asked to use the Five Lives MED app on their mobile device at home for the 12-week intervention period. The control group will receive a lifestyle recommendations leaflet ( e.g. physical activity, cardiovascular health, nutritional advice, sleep hygiene, alcohol consumption, smoking cessation, avoiding social isolation, and mental health). All participants will receive standard care according to local practices. This protocol is conducted according to the “Standard Protocol Items: Recommendations for Interventional Trials” (SPIRIT) checklist for clinical trials (45). The completed SPIRIT checklist (2025 version) is submitted as supplementary material. Setting The study will be conducted in the United Kingdom (UK) and France. In the UK, research sites include: Oxford University Hospitals NHS Foundation Trust (Oxfordshire) Devon Partnership NHS Trust (Devon) Somerset NHS Foundation Trust (Somerset) Lancashire & South Cumbria NHS Foundation Trust (Lancashire) East London NHS Foundation Trust (London) South London & Maudsley NHS Foundation Trust (London) In France, research sites include: Hôpital Broca (Paris, Ile de France) Hôpital de la Timone (Marseilles) Participant eligibility criteria Inclusion criteria : Diagnosis of Mild Cognitive Impairment (also known as mild cognitive disorder [ICD-10-CM; G31.84] or mild neurocognitive disorder (DSM-5) Age ≥ 50 The participant or informant is willing and able to give informed consent for participation in the study Ability to read and understand English (UK) or French (France) Daily access to a mobile phone (Apple iOS 12.4 or above or Android 6.0 (Marshmallow) or above) or iPad (Apple iOS 12.4 or above only) with internet connection (mobile or WiFi). Exclusion criteria: The participant may not enter the study if ANY of the following apply: Diagnosis of dementia or evidence of functional impairment inconsistent with MCI Severe visual impairment Currently undergoing any other cognitive remediation programme Currently taking part in any other investigational study that in the opinion of the investigator may impact the data integrity of the current study Physical impairment that makes using a mobile device impossible Lack of access to an informant Participant under guardianship Unwilling or unable to tolerate or engage with study procedures Physical impairment that makes standing/walking unassisted impossible. Intervention description (Five Lives MED) The Five Lives MED app is a 12-week digital multi-domain intervention, consisting of: CCT exercises, educational articles about health and lifestyle, and a goal-setting programme focused on physical activity, balance and strength (“Habit Quests”). This intervention is delivered at home on the participant’s mobile device. Each session starts with a daily Habit Quest, then flows into 11 cognitive training exercises. After completion, there is access to educational articles, additional cognitive training games, and breathing exercises. The content of the app was fine-tuned to the study population after offering the first prototype to a focus group of 12 persons with an MCI diagnosis. Habit Quests. Habit Quests is a feature to encourage physical activity habit formation. It appears as a “chatbot” to help the user set goals and habits in a fun and engaging way, offering daily tasks that build upon the previous day. Cognitive training exercises. Each of the 11 cognitive training exercises takes a few minutes each and covers cognitive domains such as language, attention, memory, mental flexibility, and processing speed. Each time one is played, it will start with a tutorial, which can be skipped after the first time. The exercises are personalized to the participant’s ability; participants can “level up”, making the exercises harder where needed. After the exercise is completed, the participant will be able to see their results, including their score, rank, and trend. Optional features. After the session is complete, the participant has the option to engage with a range of psychoeducational articles and quizzes, with categories including: diet, exercise, sleep, mood, mental stimulation, and general brain health. There is also a breathing exercise to encourage relaxation. Participants will be given an onboarding pack of materials that contains an informational leaflet on how to download, log in, and use the app, and information about how to contact the manufacturer for technical support. A new session refreshes every day, which takes approximately 30 minutes to complete. Participants are asked to use the app for 12 weeks, in which they are encouraged to complete 3 sessions a week. Reminders will be sent through the app. App usage will be monitored, and reminder telephone calls will be made to those participants who have not engaged with the app for more than 7 days in a row. At the end of the intervention period, all participants will have access to the app and will be able to continue using the app for at least 6 months. Comparator The control group will receive a lifestyle recommendations leaflet ( e.g. physical activity, cardiovascular health, nutritional advice, sleep hygiene, alcohol consumption, smoking cessation, avoiding social isolation, and mental health). All participants will receive standard care according to local practices. The provision of this type of information is the standard of care for MCI in both France and the UK. Outcomes The primary endpoint is the Montreal Cognitive Assessment (MoCA). The Montreal Cognitive Assessment (MoCA) is a brief assessment tool used to evaluate multiple cognitive domains: visuospatial and executive functions (5 points), animal naming (3 points), memory (5 points), attention (6 points), language (3 points), abstraction (2 points), delayed recall (5 points) and orientation (6 points). MoCA is scored out of 30 points, with one point added to the total score for participants with 12 years of education or less to account for educational differences. Secondary endpoints included specific cognitive measures and other health and lifestyle measures: Executive function. The Delis-Kaplan Trail Making Test (TMT) is a measure of cognitive flexibility and processing speed using a visuomotor sequencing task, with five conditions: Condition 1 (Visual Scanning), Condition 2 (Number sequencing), Condition 3 (Letter sequencing), Condition 4 (Number-letter sequencing) and Condition 5 (Motor speed). For each, the score is the number of seconds required to complete the task. Quality of Life. The Quality of Life in Alzheimer’s Disease questionnaire (QOL-AD) is a 13-item measure designed to obtain a rating of the patient's quality of life from both the patient and the caregiver. It was developed specifically for individuals with dementia and focuses on quality of life domains thought to be important in cognitively impaired older adults (46). The measure consists of 13 items, rated on a four-point scale, with 1 being poor and 4 being excellent. Total scores are summed and range from 13 to 52. Dementia literacy. The Alzheimer’s Disease Knowledge Scale (47) is a measure of dementia literacy. There are 30 items across 7 domains: risk factors, assessment/diagnosis, symptoms, course, caregiving, life impact, and treatment/management. The total score is calculated by summing the number of correct responses, with higher scores indicating greater health literacy. For participants in France, a translated version of this questionnaire, following recommended guidelines (48). Activities of Daily Living. The A-IADL-Q (Short Version) (49) is a 30-item questionnaire assessing functional decline in a broad range of daily activities, including: household activities, using household appliances, finances, work, using the computer, using small appliances and leisure activities. Responses are on a 5-item Likert scale from “no difficulty in performing this task” to “no longer able to perform this task”. Behavioural impairment. The Mild Behavioural Impairment Checklist (MBI-C) (50) is a 34-item scale covering 5 domains, completed by the participant’s informant. The following domains are: apathy, affect, impulse dyscontrol, recklessness and abnormal reward and reinforcement, social appropriateness, abnormal thought and perception domain, and grandiosity/auditory and visual hallucinations. Physical activity. Two physical activity outcomes will be collected. The International Physical Activity Questionnaire (IPAQ) and the 30-second chair stand test (30CST). The IPAQ is a freely available questionnaire designed to be used internationally to obtain estimates of physical activity. For participants ≤ 69 years of age, the short form for the last 7 days will be self-administered. For participants ≥ 70 years, an elderly version will be self-administered. The 30CST is a test of physical performance for people of all ages. It is administered by having the participant seated in a chair with their arms crossed at the wrists and held against the chest. The participant is encouraged to complete as many full stands as possible within 30 seconds while fully sitting between each stand. The score is the total number of stands. Digital cognitive tests. As an exploratory outcome measure, participants will complete Five Lives proprietary standalone digital cognitive tests administered through an iPad or smartphone. There are five tests covering verbal fluency, immediate verbal memory, immediate spatial memory, inhibition, and executive function. Engagement with the mobile application. Participant usage of the app will be monitored remotely and daily. Timestamped events marking the start and completion of a session will be recorded and monitored to detect participant inactivity. If a participant is flagged as inactive for a week, the study site will attempt to contact them to remind them to use the app. Each participant will receive a maximum of 3 reminder calls (regardless of whether the calls are answered or not). Procedure Sample size This sample size calculation was performed with G*Power 3.1. An internal systematic review was performed to determine a valid clinical association between CCT and/or motor-cognitive interventions and improving cognition in people with MCI; the results suggest that this study, employing the Five Lives MED device, can expect a medium effect size with a global cognitive measure as an endpoint. This is consistent with the results of recently published meta-analyses (16,41,51–54) and competitors (19,21,55). To detect a medium effect size of Cohen’s d = 0.5 (t-test for independent samples) with one-tailed significance level α = .05 and power = 80% and 1:1 allocation ratio, 128 participants are required. However, this is the first investigation of the Five Lives MED app, which is a home-based, self-initiated, and self-guided intervention. Study drop-out rates and app retention rates are not fully known, but are assumed from previous studies to range from 15-25%. To be conservative, this study will allow for a 25% dropout rate; this results in a sample size to be recruited of n=170. Recruitment Participants will be pre-screened and identified through research-ready lists available to the sites, memory services at sites (e.g., searches of clinical notes and upcoming scheduled visits) or primary care sites (known as patient identification centres) aligned with the research sites. Participants meeting the eligibility criteria will be offered to participate after the investigator/research staff has thoroughly explained the study to them and provided the Participant Information Sheet and Consent Form. Before any procedures specified in the protocol are performed, the subject must sign and date the approved informed consent form. Randomisation Participants will be randomly assigned to the intervention group (IG) or control group (CG) using stratified block randomisation (56) at a 1:1 allocation ratio. The stratification factors will be: age (2 levels: [= 70], sex (2 levels: male, female) and education level (2 levels: graduated high school or less, university degree or more). Participants will be randomised in permuted blocks of fixed size 4. The eCRF software will generate the randomisation sequence, manage stratification factors and block sizes, and allocate participants to their respective groups. Study personnel will input stratification variables into the eCRF system, which will then randomly assign the participant to the IG or CG. Blinding This is a single-blinded trial. The study personnel administering the cognitive assessments will be blinded to the allocation group. The eCRF software will control access to the randomisation sequence to ensure that blinded personnel will not have access to group assignments. Visits Baseline (T0). After informed consent has been obtained, the participant will undergo cognitive testing with the MoCA, TMT and Five Lives cognitive tests, and will be asked to complete questionnaires (QoL-AD, ADKS, IPAQ). Participants will also be asked to perform the 30 Second Chair Stand Test (30CST) with the researcher. The participant’s informant will be asked to complete the QoL-AD (caregiver version), A-IADL-Q-SV, and MBI-C either in-person, by telephone or online. Exit visit (T1). At study exit, participants will undergo the same assessments as at Baseline. Participants and informants will be asked about any adverse events or changes in medications. After the study ends, all participants in the intervention group will be invited to complete a User Experience Questionnaire. The questionnaire will address the quality of their experience with the Five Lives MED application, and answering it will not be mandatory. Follow-up visit (T2). All participants will undergo a follow-up visit 6 months after the exit visit ( i.e. 9 months from baseline). The follow-up visit will consist of a 20-minute telephone call in which the telephone version of the MoCA will be administered. The study design and timeline is summarised in Supplementary Figure 1 (see end of manuscript). Data Management Statistical analysis This study plans to recruit 170 participants who have a diagnosis of mild cognitive impairment from centres in both the UK (from research registers and NHS memory clinics) and France (geriatric and/or memory centres). All statistical analyses will be conducted by an independent statistician with experience in analysing trial data who is not involved in the trial's conduct or data collection. Efficacy The endpoints will be evaluated within an intention-to-treat (ITT) analysis, encompassing all randomised participants. The effect of the intervention on change in the primary outcome will be evaluated using paired samples t-tests comparing pre- and post-intervention primary outcome measures in the IC and CG, respectively. In case the assumptions for parametric tests are not met, we will use a Wilcoxon matched-pairs test. To control for the effect of extraneous variable and baseline differences, we will also run an analysis of covariance (ANCOVA), with the baseline values, age, sex, years of education and study centre as covariates, experimental group (intervention or control) as the independent variable, and the post-assessment score as the dependent variable. The effect of the intervention on change in the secondary outcome measures will be similarly evaluated using t-tests (or Wilcoxon tests) and ANCOVA with age, sex, years of education and study centre as a covariate. Effect sizes and confidence intervals will be presented from the respective statistical tests to enhance result interpretability. To address missing data, we will employ several strategies to ensure the robustness of our findings, which will be guided by the pattern and mechanism of the missing data to minimise bias. We will test whether the data is missing completely at random (MCAR) by comparing the baseline characteristics of those who completed the 12-week assessment vs. those who did not. If necessary, a sensitivity analysis will be employed involving multiple imputation to assess the robustness of our primary findings. In addition to the ITT analysis, we plan to conduct a complementary as-treated (per-protocol) analysis if sample size allows, including only those participants who engaged with the app. The purpose of this analysis will be to assess the efficacy of the app under real-world conditions. Interim analysis An interim analysis will be conducted when half the required sample size (n=64) has completed the exit (T1) assessments. Because this is the first investigation of this medical device and an effect size has been assumed from the literature, this interim analysis will be planned for efficacy (to see if a potentially larger effect size can be seen in fewer participants) and safety (to check the adverse event log for safety reporting). Employing the alpha-spending function (the O’Brien-Fleming method), we will use a highly conservative alpha at the interim phase a = 0.0088 and an alpha of 0.0412 for the final analysis of the primary outcome. We will use the Benjamini-Hochberg Procedure to control the False Discovery Rate. Communication of results Once all data has been collected and analysed, the results of the study will be communicated through the trial registry and through a peer-reviewed publication. Confidentiality Personally identifiable data will be available only to the study sites. All other data will be collected in a pseudonymised form and stored in password and encryption-protected EDC platform. Discussion This trial is designed to evaluate the efficacy of Five Lives MED, a fully remote, multi-domain digital motor-cognitive intervention for individuals with mild cognitive impairment. In addition to assessing clinical outcomes, the study addresses broader methodological and implementation considerations relevant to the growing use of digital cognitive remediation therapies (CRT) in ageing and neurocognitive populations. A central consideration in the deployment of digital interventions is the risk of digital exclusion (57). Although smartphone and tablet use among older adults has increased substantially, access to suitable devices, reliable internet connectivity, and digital literacy remain unevenly distributed. Individuals with lower socioeconomic status, lower educational attainment, or greater functional impairment may be systematically underrepresented in digital trials. While the present study requires access to a mobile device and basic digital competence, these criteria reflect the real-world conditions under which such interventions would be deployed. Nonetheless, digital exclusion remains a potential barrier to equitable access, and findings from this trial should be interpreted in the context of a population able to engage with mobile health technologies. Future implementation studies should explore strategies to mitigate exclusion, including supported onboarding, caregiver involvement, and alternative delivery formats. Within the broader CRT literature, digital delivery represents both a continuation and a departure from conventional, therapist-led approaches (58–61). Traditional CRT has demonstrated benefits in MCI when delivered in structured, supervised settings, often requiring substantial clinical resources. Digital CRT offers increased scalability, reduced costs, and the ability to deliver personalised, adaptive training at home. However, the reduced level of direct therapist involvement may limit opportunities for real-time feedback, motivational support, and individual tailoring beyond algorithmic adaptation. Existing evidence suggests that digital CRT can achieve comparable improvements in cognitive outcomes to conventional formats (62), particularly when interventions are multi-domain and sufficiently intensive, but heterogeneity in intervention design and outcome measures has limited definitive conclusions. This trial contributes to the literature by evaluating a digital intervention that integrates cognitive and physical components while maintaining ecological validity through home-based delivery. Adherence is a critical determinant of effectiveness in digital interventions. Attrition and declining engagement over time are well-documented challenges across digital health studies, particularly in older populations and in self-guided programmes (63,64). Prior research indicates that adherence is influenced by perceived relevance, usability, feedback, and the integration of interventions into daily routines. The design of Five Lives MED incorporates daily habit formation, adaptive difficulty, and varied content to promote sustained engagement. By capturing detailed usage data and including both intention-to-treat and per-protocol analyses, this study will provide insights into patterns of adherence and their relationship to cognitive outcomes. These findings may help inform optimal dosing and engagement strategies for digital CRT in MCI. Finally, the trial addresses broader questions regarding what constitutes an effective CRT intervention. Contemporary evidence suggests that interventions targeting multiple cognitive domains, delivered with sufficient frequency and duration, and embedded within a broader lifestyle context are more likely to yield meaningful benefits (27-36). The inclusion of motor-cognitive elements reflects growing evidence of synergistic effects between physical activity and cognitive training, potentially mediated through neuroplastic and vascular mechanisms (65). By combining cognitive exercises, physical activity habit formation, and psychoeducation within a single digital platform, this study examines a comprehensive model of CRT aligned with current theoretical and empirical frameworks. In summary, this trial will generate important evidence on the clinical efficacy and practical considerations of a digital motor-cognitive intervention for MCI. The results will have implications not only for cognitive outcomes but also for the future design, delivery, and equitable implementation of digital CRT in ageing populations. Trial Status Recruitment ongoing. Recruitment start: 2025-02-20, projected recruitment end: 2026-04-01. Protocol v1.2 February 24, 2025, available on the ClinicalTrials.gov site. Abbreviations 30CST - 30 sec chair-stant test A-IADL-Q-SV - Amsterdam Instrumental Activities of Daily Living ANCOVA - analysis of covariance CCT - computerised cognitive training CG - control group CRT - cognitive remediation therapy eCRF - electronic case report form EDC - electronic data capture IG - intervention group IPAQ - International Physical Activity Quesitonnaire ITT - intention to treat MBI-C - Mild Behavioural Impairment Checklist MCAR - missing completely at random MCI - mild cognitive impairment MoCA - Montreal Cognitive Assessment NHS - National Health Service QoL-AD - Quality of Life in Alzheimer’s Disease TMT - Trail-Making Test Declarations Ethics approval and consent to participate Ethical approval was granted from the UK Health Research Authority - London Dulwich Research Ethics Committee (24/LO/0771), and written, informed consent to participate will be obtained from all participants. Consent for publication All authors consent to the publication of this manuscript. Availability of data and materials No original data are reported. Competing interests This study is sponsored and funded by Five Lives SAS, which is the manufacturer of Five Lives MED. The Chief Investigator (IK) serves as Chief Medical Officer at Five Lives SAS and receives for this ongoing advisory role a monthly retainer fee as well as a set number of options in the company. Funding This study is funded by Five Lives SAS, 1 Impasse du Palais 37000 Tours, France. [email protected] Authors' contributions All study authors contributed to the design of the study and the manuscript draft. IK is the study Chief Investigator providing supervision and oversight. JM, PV, MB lead on the delivery of the study. JB provides ongoing expert advice and supervision. Acknowledgements The study is funded by Five Lives SAS. References Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, et al. 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Geriatr Gerontol Int. 2016 Sep;16(9):1043–50. Ferizaj D, Stamm O, Perotti L, Martin EM, Finke K, Finke C, et al. Effectiveness of mobile computerized cognitive training in adults with mild cognitive impairment: interim analysis of a randomized controlled trial [Internet]. 2024 [cited 2024 Apr 9]. Available from: https://www.researchsquare.com/article/rs-3099721/v1 Küster OC, Fissler P, Laptinskaya D, Thurm F, Scharpf A, Woll A, et al. Cognitive change is more positively associated with an active lifestyle than with training interventions in older adults at risk of dementia: a controlled interventional clinical trial. BMC Psychiatry. 2016 Sep 8;16(1):315. Bahar-Fuchs A, Webb S, Bartsch L, Clare L, Rebok G, Cherbuin N, et al. Tailored and Adaptive Computerized Cognitive Training in Older Adults at Risk for Dementia: A Randomized Controlled Trial. J Alzheimers Dis. 2017 Oct 3;60(3):889–911. Hyer L, Scott C, Atkinson MM, Mullen CM, Lee A, Johnson A, et al. Cognitive Training Program to Improve Working Memory in Older Adults with MCI. Clin Gerontol. 2016 Oct 19;39(5):410–27. Ngandu T, Lehtisalo J, Solomon A, Levälahti E, Ahtiluoto S, Antikainen R, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. The Lancet. 2015 Jun;385(9984):2255–63. Hafdi M, Hoevenaar-Blom MP, Richard E. Multi‐domain interventions for the prevention of dementia and cognitive decline. Cochrane Database Syst Rev [Internet]. 2021 [cited 2023 Oct 11];(11). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013572.pub2/full Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol. 2018 Nov;14(11):653–66. Lauenroth A, Ioannidis AE, Teichmann B. 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J Am Med Dir Assoc. 2018 Jun;19(6):484-491.e3. Karssemeijer EGA, Aaronson JA, Bossers WJ, Smits T, Olde Rikkert MGM, Kessels RPC. Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis. Ageing Res Rev. 2017 Nov;40:75–83. Ali N, Tian H, Thabane L, Ma J, Wu H, Zhong Q, et al. The Effects of Dual-Task Training on Cognitive and Physical Functions in Older Adults with Cognitive Impairment; A Systematic Review and Meta-Analysis. J Prev Alzheimers Dis [Internet]. 2022 [cited 2024 Mar 26]; Available from: https://link.springer.com/article/10.14283/jpad.2022.16 Gavelin HM, Dong C, Minkov R, Bahar-Fuchs A, Ellis KA, Lautenschlager NT, et al. Combined physical and cognitive training for older adults with and without cognitive impairment: A systematic review and network meta-analysis of randomized controlled trials. Ageing Res Rev. 2021 Mar;66:101232. Bherer L, Gagnon C, Langeard A, Lussier M, Desjardins-Crépeau L, Berryman N, et al. Synergistic Effects of Cognitive Training and Physical Exercise on Dual-Task Performance in Older Adults. J Gerontol B Psychol Sci Soc Sci. 2021 Sep 13;76(8):1533–41. Montero-Odasso M, Almeida QJ, Burhan AM, Camicioli R, Doyon J, Fraser S, et al. SYNERGIC TRIAL (SYNchronizing Exercises, Remedies in Gait and Cognition) a multi-Centre randomized controlled double blind trial to improve gait and cognition in mild cognitive impairment. BMC Geriatr. 2018 Apr 16;18(1):93. Bruderer-Hofstetter M, Rausch-Osthoff AK, Meichtry A, Münzer T, Niedermann K. Effective multicomponent interventions in comparison to active control and no interventions on physical capacity, cognitive function and instrumental activities of daily living in elderly people with and without mild impaired cognition – A systematic review and network meta-analysis. Ageing Res Rev. 2018 Aug 1;45:1–14. Zokaei N, MacKellar C, Čepukaitytė G, Patai EZ, Nobre AC. Cognitive Training in the Elderly: Bottlenecks and New Avenues. J Cogn Neurosci. 2017 Sep;29(9):1473–82. Pedullà L, Brichetto G, Tacchino A, Vassallo C, Zaratin P, Battaglia MA, et al. Adaptive vs. non-adaptive cognitive training by means of a personalized App: a randomized trial in people with multiple sclerosis. J NeuroEngineering Rehabil. 2016 Oct 4;13:88. Bodner KA, Goldberg TE, Devanand DP, Doraiswamy PM. Advancing Computerized Cognitive Training for MCI and Alzheimer’s Disease in a Pandemic and Post-pandemic World. Front Psychiatry. 2020;11:557571. Costanzo MC, Arcidiacono C, Rodolico A, Panebianco M, Aguglia E, Signorelli MS. Diagnostic and interventional implications of telemedicine in Alzheimer’s disease and mild cognitive impairment: A literature review. Int J Geriatr Psychiatry. 2020 Jan;35(1):12–28. Zuschnegg J, Schoberer D, Häussl A, Herzog SA, Russegger S, Ploder K, et al. Effectiveness of computer-based interventions for community-dwelling people with cognitive decline: a systematic review with meta-analyses. BMC Geriatr. 2023 Apr 12;23(1):229. Walton CC, Mowszowski L, Lewis SJ, Naismith SL. Stuck in the mud: time for change in the implementation of cognitive training research in ageing? Front Aging Neurosci [Internet]. 2014 Mar 17 [cited 2024 Jul 8];6. Available from: https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2014.00043/full Liu L, Wang H, Xing Y, Zhang Z, Zhang Q, Dong M, et al. Dose-response relationship between computerized cognitive training and cognitive improvement. NPJ Digit Med. 2024 Aug 15;7(1):214. Gates NJ, Vernooij RW, Di Nisio M, Karim S, March E, Martínez G, et al. Computerised cognitive training for preventing dementia in people with mild cognitive impairment. Cochrane Database Syst Rev. 2019 Mar 13;3(3):CD012279. Chan AW, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013 Jan 9;346:e7586. Logsdon RG, Gibbons LE, McCurry SM, Teri L. Assessing quality of life in older adults with cognitive impairment. Psychosom Med. 2002;64(3):510–9. Carpenter BD, Balsis S, Otilingam PG, Hanson PK, Gatz M. The Alzheimer’s Disease Knowledge Scale: Development and Psychometric Properties. The Gerontologist. 2009 Apr;49(2):236–47. Tsang S, Royse CF, Terkawi AS. Guidelines for developing, translating, and validating a questionnaire in perioperative and pain medicine. Saudi J Anaesth. 2017 May;11(Suppl 1):S80–9. Jutten RJ, Peeters CFW, Leijdesdorff SMJ, Visser PJ, Maier AB, Terwee CB, et al. Detecting functional decline from normal aging to dementia: Development and validation of a short version of the Amsterdam IADL Questionnaire. Alzheimers Dement Diagn Assess Dis Monit. 2017 Jan 1;8:26–35. Ismail Z, Agüera-Ortiz L, Brodaty H, Cieslak A, Cummings J, Fischer CE, et al. The Mild Behavioral Impairment Checklist (MBI-C): A rating scale for neuropsychiatric symptoms in pre-dementia populations. J Alzheimers Dis JAD. 2017;56(3):929–38. Chan ATC, Ip RTF, Tran JYS, Chan JYC, Tsoi KKF. Computerized cognitive training for memory functions in mild cognitive impairment or dementia: a systematic review and meta-analysis. Npj Digit Med. 2024 Jan 3;7(1):1–11. Irazoki E, Contreras-Somoza LM, Toribio-Guzmán JM, Jenaro-Río C, van der Roest H, Franco-Martín MA. Technologies for Cognitive Training and Cognitive Rehabilitation for People With Mild Cognitive Impairment and Dementia. A Systematic Review. Front Psychol. 2020 Apr 9;11:648. Alnajjar F, Khalid S, Vogan AA, Shimoda S, Nouchi R, Kawashima R. Emerging Cognitive Intervention Technologies to Meet the Needs of an Aging Population: A Systematic Review. Front Aging Neurosci. 2019 Oct 24;11:291. Gates NJ, Vernooij RW, Nisio MD, Karim S, March E, Martínez G, et al. Computerised cognitive training for preventing dementia in people with mild cognitive impairment - Gates, NJ - 2019 | Cochrane Library. [cited 2024 Jun 20]; Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012279.pub2/full Chuang IC, Chiau HY, Liao WW, Wu YR, Chang CH, Wu CY. Effects of computer-based cognitive training combined with physical training for older adults with cognitive impairment: A four-arm randomized controlled trial. Digit Health. 2023 Jan 1;9:20552076231203633. Kang M, Ragan BG, Park JH. Issues in Outcomes Research: An Overview of Randomization Techniques for Clinical Trials. J Athl Train. 2008;43(2):215–21. Mubarak F, Suomi R. Elderly Forgotten? Digital Exclusion in the Information Age and the Rising Grey Digital Divide. Inq J Health Care Organ Provis Financ. 2022 Jan 1;59:00469580221096272. Bell I, Pot-Kolder RMCA, Wood SJ, Nelson B, Acevedo N, Stainton A, et al. Digital technology for addressing cognitive impairment in recent-onset psychosis: A perspective. Schizophr Res Cogn. 2022 Jun 1;28:100247. Jeong HS, Lee YW, Rhee TG, Shim SR. Efficacy of digital therapeutic applications for cognitive training among older adults with mild cognitive impairment or dementia: A systematic review and network meta-analysis of randomized controlled trials. Psychiatry Res. 2025 Jun 1;348:116426. Lin X, Xu G, Zhao M, Jiang Y. Efficacy of different digital interventions in patients with mild cognitive impairment or dementia: A systematic review and network meta-analysis. Int J Nurs Stud. 2025 Sep 1;169:105129. He C, Chen K, Yu Y, Xiao Y, Zhang Y, Wu XV, et al. Effectiveness of digital interventions in middle-aged and older adults with mild cognitive impairment: A systematic review and meta-analysis of randomized controlled trials. Ageing Res Rev. 2026 Jan 1;114:102951. Barasabha T, Hoefer L, Bennett M, Gallacher J, Holling H, Koychev I. Conventional versus Digital Cognitive Remediation Therapy: Meta- Analysis in People with Mild Cognitive Impairment and Dementia [Internet]. Research Square; 2025 [cited 2026 Feb 12]. Available from: https://www.researchsquare.com/article/rs-8224433/v1 Baumel A, Muench F, Edan S, Kane JM. Objective User Engagement With Mental Health Apps: Systematic Search and Panel-Based Usage Analysis. J Med Internet Res. 2019 Sep 25;21(9):e14567. Turunen M, Hokkanen L, Bäckman L, Stigsdotter-Neely A, Hänninen T, Paajanen T, et al. Computer-based cognitive training for older adults: Determinants of adherence. PLOS ONE. 2019 Jul 10;14(7):e0219541. Demurtas J, Schoene D, Torbahn G, Marengoni A, Grande G, Zou L, et al. Physical Activity and Exercise in Mild Cognitive Impairment and Dementia: An Umbrella Review of Intervention and Observational Studies. J Am Med Dir Assoc. 2020 Oct 1;21(10):1415-1422.e6. Additional Declarations Competing interest reported. This study is sponsored and funded by Five Lives SAS, which is the manufacturer of Five Lives MED. The Chief Investigator (IK) serves as Chief Medical Officer at Five Lives SAS and receives for this ongoing advisory role a monthly retainer fee as well as a set number of options in the company. Supplementary Files SPIRIT2025editablechecklist.docx Supplementaryfig.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 29 Apr, 2026 Editor assigned by journal 16 Feb, 2026 Submission checks completed at journal 16 Feb, 2026 First submitted to journal 15 Feb, 2026 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-8885992","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":591877701,"identity":"dab24049-71ff-441f-bd53-5fb864014da3","order_by":0,"name":"Jamie M. Kawadler","email":"","orcid":"","institution":"Five Lives SAS","correspondingAuthor":false,"prefix":"","firstName":"Jamie","middleName":"M.","lastName":"Kawadler","suffix":""},{"id":591877702,"identity":"6ab1db88-62c3-4f5f-b6d3-eaa1db34d825","order_by":1,"name":"Philip Vassilev","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/klEQVRIie3QMUsDMRTA8XcIcSl2faWCX+Ema+HofZUXAnEpuHaSyEEmP4CDH6TjKwdOh10LdTAIzgcu56TvQFCEXB0d8oeEEPLLhQNIpf5jmN0wQTFWAJks+h0Zz8BDxMlJO/Gy/iZEQwT6C+uJA/i6+RCZTSvHYb3FEzTMwRclTKtNq7unKJnfbxzrZo8KLbH2VrvTB4NEr1GS77QQv79WoyZnamoCXOZC6kPkEdVo2wr5KAGv3ro/EEZ1fCt/bMWZw6Ua/Mr8rieNEeLlYSujPdrzC7JxMsPLEN7XCzyrjkLo8kU5RvOya4uBh/VT5n7sqOjZKEmlUqnU7z4BamBiy7mrYvIAAAAASUVORK5CYII=","orcid":"","institution":"Five Lives SAS","correspondingAuthor":true,"prefix":"","firstName":"Philip","middleName":"","lastName":"Vassilev","suffix":""},{"id":591877703,"identity":"aa7fdd5c-9849-4e9a-bc42-06283856ac07","order_by":2,"name":"Maria Bunyan","email":"","orcid":"","institution":"University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Bunyan","suffix":""},{"id":591877704,"identity":"b5b2b171-817d-4e9f-93a1-20f9f4029f52","order_by":3,"name":"Jenny Barnett","email":"","orcid":"","institution":"Five Lives SAS","correspondingAuthor":false,"prefix":"","firstName":"Jenny","middleName":"","lastName":"Barnett","suffix":""},{"id":591877705,"identity":"90e36cc0-9bd5-4c0a-a1ae-a455a066061b","order_by":4,"name":"Ivan Koychev","email":"","orcid":"","institution":"University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Ivan","middleName":"","lastName":"Koychev","suffix":""}],"badges":[],"createdAt":"2026-02-15 12:39:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8885992/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8885992/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103509720,"identity":"16c066a1-ff05-485d-9f7a-9a6752928800","added_by":"auto","created_at":"2026-02-26 14:00:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":586220,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8885992/v1/75d420ad-e732-4072-9b44-7f9b2ec6196f.pdf"},{"id":103216007,"identity":"8305845b-0571-42d6-855b-fb613c88fa6c","added_by":"auto","created_at":"2026-02-23 09:28:57","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":33822,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRIT2025editablechecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-8885992/v1/393aec834cc8c9f23c59eead.docx"},{"id":103505616,"identity":"0f95585d-1321-40c7-b0bf-8f1c3ad830a0","added_by":"auto","created_at":"2026-02-26 13:32:13","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":36647,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfig.docx","url":"https://assets-eu.researchsquare.com/files/rs-8885992/v1/bb278c9ad9e442f48df413c9.docx"}],"financialInterests":"Competing interest reported. This study is sponsored and funded by Five Lives SAS, which is the manufacturer of Five Lives MED. The Chief Investigator (IK) serves as Chief Medical Officer at Five Lives SAS and receives for this ongoing advisory role a monthly retainer fee as well as a set number of options in the company.","formattedTitle":"The efficacy of a digital health app Five Lives MED to improve cognitive function in patients with mild cognitive impairment: study protocol for a randomised controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eAs population life expectancy increases, research has focused on the differentiation between the cognitive profile of “healthy ageing”, mostly driven by psychomotor slowing, and pathological cognitive dysfunction. Mild cognitive impairment (MCI) is identified by the Diagnostic and Statistical Manual for Mental Disorders as a neurocognitive disorder, defined as “cognitive decline greater than that expected for an individual’s age and education level but that does not interfere notably with activities of daily life” (1). Diagnostic criteria for MCI are determined by abnormal cognitive function in one or more domains: memory, attention, executive functioning, language, and visuospatial processing (2,3). MCI prevalence is reported to range between 6% (4) and 20% (5) in the population from age 65 years onwards, with specific country estimates of 15-18% in the UK (6), 24% in France (7), and 13.11% in Greece (8). This poses a significant public health concern, as 10-15% (9,10) of people with MCI go on to develop dementia each year, with 80% developing dementia within 5 years (10).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn some countries, pharmacological interventions (i.e. amyloid clearance therapies) are available to some with early-stage, isolated Alzheimer’s disease (AD) pathology; however, they pose limitations in both supply, patient eligibility, local reimbursement and clinical risks. Non-pharmacological approaches (i.e., cognitive, occupational therapy, and/or lifestyle interventions) intended to curb modifiable risk factors for dementia, and thus slow the progression of cognitive decline are generally accepted as effective alternatives. In 2018, the American Academy of Neurology recommended in their guidelines that cognitive interventions may be effective and that clinicians may recommend them to people with MCI (11).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCognitive training interventions have shown promising results in remediating cognitive function in healthy older individuals (12) and those with MCI (13) through strengthening cognitive abilities using structured tasks. Systematic reviews and meta-analyses have shown CCT can improve both global cognitive functioning (14) with small to moderate effect sizes (\u003cem\u003ed\u003c/em\u003e = 0.37 (15); \u003cem\u003ed\u003c/em\u003e = 0.54 (16)), especially when delivered on computers/tablets (\u003cem\u003ed\u003c/em\u003e = 0.61 (16)). Individual studies in MCI have reported effect sizes ranging from small (0.33 (17), 0.38 (18)) to medium (0.56 (19), 0.56 (20)) to large (0.80 (21), 0.88 (22)).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eApproaches vary widely, with the options of targeting a single cognitive area (e.g., working memory) or multiple cognitive areas (multiple cognitive domains) and with or without other lifestyle interventions (23), in domains such as physical activity or nutrition. A recent Cochrane review found that multi-domain interventions, especially when cognitive training was offered as one of the domains, were effective in improving cognitive function (24). This mirrors findings from the landmark FINGER trial, which was the first to demonstrate the effectiveness of multi-domain lifestyle interventions in improving cognitive performance (23,25) in people at risk for dementia. Results from the FINGER trial showed that the odds of cognitive decline in the control group were estimated to be 31% higher in comparison with the intervention group.\u003c/p\u003e\n\u003cp\u003eMotor-cognitive training (26), where CCT is delivered alongside physical activity interventions, aims to utilise the long-known benefits of physical activity on improving cognition in MCI (27,28). In older adults, motor-cognitive training has been shown to improve postural control (29) and mobility (30). Meta-analyses have shown small-to-moderate effect sizes of motor-cognitive interventions on global cognition in adults with MCI or dementia (\u003cem\u003ed\u003c/em\u003e = 0.32 (31), \u003cem\u003ed\u003c/em\u003e = 0.24 (32), \u003cem\u003eg\u003c/em\u003e = 0.22 (33)), and some have suggested there may be a synergistic effect on cognition (34–36).\u003c/p\u003e\n\u003cp\u003eCognitive training administered digitally (\u003cem\u003ee.g.,\u0026nbsp;\u003c/em\u003ethrough smartphones, tablets or computers) has several advantages over traditional in-person/paper-based programmes:\u003c/p\u003e\n\u003cp\u003ea) Specific and personalised. Digital programmes can be directed to specific cognitive domains such as memory or attention and can be personalised and adaptive to the performance of the individual (37,38);\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eb) Accessible and scalable. Digital tools are convenient and overcome accessibility issues (39), such as the expense and physical challenge of travelling to appointments. Remote CCT delivered at home or at community centres may also increase autonomy (40) and independence for living at home as long as possible (41). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ec) Engagement.\u003cem\u003e\u0026nbsp;\u003c/em\u003eDigital programmes can provide immediate feedback and can be designed to be highly immersive and enjoyable (37).\u003c/p\u003e\n\u003cp\u003eCurrently, there are not yet any established standards for the design, optimal “dose” or delivery of CCT (42); although retrospective analyses highlight the need for age-specific optimal dosing (43). Commercially-available CCT programmes that claim to have clinical benefits have been scrutinised for lacking appropriate scientific evaluation; a Cochrane review from 2019 found the quality of evidence for CCT was very low and no conclusions were able to be drawn about the outcome (44). A recent review of only commercially available CCT programmes (13) noted a lack of empirical evidence but also that it is a rapidly expanding industry in which substantial evidence may still be gained with appropriate clinical evaluation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCurrent study\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis protocol details the first investigation of the Five Lives MED, a 12-week digital motor-cognitive intervention delivered on mobile devices at home, consisting of CCT and physical activity exercises as well as educational articles.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe aim of the study is to investigate if 12-weeks of Five Lives MED improves global cognitive function compared to a control group receiving standard health information. As secondary outcomes, this study will also evaluate the effectiveness of the Five Lives MED app on specific cognitive function subtests and also quality of life, dementia literacy, activities of daily living, behavioural symptoms, and physical activity measures.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eStudy design\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a single-blind, multicentre, randomised controlled trial. Participants will be randomly assigned to the intervention (Five Lives MED) or control group for a 12-week period on a 1:1 allocation ratio. Outcome measures will be conducted at baseline (T\u003csub\u003e0\u003c/sub\u003e) study exit (T\u003csub\u003e1\u003c/sub\u003e, 12 weeks). A follow-up visit (T\u003csub\u003e2\u003c/sub\u003e) will be conducted 6 months after study exit.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe intervention group will be asked to use the Five Lives MED app on their mobile device at home for the 12-week intervention period. The control group will receive a lifestyle recommendations leaflet (\u003cem\u003ee.g.\u0026nbsp;\u003c/em\u003ephysical activity, cardiovascular health, nutritional advice, sleep hygiene, alcohol consumption, smoking cessation, avoiding social isolation, and mental health). All participants will receive standard care according to local practices. This protocol is conducted according to the “Standard Protocol Items: Recommendations for Interventional Trials” (SPIRIT) checklist for clinical trials (45). The completed SPIRIT checklist (2025 version) is submitted as supplementary material.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSetting\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study will be conducted in the United Kingdom (UK) and France. In the UK, research sites include:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eOxford University Hospitals NHS Foundation Trust (Oxfordshire)\u003c/li\u003e\n \u003cli\u003eDevon Partnership NHS Trust (Devon)\u003c/li\u003e\n \u003cli\u003eSomerset NHS Foundation Trust (Somerset)\u003c/li\u003e\n \u003cli\u003eLancashire \u0026amp; South Cumbria NHS Foundation Trust (Lancashire)\u003c/li\u003e\n \u003cli\u003eEast London NHS Foundation Trust (London)\u003c/li\u003e\n \u003cli\u003eSouth London \u0026amp; Maudsley NHS Foundation Trust (London)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eIn France, research sites include:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eHôpital Broca (Paris, Ile de France)\u003c/li\u003e\n \u003cli\u003eHôpital de la Timone\u003cem\u003e\u0026nbsp;\u003c/em\u003e(Marseilles)\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cem\u003eParticipant eligibility criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eDiagnosis of Mild Cognitive Impairment (also known as mild cognitive disorder [ICD-10-CM; G31.84] or mild neurocognitive disorder (DSM-5)\u003c/li\u003e\n \u003cli\u003eAge ≥ 50\u003c/li\u003e\n \u003cli\u003eThe participant or informant is willing and able to give informed consent for participation in the study\u003c/li\u003e\n \u003cli\u003eAbility to read and understand English (UK) or French (France)\u003c/li\u003e\n \u003cli\u003eDaily access to a mobile phone (Apple iOS 12.4 or above or Android 6.0 (Marshmallow) or above) or iPad (Apple iOS 12.4 or above only) with internet connection (mobile or WiFi).\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participant may not enter the study if ANY of the following apply:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eDiagnosis of dementia or evidence of functional impairment inconsistent with MCI\u003c/li\u003e\n \u003cli\u003eSevere visual impairment\u003c/li\u003e\n \u003cli\u003eCurrently undergoing any other cognitive remediation programme\u003c/li\u003e\n \u003cli\u003eCurrently taking part in any other investigational study that in the opinion of the investigator may impact the data integrity of the current study\u003c/li\u003e\n \u003cli\u003ePhysical impairment that makes using a mobile device impossible\u003c/li\u003e\n \u003cli\u003eLack of access to an informant\u003c/li\u003e\n \u003cli\u003eParticipant under guardianship\u003c/li\u003e\n \u003cli\u003eUnwilling or unable to tolerate or engage with study procedures\u003c/li\u003e\n \u003cli\u003ePhysical impairment that makes standing/walking unassisted impossible.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cem\u003eIntervention description (Five Lives MED)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe Five Lives MED app is a 12-week digital multi-domain intervention, consisting of: CCT exercises, educational articles about health and lifestyle, and a goal-setting programme focused on physical activity, balance and strength (“Habit Quests”). This intervention is delivered at home on the participant’s mobile device. Each session starts with a daily Habit Quest, then flows into 11 cognitive training exercises. After completion, there is access to educational articles, additional cognitive training games, and breathing exercises. The content of the app was fine-tuned to the study population after offering the first prototype to a focus group of 12 persons with an MCI diagnosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHabit Quests.\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eHabit Quests is a feature to encourage physical activity habit formation. It appears as a “chatbot” to help the user set goals and habits in a fun and engaging way, offering daily tasks that build upon the previous day.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCognitive training exercises.\u0026nbsp;\u003c/strong\u003eEach of the 11 cognitive training exercises takes a few minutes each and covers cognitive domains such as language, attention, memory, mental flexibility, and processing speed. Each time one is played, it will start with a tutorial, which can be skipped after the first time. The exercises are personalized to the participant’s ability; participants can “level up”, making the exercises harder where needed. After the exercise is completed, the participant will be able to see their results, including their score, rank, and trend.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOptional features.\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eAfter the session is complete, the participant has the option to engage with a range of psychoeducational articles and quizzes, with categories including: diet, exercise, sleep, mood, mental stimulation, and general brain health. There is also a breathing exercise to encourage relaxation.\u003c/p\u003e\n\u003cp\u003eParticipants will be given an onboarding pack of materials that contains an informational leaflet on how to download, log in, and use the app, and information about how to contact the manufacturer for technical support. A new session refreshes every day, which takes approximately 30 minutes to complete. Participants are asked to use the app for 12 weeks, in which they are encouraged to complete 3 sessions a week. Reminders will be sent through the app. App usage will be monitored, and reminder telephone calls will be made to those participants who have not engaged with the app for more than 7 days in a row. At the end of the intervention period, all participants will have access to the app and will be able to continue using the app for at least 6 months.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eComparator\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe control group will receive a lifestyle recommendations leaflet (\u003cem\u003ee.g.\u003c/em\u003e physical activity, cardiovascular health, nutritional advice, sleep hygiene, alcohol consumption, smoking cessation, avoiding social isolation, and mental health). All participants will receive standard care according to local practices. The provision of this type of information is the standard of care for MCI in both France and the UK.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eOutcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint is the Montreal Cognitive Assessment (MoCA). The Montreal Cognitive Assessment (MoCA) is a brief assessment tool used to evaluate multiple cognitive domains: visuospatial and executive functions (5 points), animal naming (3 points), memory (5 points), attention (6 points), language (3 points), abstraction (2 points), delayed recall (5 points) and orientation (6 points). MoCA is scored out of 30 points, with one point added to the total score for participants with 12 years of education or less to account for educational differences.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecondary endpoints included specific cognitive measures and other health and lifestyle measures:\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExecutive function.\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eThe Delis-Kaplan Trail Making Test (TMT) is a measure of cognitive flexibility and processing speed using a visuomotor sequencing task, with five conditions: Condition 1 (Visual Scanning), Condition 2 (Number sequencing), Condition 3 (Letter sequencing), Condition 4 (Number-letter sequencing) and Condition 5 (Motor speed). For each, the score is the number of seconds required to complete the task.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality of Life.\u0026nbsp;\u003c/strong\u003eThe Quality of Life in Alzheimer’s Disease questionnaire (QOL-AD) is a 13-item measure designed to obtain a rating of the patient's quality of life from both the patient and the caregiver. It was developed specifically for individuals with dementia and focuses on quality of life domains thought to be important in cognitively impaired older adults (46). The measure consists of 13 items, rated on a four-point scale, with 1 being poor and 4 being excellent. Total scores are summed and range from 13 to 52.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDementia literacy.\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eThe Alzheimer’s Disease Knowledge Scale (47) is a measure of dementia literacy. There are 30 items across 7 domains: risk factors, assessment/diagnosis, symptoms, course, caregiving, life impact, and treatment/management. The total score is calculated by summing the number of correct responses, with higher scores indicating greater health literacy. For participants in France, a translated version of this questionnaire, following recommended guidelines (48).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eActivities of Daily Living.\u003c/strong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eThe A-IADL-Q (Short Version) (49) is a 30-item questionnaire assessing functional decline in a broad range of daily activities, including: household activities, using household appliances, finances, work, using the computer, using small appliances and leisure activities. Responses are on a 5-item Likert scale from “no difficulty in performing this task” to “no longer able to perform this task”.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBehavioural impairment.\u0026nbsp;\u003c/strong\u003eThe Mild Behavioural Impairment Checklist (MBI-C) (50) is a 34-item scale covering 5 domains, completed by the participant’s informant. The following domains are: apathy, affect, impulse dyscontrol, recklessness and abnormal reward and reinforcement, social appropriateness, abnormal thought and perception domain, and grandiosity/auditory and visual hallucinations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePhysical activity.\u0026nbsp;\u003c/strong\u003eTwo physical activity outcomes will be collected. The International Physical Activity Questionnaire (IPAQ) and the 30-second chair stand test (30CST). The IPAQ is a freely available questionnaire designed to be used internationally to obtain estimates of physical activity. For participants ≤ 69 years of age, the short form for the last 7 days will be self-administered. For participants ≥ 70 years, an elderly version will be self-administered. The 30CST is a test of physical performance for people of all ages. It is administered by having the participant seated in a chair with their arms crossed at the wrists and held against the chest. The participant is encouraged to complete as many full stands as possible within 30 seconds while fully sitting between each stand. The score is the total number of stands.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDigital cognitive tests.\u0026nbsp;\u003c/strong\u003eAs an exploratory outcome measure, participants will complete Five Lives proprietary standalone digital cognitive tests administered through an iPad or smartphone. There are five tests covering verbal fluency, immediate verbal memory, immediate spatial memory, inhibition, and executive function.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEngagement with the mobile application.\u0026nbsp;\u003c/strong\u003eParticipant usage of the app will be monitored remotely and daily. Timestamped events marking the start and completion of a session will be recorded and monitored to detect participant inactivity. If a participant is flagged as inactive for a week, the study site will attempt to contact them to remind them to use the app. Each participant will receive a maximum of 3 reminder calls (regardless of whether the calls are answered or not).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSample size\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis sample size calculation was performed with G*Power 3.1. An internal systematic review was performed to determine a valid clinical association between CCT and/or motor-cognitive interventions and improving cognition in people with MCI; the results suggest that this study, employing the Five Lives MED device, can expect a medium effect size with a global cognitive measure as an endpoint. This is consistent with the results of recently published meta-analyses (16,41,51–54) and competitors (19,21,55).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo detect a medium effect size of Cohen’s d = 0.5 (t-test for independent samples) with one-tailed significance level α = .05 and power = 80% and 1:1 allocation ratio, 128 participants are required. However, this is the first investigation of the Five Lives MED app, which is a home-based, self-initiated, and self-guided intervention. Study drop-out rates and app retention rates are not fully known, but are assumed from previous studies to range from 15-25%. To be conservative, this study will allow for a 25% dropout rate; this results in a sample size to be recruited of n=170.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRecruitment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be pre-screened and identified through research-ready lists available to the sites, memory services at sites (e.g., searches of clinical notes and upcoming scheduled visits) or primary care sites (known as patient identification centres) aligned with the research sites.\u003c/p\u003e\n\u003cp\u003eParticipants meeting the eligibility criteria will be offered to participate after the investigator/research staff has thoroughly explained the study to them and provided the Participant Information Sheet and Consent Form. Before any procedures specified in the protocol are performed, the subject must sign and date the approved informed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRandomisation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be randomly assigned to the intervention group (IG) or control group (CG) using stratified block randomisation (56) at a 1:1 allocation ratio. The stratification factors will be: age (2 levels: [\u0026lt;70, \u0026gt;= 70], sex (2 levels: male, female) and education level (2 levels: graduated high school or less, university degree or more). Participants will be randomised in permuted blocks of fixed size 4. \u0026nbsp;The eCRF software will generate the randomisation sequence, manage stratification factors and block sizes, and allocate participants to their respective groups. Study personnel will input stratification variables into the eCRF system, which will then randomly assign the participant to the IG or CG.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBlinding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis is a single-blinded trial. The study personnel administering the cognitive assessments will be blinded to the allocation group. The eCRF software will control access to the randomisation sequence to ensure that blinded personnel will not have access to group assignments.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVisits\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline (T0).\u003c/strong\u003e After informed consent has been obtained, the participant will undergo cognitive testing with the MoCA, TMT and Five Lives cognitive tests, and will be asked to complete questionnaires (QoL-AD, ADKS, IPAQ). Participants will also be asked to perform the 30 Second Chair Stand Test (30CST) with the researcher. The participant’s informant will be asked to complete the QoL-AD (caregiver version), A-IADL-Q-SV, and MBI-C either in-person, by telephone or online.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExit visit (T1).\u003c/strong\u003e At study exit, participants will undergo the same assessments as at Baseline. Participants and informants will be asked about any adverse events or changes in medications. After the study ends, all participants in the intervention group will be invited to complete a User Experience Questionnaire. The questionnaire will address the quality of their experience with the Five Lives MED application, and answering it will not be mandatory.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up visit (T2).\u003c/strong\u003e All participants will undergo a follow-up visit 6 months after the exit visit (\u003cem\u003ei.e.\u003c/em\u003e 9 months from baseline). The follow-up visit will consist of a 20-minute telephone call in which the telephone version of the MoCA will be administered.\u003c/p\u003e\n\u003cp\u003eThe study design and timeline is summarised in Supplementary Figure 1 (see end of manuscript).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study plans to recruit 170 participants who have a diagnosis of mild cognitive impairment from centres in both the UK (from research registers and NHS memory clinics) and France (geriatric and/or memory centres). All statistical analyses will be conducted by an independent statistician with experience in analysing trial data who is not involved in the trial's conduct or data collection.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEfficacy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe endpoints will be evaluated within an intention-to-treat (ITT) analysis, encompassing\u003c/p\u003e\n\u003cp\u003eall randomised participants. The effect of the intervention on change in the primary outcome will be evaluated using paired samples t-tests comparing pre- and post-intervention primary outcome measures in the IC and CG, respectively. In case the assumptions for parametric tests are not met, we will use a Wilcoxon matched-pairs test. To control for the effect of extraneous variable and baseline differences, we will also run an analysis of covariance (ANCOVA), with the baseline values, age, sex, years of education and study centre as covariates, experimental group (intervention or control) as the independent variable, and the post-assessment score as the dependent variable. The effect of the intervention on change in the secondary outcome measures will be similarly evaluated using t-tests (or Wilcoxon tests) and ANCOVA with age, sex, years of education and study centre as a covariate. Effect sizes and confidence intervals will be presented from the respective statistical tests to enhance result interpretability.\u003c/p\u003e\n\u003cp\u003eTo address missing data, we will employ several strategies to ensure the robustness of our findings, which will be guided by the pattern and mechanism of the missing data to minimise bias. We will test whether the data is missing completely at random (MCAR) by comparing the baseline characteristics of those who completed the 12-week assessment vs. those who did not. If necessary, a sensitivity analysis will be employed involving multiple imputation to assess the robustness of our primary findings. In addition to the ITT analysis, we plan to conduct a complementary as-treated (per-protocol) analysis if sample size allows, including only those participants who engaged with the app. The purpose of this analysis will be to assess the efficacy of the app under real-world conditions.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInterim analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAn interim analysis will be conducted when half the required sample size (n=64) has\u003c/p\u003e\n\u003cp\u003ecompleted the exit (T1) assessments. Because this is the first investigation of this medical device and an effect size has been assumed from the literature, this interim analysis will be planned for efficacy (to see if a potentially larger effect size can be seen in fewer participants) and safety (to check the adverse event log for safety reporting). Employing the alpha-spending function (the O’Brien-Fleming method), we will use a highly conservative alpha at the interim phase a = 0.0088 and an alpha of 0.0412 for the final analysis of the primary outcome. We will use the Benjamini-Hochberg Procedure to control the False Discovery Rate.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCommunication of results\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOnce all data has been collected and analysed, the results of the study will be communicated through the trial registry and through a peer-reviewed publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConfidentiality\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePersonally identifiable data will be available only to the study sites. All other data will be collected in a pseudonymised form and stored in password and encryption-protected EDC platform.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis trial is designed to evaluate the efficacy of Five Lives MED, a fully remote, multi-domain digital motor-cognitive intervention for individuals with mild cognitive impairment. In addition to assessing clinical outcomes, the study addresses broader methodological and implementation considerations relevant to the growing use of digital cognitive remediation therapies (CRT) in ageing and neurocognitive populations.\u003c/p\u003e\n\u003cp\u003eA central consideration in the deployment of digital interventions is the risk of digital exclusion (57). Although smartphone and tablet use among older adults has increased substantially, access to suitable devices, reliable internet connectivity, and digital literacy remain unevenly distributed. Individuals with lower socioeconomic status, lower educational attainment, or greater functional impairment may be systematically underrepresented in digital trials. While the present study requires access to a mobile device and basic digital competence, these criteria reflect the real-world conditions under which such interventions would be deployed. Nonetheless, digital exclusion remains a potential barrier to equitable access, and findings from this trial should be interpreted in the context of a population able to engage with mobile health technologies. Future implementation studies should explore strategies to mitigate exclusion, including supported onboarding, caregiver involvement, and alternative delivery formats.\u003c/p\u003e\n\u003cp\u003eWithin the broader CRT literature, digital delivery represents both a continuation and a departure from conventional, therapist-led approaches (58\u0026ndash;61). Traditional CRT has demonstrated benefits in MCI when delivered in structured, supervised settings, often requiring substantial clinical resources. Digital CRT offers increased scalability, reduced costs, and the ability to deliver personalised, adaptive training at home. However, the reduced level of direct therapist involvement may limit opportunities for real-time feedback, motivational support, and individual tailoring beyond algorithmic adaptation. Existing evidence suggests that digital CRT can achieve comparable improvements in cognitive outcomes to conventional formats (62), particularly when interventions are multi-domain and sufficiently intensive, but heterogeneity in intervention design and outcome measures has limited definitive conclusions. This trial contributes to the literature by evaluating a digital intervention that integrates cognitive and physical components while maintaining ecological validity through home-based delivery.\u003c/p\u003e\n\u003cp\u003eAdherence is a critical determinant of effectiveness in digital interventions. Attrition and declining engagement over time are well-documented challenges across digital health studies, particularly in older populations and in self-guided programmes (63,64). Prior research indicates that adherence is influenced by perceived relevance, usability, feedback, and the integration of interventions into daily routines. The design of Five Lives MED incorporates daily habit formation, adaptive difficulty, and varied content to promote sustained engagement. By capturing detailed usage data and including both intention-to-treat and per-protocol analyses, this study will provide insights into patterns of adherence and their relationship to cognitive outcomes. These findings may help inform optimal dosing and engagement strategies for digital CRT in MCI.\u003c/p\u003e\n\u003cp\u003eFinally, the trial addresses broader questions regarding what constitutes an effective CRT intervention. Contemporary evidence suggests that interventions targeting multiple cognitive domains, delivered with sufficient frequency and duration, and embedded within a broader lifestyle context are more likely to yield meaningful benefits (27-36). The inclusion of motor-cognitive elements reflects growing evidence of synergistic effects between physical activity and cognitive training, potentially mediated through neuroplastic and vascular mechanisms (65). By combining cognitive exercises, physical activity habit formation, and psychoeducation within a single digital platform, this study examines a comprehensive model of CRT aligned with current theoretical and empirical frameworks.\u003c/p\u003e\n\u003cp\u003eIn summary, this trial will generate important evidence on the clinical efficacy and practical considerations of a digital motor-cognitive intervention for MCI. The results will have implications not only for cognitive outcomes but also for the future design, delivery, and equitable implementation of digital CRT in ageing populations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecruitment ongoing. Recruitment start: 2025-02-20, projected recruitment end: 2026-04-01.\u003c/p\u003e\n\u003cp\u003eProtocol v1.2 February 24, 2025, available on the ClinicalTrials.gov site.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e30CST - 30 sec chair-stant test\u003c/p\u003e\n\u003cp\u003eA-IADL-Q-SV - Amsterdam Instrumental Activities of Daily Living\u003c/p\u003e\n\u003cp\u003eANCOVA - analysis of covariance\u003c/p\u003e\n\u003cp\u003eCCT - computerised cognitive training\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCG - control group\u003c/p\u003e\n\u003cp\u003eCRT - cognitive remediation therapy\u003c/p\u003e\n\u003cp\u003eeCRF - electronic case report form\u003c/p\u003e\n\u003cp\u003eEDC - electronic data capture\u003c/p\u003e\n\u003cp\u003eIG - intervention group\u003c/p\u003e\n\u003cp\u003eIPAQ - International Physical Activity Quesitonnaire\u003c/p\u003e\n\u003cp\u003eITT - intention to treat\u003c/p\u003e\n\u003cp\u003eMBI-C - Mild Behavioural Impairment Checklist\u003c/p\u003e\n\u003cp\u003eMCAR - missing completely at random\u003c/p\u003e\n\u003cp\u003eMCI - mild cognitive impairment\u003c/p\u003e\n\u003cp\u003eMoCA - Montreal Cognitive Assessment\u003c/p\u003e\n\u003cp\u003eNHS - National Health Service\u003c/p\u003e\n\u003cp\u003eQoL-AD - Quality of Life in Alzheimer\u0026rsquo;s Disease\u003c/p\u003e\n\u003cp\u003eTMT - Trail-Making Test\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was granted from the UK Health Research Authority - London Dulwich Research Ethics Committee (24/LO/0771), and written, informed consent to participate will be obtained from all participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll authors consent to the publication of this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNo original data are reported.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study is sponsored and funded by Five Lives SAS, which is the manufacturer of Five Lives MED. The Chief Investigator (IK) serves as Chief Medical Officer at Five Lives SAS and receives for this ongoing advisory role a monthly retainer fee as well as a set number of options in the company.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study is funded by Five Lives SAS, 1 Impasse du Palais 37000 Tours, France. [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors' contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll study authors contributed to the design of the study and the manuscript draft. IK is the study Chief Investigator providing supervision and oversight. JM, PV, MB lead on the delivery of the study. JB provides ongoing expert advice and supervision.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study is funded by Five Lives SAS.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, et al. Mild cognitive impairment. The Lancet. 2006 Apr 15;367(9518):1262\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003ePetersen RC. Mild Cognitive Impairment. Contin Minneap Minn. 2016 Apr;22(2 Dementia):404\u0026ndash;18. \u003c/li\u003e\n\u003cli\u003eJongsiriyanyong S, Limpawattana P. Mild Cognitive Impairment in Clinical Practice: A Review Article. Am J Alzheimers Dis Other Demen. 2018 Dec;33(8):500\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eSachdev PS, Lipnicki DM, Kochan NA, Crawford JD, Thalamuthu A, Andrews G, et al. 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J Prev Alzheimers Dis. 2023;10(2):259\u0026ndash;66. \u003c/li\u003e\n\u003cli\u003eVlachos GS, Kosmidis MH, Yannakoulia M, Dardiotis E, Hadjigeorgiou G, Sakka P, et al. Prevalence of Mild Cognitive Impairment in the Elderly Population in Greece: Results From the HELIAD Study. Alzheimer Dis Assoc Disord. 2020;34(2):156\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003ePetersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild Cognitive Impairment: Clinical Characterization and Outcome. Arch Neurol. 1999 Mar 1;56(3):303\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eTierney MC, Szalai JP, Snow WG, Fisher RH, Nores A, Nadon G, et al. Prediction of probable Alzheimer\u0026rsquo;s disease in memory-impaired patients: A prospective longitudinal study. Neurology. 1996 Mar;46(3):661\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eWorld Health Organization. Global status report on the public health response to dementia [Internet]. Geneva: World Health Organization; 2021 p. 137. Available from: https://www.who.int/publications/i/item/9789240033245 \u003c/li\u003e\n\u003cli\u003eLampit A, Hallock H, Valenzuela M. Computerized cognitive training in cognitively healthy older adults: a systematic review and meta-analysis of effect modifiers. PLoS Med. 2014 Nov;11(11):e1001756. \u003c/li\u003e\n\u003cli\u003eNguyen L, Murphy K, Andrews G. A Game a Day Keeps Cognitive Decline Away? A Systematic Review and Meta-Analysis of Commercially-Available Brain Training Programs in Healthy and Cognitively Impaired Older Adults. Neuropsychol Rev. 2022 Sep;32(3):601\u0026ndash;30. \u003c/li\u003e\n\u003cli\u003eJeong HS, Lee YW, Rhee TG, Shim SR. Efficacy of digital therapeutic applications for cognitive training among older adults with mild cognitive impairment or dementia: A systematic review and network meta-analysis of randomized controlled trials. Psychiatry Res. 2025 Jun;348:116426. \u003c/li\u003e\n\u003cli\u003eChae HJ, Lee SH. Effectiveness of online-based cognitive intervention in community-dwelling older adults with cognitive dysfunction: A systematic review and meta-analysis. Int J Geriatr Psychiatry. 2023 Jan;38(1):e5853. \u003c/li\u003e\n\u003cli\u003eLi R, Geng J, Yang R, Ge Y, Hesketh T. Effectiveness of Computerized Cognitive Training in Delaying Cognitive Function Decline in People With Mild Cognitive Impairment: Systematic Review and Meta-analysis. J Med Internet Res. 2022 Oct 27;24(10):e38624. \u003c/li\u003e\n\u003cli\u003eFiatarone Singh MA, Gates N, Saigal N, Wilson GC, Meiklejohn J, Brodaty H, et al. The Study of Mental and Resistance Training (SMART) Study\u0026mdash;Resistance Training and/or Cognitive Training in Mild Cognitive Impairment: A Randomized, Double-Blind, Double-Sham Controlled Trial. J Am Med Dir Assoc. 2014 Dec;15(12):873\u0026ndash;80. \u003c/li\u003e\n\u003cli\u003eHagovsk\u0026aacute; M, Olekszyov\u0026aacute; Z. 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BMC Psychiatry. 2016 Sep 8;16(1):315. \u003c/li\u003e\n\u003cli\u003eBahar-Fuchs A, Webb S, Bartsch L, Clare L, Rebok G, Cherbuin N, et al. Tailored and Adaptive Computerized Cognitive Training in Older Adults at Risk for Dementia: A Randomized Controlled Trial. J Alzheimers Dis. 2017 Oct 3;60(3):889\u0026ndash;911. \u003c/li\u003e\n\u003cli\u003eHyer L, Scott C, Atkinson MM, Mullen CM, Lee A, Johnson A, et al. Cognitive Training Program to Improve Working Memory in Older Adults with MCI. Clin Gerontol. 2016 Oct 19;39(5):410\u0026ndash;27. \u003c/li\u003e\n\u003cli\u003eNgandu T, Lehtisalo J, Solomon A, Lev\u0026auml;lahti E, Ahtiluoto S, Antikainen R, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. The Lancet. 2015 Jun;385(9984):2255\u0026ndash;63. \u003c/li\u003e\n\u003cli\u003eHafdi M, Hoevenaar-Blom MP, Richard E. Multi‐domain interventions for the prevention of dementia and cognitive decline. Cochrane Database Syst Rev [Internet]. 2021 [cited 2023 Oct 11];(11). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013572.pub2/full \u003c/li\u003e\n\u003cli\u003eKivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nat Rev Neurol. 2018 Nov;14(11):653\u0026ndash;66. \u003c/li\u003e\n\u003cli\u003eLauenroth A, Ioannidis AE, Teichmann B. Influence of combined physical and cognitive training on cognition: a systematic review. BMC Geriatr. 2016 Jul 18;16:141. \u003c/li\u003e\n\u003cli\u003eDemurtas J, Schoene D, Torbahn G, Marengoni A, Grande G, Zou L, et al. Physical Activity and Exercise in Mild Cognitive Impairment and Dementia: An Umbrella Review of Intervention and Observational Studies. J Am Med Dir Assoc. 2020 Oct;21(10):1415-1422.e6. \u003c/li\u003e\n\u003cli\u003eHu M, Hu H, Shao Z, Gao Y, Zeng X, Shu X, et al. Effectiveness and acceptability of non-pharmacological interventions in people with mild cognitive impairment: Overview of systematic reviews and network meta-analysis. J Affect Disord. 2022 Aug;311:383\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eLi KZH, Roudaia E, Lussier M, Bherer L, Leroux A, McKinley PA. Benefits of cognitive dual-task training on balance performance in healthy older adults. J Gerontol A Biol Sci Med Sci. 2010 Dec;65(12):1344\u0026ndash;52. \u003c/li\u003e\n\u003cli\u003eMarusic U, Verghese J, Mahoney JR. Cognitive-Based Interventions to Improve Mobility: A Systematic Review and Meta-analysis. J Am Med Dir Assoc. 2018 Jun;19(6):484-491.e3. \u003c/li\u003e\n\u003cli\u003eKarssemeijer EGA, Aaronson JA, Bossers WJ, Smits T, Olde Rikkert MGM, Kessels RPC. Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis. Ageing Res Rev. 2017 Nov;40:75\u0026ndash;83. \u003c/li\u003e\n\u003cli\u003eAli N, Tian H, Thabane L, Ma J, Wu H, Zhong Q, et al. The Effects of Dual-Task Training on Cognitive and Physical Functions in Older Adults with Cognitive Impairment; A Systematic Review and Meta-Analysis. J Prev Alzheimers Dis [Internet]. 2022 [cited 2024 Mar 26]; Available from: https://link.springer.com/article/10.14283/jpad.2022.16 \u003c/li\u003e\n\u003cli\u003eGavelin HM, Dong C, Minkov R, Bahar-Fuchs A, Ellis KA, Lautenschlager NT, et al. Combined physical and cognitive training for older adults with and without cognitive impairment: A systematic review and network meta-analysis of randomized controlled trials. Ageing Res Rev. 2021 Mar;66:101232. \u003c/li\u003e\n\u003cli\u003eBherer L, Gagnon C, Langeard A, Lussier M, Desjardins-Cr\u0026eacute;peau L, Berryman N, et al. Synergistic Effects of Cognitive Training and Physical Exercise on Dual-Task Performance in Older Adults. J Gerontol B Psychol Sci Soc Sci. 2021 Sep 13;76(8):1533\u0026ndash;41. \u003c/li\u003e\n\u003cli\u003eMontero-Odasso M, Almeida QJ, Burhan AM, Camicioli R, Doyon J, Fraser S, et al. SYNERGIC TRIAL (SYNchronizing Exercises, Remedies in Gait and Cognition) a multi-Centre randomized controlled double blind trial to improve gait and cognition in mild cognitive impairment. BMC Geriatr. 2018 Apr 16;18(1):93. \u003c/li\u003e\n\u003cli\u003eBruderer-Hofstetter M, Rausch-Osthoff AK, Meichtry A, M\u0026uuml;nzer T, Niedermann K. 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Advancing Computerized Cognitive Training for MCI and Alzheimer\u0026rsquo;s Disease in a Pandemic and Post-pandemic World. Front Psychiatry. 2020;11:557571. \u003c/li\u003e\n\u003cli\u003eCostanzo MC, Arcidiacono C, Rodolico A, Panebianco M, Aguglia E, Signorelli MS. Diagnostic and interventional implications of telemedicine in Alzheimer\u0026rsquo;s disease and mild cognitive impairment: A literature review. Int J Geriatr Psychiatry. 2020 Jan;35(1):12\u0026ndash;28. \u003c/li\u003e\n\u003cli\u003eZuschnegg J, Schoberer D, H\u0026auml;ussl A, Herzog SA, Russegger S, Ploder K, et al. Effectiveness of computer-based interventions for community-dwelling people with cognitive decline: a systematic review with meta-analyses. BMC Geriatr. 2023 Apr 12;23(1):229. \u003c/li\u003e\n\u003cli\u003eWalton CC, Mowszowski L, Lewis SJ, Naismith SL. Stuck in the mud: time for change in the implementation of cognitive training research in ageing? Front Aging Neurosci [Internet]. 2014 Mar 17 [cited 2024 Jul 8];6. Available from: https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2014.00043/full \u003c/li\u003e\n\u003cli\u003eLiu L, Wang H, Xing Y, Zhang Z, Zhang Q, Dong M, et al. Dose-response relationship between computerized cognitive training and cognitive improvement. NPJ Digit Med. 2024 Aug 15;7(1):214. \u003c/li\u003e\n\u003cli\u003eGates NJ, Vernooij RW, Di Nisio M, Karim S, March E, Mart\u0026iacute;nez G, et al. Computerised cognitive training for preventing dementia in people with mild cognitive impairment. Cochrane Database Syst Rev. 2019 Mar 13;3(3):CD012279. \u003c/li\u003e\n\u003cli\u003eChan AW, Tetzlaff JM, G\u0026oslash;tzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013 Jan 9;346:e7586. \u003c/li\u003e\n\u003cli\u003eLogsdon RG, Gibbons LE, McCurry SM, Teri L. 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Alzheimers Dement Diagn Assess Dis Monit. 2017 Jan 1;8:26\u0026ndash;35. \u003c/li\u003e\n\u003cli\u003eIsmail Z, Ag\u0026uuml;era-Ortiz L, Brodaty H, Cieslak A, Cummings J, Fischer CE, et al. The Mild Behavioral Impairment Checklist (MBI-C): A rating scale for neuropsychiatric symptoms in pre-dementia populations. J Alzheimers Dis JAD. 2017;56(3):929\u0026ndash;38. \u003c/li\u003e\n\u003cli\u003eChan ATC, Ip RTF, Tran JYS, Chan JYC, Tsoi KKF. Computerized cognitive training for memory functions in mild cognitive impairment or dementia: a systematic review and meta-analysis. Npj Digit Med. 2024 Jan 3;7(1):1\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eIrazoki E, Contreras-Somoza LM, Toribio-Guzm\u0026aacute;n JM, Jenaro-R\u0026iacute;o C, van der Roest H, Franco-Mart\u0026iacute;n MA. Technologies for Cognitive Training and Cognitive Rehabilitation for People With Mild Cognitive Impairment and Dementia. A Systematic Review. Front Psychol. 2020 Apr 9;11:648. \u003c/li\u003e\n\u003cli\u003eAlnajjar F, Khalid S, Vogan AA, Shimoda S, Nouchi R, Kawashima R. Emerging Cognitive Intervention Technologies to Meet the Needs of an Aging Population: A Systematic Review. Front Aging Neurosci. 2019 Oct 24;11:291. \u003c/li\u003e\n\u003cli\u003eGates NJ, Vernooij RW, Nisio MD, Karim S, March E, Mart\u0026iacute;nez G, et al. Computerised cognitive training for preventing dementia in people with mild cognitive impairment - Gates, NJ - 2019 | Cochrane Library. [cited 2024 Jun 20]; Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012279.pub2/full \u003c/li\u003e\n\u003cli\u003eChuang IC, Chiau HY, Liao WW, Wu YR, Chang CH, Wu CY. Effects of computer-based cognitive training combined with physical training for older adults with cognitive impairment: A four-arm randomized controlled trial. Digit Health. 2023 Jan 1;9:20552076231203633. \u003c/li\u003e\n\u003cli\u003eKang M, Ragan BG, Park JH. Issues in Outcomes Research: An Overview of Randomization Techniques for Clinical Trials. J Athl Train. 2008;43(2):215\u0026ndash;21. \u003c/li\u003e\n\u003cli\u003eMubarak F, Suomi R. Elderly Forgotten? Digital Exclusion in the Information Age and the Rising Grey Digital Divide. Inq J Health Care Organ Provis Financ. 2022 Jan 1;59:00469580221096272. \u003c/li\u003e\n\u003cli\u003eBell I, Pot-Kolder RMCA, Wood SJ, Nelson B, Acevedo N, Stainton A, et al. Digital technology for addressing cognitive impairment in recent-onset psychosis: A perspective. Schizophr Res Cogn. 2022 Jun 1;28:100247. \u003c/li\u003e\n\u003cli\u003eJeong HS, Lee YW, Rhee TG, Shim SR. Efficacy of digital therapeutic applications for cognitive training among older adults with mild cognitive impairment or dementia: A systematic review and network meta-analysis of randomized controlled trials. Psychiatry Res. 2025 Jun 1;348:116426. \u003c/li\u003e\n\u003cli\u003eLin X, Xu G, Zhao M, Jiang Y. Efficacy of different digital interventions in patients with mild cognitive impairment or dementia: A systematic review and network meta-analysis. Int J Nurs Stud. 2025 Sep 1;169:105129. \u003c/li\u003e\n\u003cli\u003eHe C, Chen K, Yu Y, Xiao Y, Zhang Y, Wu XV, et al. Effectiveness of digital interventions in middle-aged and older adults with mild cognitive impairment: A systematic review and meta-analysis of randomized controlled trials. Ageing Res Rev. 2026 Jan 1;114:102951. \u003c/li\u003e\n\u003cli\u003eBarasabha T, Hoefer L, Bennett M, Gallacher J, Holling H, Koychev I. Conventional versus Digital Cognitive Remediation Therapy: Meta- Analysis in People with Mild Cognitive Impairment and Dementia [Internet]. Research Square; 2025 [cited 2026 Feb 12]. Available from: https://www.researchsquare.com/article/rs-8224433/v1 \u003c/li\u003e\n\u003cli\u003eBaumel A, Muench F, Edan S, Kane JM. Objective User Engagement With Mental Health Apps: Systematic Search and Panel-Based Usage Analysis. J Med Internet Res. 2019 Sep 25;21(9):e14567. \u003c/li\u003e\n\u003cli\u003eTurunen M, Hokkanen L, B\u0026auml;ckman L, Stigsdotter-Neely A, H\u0026auml;nninen T, Paajanen T, et al. Computer-based cognitive training for older adults: Determinants of adherence. PLOS ONE. 2019 Jul 10;14(7):e0219541. \u003c/li\u003e\n\u003cli\u003eDemurtas J, Schoene D, Torbahn G, Marengoni A, Grande G, Zou L, et al. Physical Activity and Exercise in Mild Cognitive Impairment and Dementia: An Umbrella Review of Intervention and Observational Studies. J Am Med Dir Assoc. 2020 Oct 1;21(10):1415-1422.e6. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Mild cognitive impairment, Digital health intervention, Computerised cognitive training, Motor-cognitive training, Randomised controlled trial, Mobile health application, Dementia prevention, Cognitive decline","lastPublishedDoi":"10.21203/rs.3.rs-8885992/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8885992/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eMild cognitive impairment (MCI) is a prevalent neurocognitive disorder associated with an increased risk of progression to dementia. While pharmacological options remain limited and are not universally accessible, non-pharmacological interventions such as cognitive training and lifestyle modification show promise in slowing cognitive decline. Digitally delivered interventions offer advantages in scalability, accessibility, and personalisation, yet there is a lack of rigorously evaluated, multi-domain digital programmes for individuals with MCI. Five Lives MED is a novel digital motor-cognitive intervention combining computerised cognitive training, physical activity habit formation, and psychoeducation, delivered remotely via mobile devices.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a single-blind, multicentre, randomised controlled trial conducted in the United Kingdom and France. A total of 170 participants aged 50 years or older with a clinical diagnosis of MCI will be randomised in a 1:1 ratio to either the intervention group or a control group receiving standard lifestyle advice. The intervention consists of a 12-week home-based programme delivered through the Five Lives MED app, incorporating daily motor-cognitive training sessions, goal-oriented physical activity tasks, and optional educational content. Outcome assessments will be conducted at baseline (T0), post-intervention at 12 weeks (T1), and at 6-month follow-up (T2). The primary outcome is change in global cognitive function measured by the Montreal Cognitive Assessment. Secondary outcomes include domain-specific cognitive performance, quality of life, dementia literacy, activities of daily living, behavioural symptoms, physical activity, and exploratory digital cognitive measures. Analyses will be conducted on an intention-to-treat basis, with additional per-protocol analyses where appropriate.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis trial will be the first randomised controlled evaluation of Five Lives MED in individuals with MCI. By integrating cognitive training with physical activity and educational components in a fully remote format, the study aims to address key limitations of existing interventions related to accessibility and scalability. The findings will provide important evidence regarding the efficacy, feasibility, and clinical utility of a digital motor-cognitive intervention for MCI and will inform future implementation and larger-scale trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e: ​​ClinicalTrials.gov ID NCT06598163, first submitted on 2024-09-10, https://clinicaltrials.gov/study/NCT06598163?tab=study\u003c/p\u003e","manuscriptTitle":"The efficacy of a digital health app Five Lives MED to improve cognitive function in patients with mild cognitive impairment: study protocol for a randomised controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-23 09:28:46","doi":"10.21203/rs.3.rs-8885992/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-29T08:52:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-16T05:39:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-16T05:36:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2026-02-15T12:25:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"121d5beb-ffe0-43e4-8fe2-29fccadaf319","owner":[],"postedDate":"February 23rd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-04-29T08:52:51+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T12:08:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-23 09:28:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8885992","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8885992","identity":"rs-8885992","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}