Association between unhealthy lifestyle and dynamic transitions of neuropsychiatric disorders: A longitudinal trajectory analysis in UK Biobank

Association between unhealthy lifestyle and dynamic transitions of neuropsychiatric disorders: A longitudinal trajectory analysis in UK Biobank | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association between unhealthy lifestyle and dynamic transitions of neuropsychiatric disorders: A longitudinal trajectory analysis in UK Biobank Chao-Hua Cong, xin li, Shu-hong Wang, Yuan Qiao, Lei Zhao, Pan-Long Li, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9242207/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background The potential difference in the impacts of unhealthy lifestyle factors (LFs) on progression from healthy to first neurological and psychiatric disorders (NPDs), subsequently to neuropsychiatric multimorbidity (NPM), and further to death is unclear. We aimed to evaluate the associations between unhealthy lifestyle and dynamic transitions of NPDs. Materials and Methods This prospective study included 317,163 participants from the UK Biobank cohort. NPM was defined as the coexistence of at least two NPDs, including dementia, Parkinson disease, anxiety, depression and sleep disorders. We used multi-state model to analyse the impacts of unhealthy LFs (current smoking, unhealthy sleep duration and physical inactivity) on the progression of NPDs. Results During a median follow-up of 12.85 years, 35,010 participants developed at least one NPD, 5,865 developed NPM and 20,932 died afterwards. Unhealthy LFs played crucial but different roles in all transitions from healthy to NPD, to NPM, and then to death. The hazard ratios (95% confidence intervals) per one-factor increase were 1.08 (1.07, 1.10) and 1.04 (1.00, 1.16) for transitions from healthy to NPD, and from first NPD to NPM, and 1.34 (1.32, 1.37), 1.23 (1.18, 1.28) and 1.26 (1.15, 1.39) for mortality risk from healthy, NPD and NPM, respectively. When we further divided NPD into dementia, Parkinson disease, anxiety, depression and sleep disorders, the associations of single and combined unhealthy LFs with NPD transitions varied depending on disease types and specific combinations of unhealthy LFs, even within the same transition stage. Conclusion Unhealthy LFs play important roles in nearly all transitions of NPD progression, highlighting the significance of LFs management for the prevention and control of NPDs. neuropsychiatric disorders multimorbidity progression lifestyle prospective cohort study Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Neurological and psychiatric diseases (NPDs) are increasingly recognised as major causes of death and disability 1–3 , affecting approximately 450 million people worldwide 4 . NPDs are typically intercorrelated and tend to co-exist in individuals 5–8 , due to shared risk factors and pathophysiology 9–10 , termed neuropsychiatric multimorbidity (NPM). Compared with isolated NPDs, NMP is suggested to be associated with poorer quality of life, worse health outcomes and higher healthcare costs 11–12 . Therefore, it is critical to identify the risk factors that drive the onset and progression of NPDs to NPM and to implement early preventive interventions. Unhealthy lifestyle factors (LFs) such as smoking 13–15 ,unhealthy sleep duration 16–18 , physical inactivity 19–21 are well-recognized risk factors for single NPD. However, their potential influence on the dynamic transitions of NPDs remains poorly understood. Although LFs may influence every stage of the NPD trajectory—from a healthy state to a single NPD, then to NPM, and ultimately to death—previous works have examined only the first transition (health→single NPD). This narrow focus underestimates the overall impact of LFs on the dynamic course of these disorders and obscures the roles that LFs might play at later stages of progression. Clarifying how LFs relates to the incidence, progression, and prognosis of NPDs would extend current knowledge of lifestyle–NPD links and inform targeted prevention and intervention strategies. Moreover, since the etiological pathways underlying individual NPDs are distinct, whether LFs are differentially associated with disease specific transitions remains to be elucidated. Therefore, we aimed to examine the associations of single and combined LFs with NPDs, NPM and death in the large UK Biobank cohort. Importantly, we used multi-state model to investigate the potentially different impacts of LFs on transitions from free of NPD to first neuropsychiatric disease (FNPD), subsequently to NPM and further to death. In line with previous study 22 , we limited NPDs to dementia, Parkinson disease, anxiety, depression and sleep disorders. Because of the large number of cases, we further examined the role of LFs in all possible transitions between healthy and individual NPDs, as well as individual NPDs to NPM and death. Methods Study design and participants The UK Biobank is a prospective, population-based cohort that recruited over 500,000 participants aged 40 to 70 years from England, Scotland, and Wales between 2006 and 2010 23 . Participants completed touchscreen and nurse-led questionnaires, underwent physical measurements, and provided biological samples at recruitment. This study was conducted in accordance with the Declaration of Helsinki. Ethical approval was granted by the North West Multicenter Research Ethics Committee, and all participants provided written informed consent. Of the participants in the UK Biobank study, we excluded those with a prior diagnosis of dementia, anxiety, depression and Parkinson disease (n = 69,461), those without complete data on smoking, sleep duration and physical activity (n = 87,693), those with a diagnosis of cancer (n = 28,053). Ultimately, 317,163 participants constituted the study population for the association analyses (Figure S1 ). Prevalent neuropsychiatric diseases were identified based on self-reported medical conditions, primary care data and hospital inpatient records. Definition of high-risk lifestyle factors We considered three modifiable LFs—smoking, sleep duration, and physical activity. Alcohol consumption was not included in the LFs because its impact on neuropsychiatric disorders and mortality varies depending on the type of beverage, dosage, duration, genetic predisposition, and baseline health status 24–26 . For smoking status, we assigned current smokers to the high-risk group 13 . Because both short and long sleep duration have been associated with a higher risk of dementia 27–28 , sleep duration of less than 7 hours or more than 9 hours per day was classified as unhealthy category. Insufficient physical activity was defined as less than 150 minutes per week of moderate-intensity activity, or less than 75 minutes per week of vigorous-intensity activity, or an equivalent combination of both 29 . The number of high-risk LFs was counted, ranging from 0 to 3. Ascertainment of outcome In the UK Biobank cohort, five NPDs were identified based on diagnostic codes from the 10th revision of the International Classification of Diseases (ICD 10): dementia (F00-F03, G30), PD (G20-G23), anxiety (F40-F43), depression (F32-F34, F38-F39) and sleep disorders (F51, G47). These diseases were selected due to their close relationships with LFs in previous studies, as well as their relatively high prevalence in the population 13,30 . Incident deaths were ascertained via linkage to the NHS Information Centre (England and Wales) and the NHS Central Register (Scotland). NPM was defined as co-occurrence of at least two of the above NPDs. Covariates Covariates for this analysis were collected via questionnaire or face-to-face interview and comprised age, sex, ethnicity (white or other), education (college/university degree or other), employment status (currently working, retired, or other), annual household income (high: ≥ £52,000; medium: £18,000–£51,999; low: < £18,000), the Townsend Deprivation Index (TDI; a lower score indicates higher socioeconomic status), body mass index (BMI), healthy drinking, healthy diet score, diabetes, prior stroke and high blood pressure. BMI was calculated by dividing weight (kg) by height squared (m 2 ). Healthy drinking was defined as moderate alcohol intake: ≤ 1 drink (14 g)/day for women and ≤ 2 drinks (28 g)/day for men 31 . The diet score (0–5) awarded 1 point for each of the following: vegetable intake ≥ median, fruit intake ≥ median, fish intake ≥ median, red meat < median, and processed red meat < median 32 . Statistical analyses Baseline characteristics of the analytic sample were summarized as percentage for categorical variables and mean (SD) for continuous variables. Multiple imputations by chained equation (MICE) method were used to handle missing covariates. Follow-up time was calculated from enrolment to the date of outcome diagnosis, death, or the censoring date (January 30, 2022), whichever came first. Models were adjusted for age, sex, education, ethnicity, TDI, BMI, household income, employment status, healthy drinking, healthy diet score, hypertension, diabetes status and stroke history. We employed Cox proportional hazards regression to quantify the hazard ratios (HRs) and corresponding 95% CIs for associations between LFs (separately or jointly) and FNPDs, NPM and all-cause mortality. In evaluating individual LFs, all other LFs were mutually adjusted. For combined exposure analyses, the number of LFs was included as a categorical variable. To determinethe HR for the events per one-factor increase in LFs, the number of LFs was fitted as an ordinal variable in a separate model. We further explored specific two LFs combinations, controlling for relevant confounders and any lifestyle components not comprising the dyad being tested. To evaluate how individual and combined LFs influence temporal progression from free of NPDs to FNPD, NPM, and death, we used multi-state model. This analytical approach extends competing risks methodology to delineate factor-specific effects across distinct disease trajectory phases 33 . We specified five transitions based on the natural history of NPM and prior research 22 (Transition Pattern A, Fig. 1 ): healthy baseline to FNPD; FNPD to NPM; baseline healthy to all-cause mortality; FNPD to death and NPM to death. The date of NPM was defined as the date of second NPD diagnosis. When participants entered multiple states simultaneously (n = 1,858), we temporally ordered these events by assigning antecedent states entry dates 0.5 days prior to subsequent states 34 . We also used the multi-state model with the same setting to analyse the effects of LFs on different pathways from baseline to NPM, and to the absorbing state—death. We divided the NPDs into five individual diseases, i.e., dementia, PD, anxiety, depression and sleep disorders, resulting in 17 transitions (transition pattern B, Fig. 2 ). In this disease-specific analysis, NPM was redefined as having two of five individual diseases. Because the temporal sequence of disease occurrence could not be ascertained if a participant was diagnosed with at least two of dementia, PD, anxiety, depression and sleep disorders on the same date, we excluded them, leaving 315,305 participants in this analysis. The multistate analyses of the transition pattern A were further stratified according to sex, age, employment, education and healthy drinking. The interactions were tested by using the likelihood ratio test comparing models with and without a cross-product term. We conducted several sensitivity analyses for the multi-state model of transition pattern A: (i) for participants who transitioned to multiple disease states simultaneously, we varied the entry time of the prior state using intervals of 0.5, 1, 3, and 5 years; (ii) we omitted participants with concurrent transitions to different states; (iii) models were further adjusted for lipid profiles (total cholesterol and triglycerides) and inflammatory markers (C-reactive protein); and (iv) events occurring during the initial 2-year follow-up were excluded. All statistical analyses were performed using R software (version 4.2.2). The multi-state models were constructed using the ‘mstate’ package. Two-tailed P < 0.05 indicated statistical significance. Results Descriptive analysis A total of 317,163 participants with complete data were included in this study; the mean age at baseline was 56.0 [SD 8.1] years, and 48.5% were male. During a median follow-up of 12.6 years, 35,010 participants (11.0%) experienced at least one NPD (Fig. 1 A). Of all incident NPDs patients, 5,865 (16.8%) developed NPM, and afterward, 20,932 died from any causes; 16,878 died without experiencing NPDs. In the separate analysis for individual diseases (transition pattern B; 1,858 participants were excluded), 3,893 participants (1.2% of the baseline healthy participants) had dementia, 1,743 (0.5%) had PD, 13,147 (4.2%) had anxiety, 11,985 (3.8%) had depression and 6,648 (2.1%) had sleep disorders, and 791 (20.5%), 518 (29.7%), 3,096 (23.3%), 3,097 (25.8%) and 796 (12.0%) of them developed NPM later respectively (Fig. 2 ). Compared with cases whose FNPD was PD, anxiety, depression, or sleep disorders, cases whose FCMD was dementia were more likely to die afterwards, with 1,963 (50.4%) died during follow-up. Participants who experienced one or more NPDs were more likely to be older and to have a higher degree of socioeconomic deprivation, lower education levels, higher BMI and to have hypertension and prior stroke than survivors free of NPDs (Table S1 ). Cox regression analyses All three high-risk LFs were associated with an increased risk of FNPD, NPM, and all-cause death (Table S2 ). Unhealthy sleep showed the strongest associations with FCMD and NPM [HRs (95%CIs):1.12 (1.09,1.15), 1.11 (1.05,1.18)], whereas smoking exhibited the strongest association with mortality [HR (95% CI): 2.29 (2.21, 2.38)]. Upward trends were observed for risks of FNPD, NPM, and death with an increasing number of high-risk LFs; the corresponding HRs (95% CIs) per one-factor increase was 1.08 (1.07, 1.10), 1.06 (1.03, 1.10), and 1.36 (1.33, 1.38), respectively. Individuals with concurrent smoking and unhealthy sleep had the highest risk of FNPD, NPM and death (HRs (95% CIs): 1.21 (1.14, 1.27), 1.20 (1.05, 1.38), and 2.41 (2.28, 2.55)). In general, the associations for transition to FNPD and death were slightly stronger than those for transition to NPM. Multi-state analyses Consistent with Cox regression results, multi-state modeling revealed comparable findings for baseline to FNPD progression while delineating distinct temporal contributions of high-risk LFs to NPM development (Fig. 3 A). Smoking, unhealthy sleep patterns, and physical inactivity exerted more pronounced effects on FNPD incidence than on subsequent NPM acquisition. Except for unhealthy sleep, the remaining two LFs demonstrated comparable HR for mortality risk regardless of whether participants transitioned from FNPD or NPM. Notably, smoking exhibited stronger associations with mortality outcomes (from healthy baseline, FNPD, or NPM) than with non-fatal disease progression. Combined LFs demonstrated dose-response relationships with all five state progressions (Fig. 3 B). The number of high-risk LFs exhibited stronger associations with initial FNPD development than with subsequent NPM progression, while mortality risk estimates were comparable regardless of whether death followed FNPD or NPM. Specifically, each additional risk factor conferred adjusted HR (95% CIs) of 1.08 (1.07, 1.10) for baseline to FNPD progression, 1.04 (1.00, 1.16) for FNPD to NPM conversion, and 1.34 (1.32, 1.37), 1.23 (1.18, 1.28), and 1.26 (1.15, 1.39) for mortality from baseline, FNPD, and NPM, respectively. Among pairwise combinations, the "smoking plus unhealthy sleep" dyad conferred the highest risk for both incident FNPD and disease progression. Notably, any pair involving smoking demonstrated uniformly strong associations with fatal outcomes across all baseline health states (Fig. 4 ). Stratification by specific disease (dementia, PD, anxiety, depression, and sleep disorders) revealed that smoking exhibited preferential associations with mortality, dementia, and sleep disorders relative to PD, anxiety, or depression (Table 1). Unhealthy sleep demonstrated attenuated effects on progression from FCMD to NMP compared with other trajectories. Physical inactivity specifically elevated PD and sleep disorder risks, concurrently increasing mortality likelihood from baseline or depression/sleep disorder states. Joint exposure analyses further indicated dose-response gradients across all transitions except progression to NPM (Table 2). For incident disease development, dementia and sleep disorders manifested the strongest susceptibility to most lifestyle dyads, though their influences on subsequent NPM and mortality varied markedly by specific disease type (Table 3). Sensitivity and stratified analyses Results remained robust across sensitivity analyses (Tables S3 and S4). While stratified analyses detected several significant interactions, most lacked clinical relevance (Figures S3 and S4). Age demonstrated significant effect modification on lifestyle factor-disease trajectories, albeit with inconsistent directions across transitions. Females exhibited heightened vulnerability to FNPD-related mortality compared with males. Obesity conferred divergent risks: elevated for baseline-to -FNPD progression but attenuated for FNPD-to-death transition. Education and healthy drinking showed limited modifying effects, influencing only one of five trajectories. Discussion In this large-scale prospective cohort study of over 317,000 participants from the UK Biobank, we comprehensively evaluated the associations between modifiable unhealthy LFs and dynamic transitions across the NPD trajectory—from a disease-free state to FNPD, subsequently to NPM, and ultimately to death—using multi-state modeling. Several key findings emerged. First, unhealthy LFs were significantly associated with nearly all transition stages in the NPD continuum. Second, the magnitude of associations differed across stages, with stronger effects observed for the transition from healthy status to FNPD than from FNPD to NPM. Third, lifestyle burden demonstrated a graded relationship with both morbidity and mortality transitions. Finally, when specific NPDs were examined separately, the influence of individual and combined LFs varied substantially across disease types and transition pathways. The adverse effects of LFs on the incidence of neurological or psychiatric disorders have been previously demonstrated 35-38 . Findings from aprospective cohort of 50,000 UK participants revealed hazardous impacts of smoking or sleep characteristics on developing dementia, PD, major depression and anxiety. A study conducted in the cohort of 106,527 Norwegian participants found that sleep and physical activity were associated with both depression and anxiety. Compared with participants who slept 7–8 h and exercised ≥3 times/week, the HRs (95% CIs) for those with slept ≤5 h and were almost physically inactive were 1.97 (1.83, 2.25) and 1.74 (1.63,1.87) for depression and anxiety, respectively. Moreover, several studies have reported that unhealthy LFs elevate the risk of depression and anxiety in individuals with PD, which suggests that LFs may play a role in the transition from FNPD to NPM. Nevertheless, some limitations in previous studies merit consideration. First, these studies merely analyse the association between LFs and a single-disease stage. It is difficult to ascertain whether lifestyle factors exert stage-specific effects across the neuropsychiatric trajectory—from healthy to FNPD, from FNPD to NPM, and from NPM to death—when these transitions are analyzed separately. Moreover, because lifestyle factors are strongly associated with mortality, death constitutes a competing event that precludes subsequent progression to NPM. Treating death as non-informative censoring in conventional Cox models may violate the independent censoring assumption and bias risk estimates, thereby obscuring the true stage-specific associations 39 .Third, although neurological and psychiatric disorders are closely interrelated, the potential role of LFs in the development of their multimorbidity is typically overlooked and demands further clarification. By applying a multi-state framework that explicitly models intermediate disease states and competing mortality risk, our study extends existing literature in several important ways. We demonstrate that LFs influence not only primary disease incidence but also subsequent multimorbidity accumulation and survival outcomes. Importantly, the relative contribution of LFs was more pronounced in the early transition (healthy to FNPD) than in later progression (FNPD to NPM), suggesting that lifestyle exposures may exert stronger etiological effects in disease initiation than in disease clustering. In addition to LFs, a range of other factors affect the progression from FNPD to NPM. They may cover up the relative importance of LFs in determining the risk of developing NPM, to some extent. A study conducted in the cohort of 402,950 UK participants concluded that cardiometabolic multimorbidity accelerates progression from FNPD to NPM 22 . Anemia, hypothyroidism, social isolation, and hearing loss markedly increase the probability of neuropsychiatric symptoms in Alzheimer’s disease, while dopaminergic medications significantly raise the risk of hallucinations and delusions in Parkinson’s disease 41-42 . Nonetheless, LFs remained critical determinants of NPM onset. Our findings corroborate their established role in primary disease prevention while highlighting potential for secondary intervention to prevent NPM progression. Amidst ageing populations facing escalating multimorbidity and polypharmacy, behavioral modifications offer a cost-effective strategy to attenuate medication burden and healthcare costs. Previous studies showed a cumulative effect of LFs on the incidence of dementia, PD, depression and anxiety disorders 13,16,35 . In this study, we have extended these findings from a single disease to multimorbidity. Participants with three high-risk LFs were roughly 25% more likely to develop both FNPD and NPM than those with only one, underscoring the vast preventive potential of lifestyle interventions across the entire disease trajectory. Stratified analysis further showed that LFs had a greater impact on the risk of transition to death among middle-aged participants compared with older adults. It is probably due to the relatively higher baseline hazard for older participants and the those most vulnerable to death have already died before enrollment (survival effect), leaving a healthier, lower-risk elderly cohort. Greater residual lifespan and modifiable risk burden in middle-aged individuals, allowing lifestyle changes to exert a larger relative effect on delayed mortality. These findings indicate greater significance in strengthening lifestyle interventions among younger adults. Unlike previous studies constrained by limited sample sizes, our investigation enabled comprehensive delineation of LFs roles across the complete disease spectrum—encompassing transitions from health to five specific disease, their subsequent progression to NPM, and ultimate mortality. Results indicate that single LF manifest distinct influences at different disease stages. Smoking, for instance, increased the risk of almost all morbidity outcomes yet showed no significant association with incident NPM in patients with FNPDs. Moreover, even within the same transition stage, individual LFs influenced disease-specific pathways differently. For example, physical inactivity was linked more strongly to incident PD and sleep disorders than to dementia, anxiety or depression. In contrast, our study observed that unhealthy sleep played roles in basically all transitions to death, suggesting a universal benefit of healthy sleep. The present study provides evidence from a large-scale, uniquely UK-based cohort—a well-represented population operating under the same health-care system as most developed countries where previous research was conducted. The principal strength of this study is the application of multi-state modeling, which enabled stage-specific estimation of LFs effects across the neuropsychiatric trajectory while accounting for competing mortality risk. Leveraging a large prospective cohort with over 12 years of follow-up, we were able to model transitions from health to individual FNPDs, subsequent NPM, and death. The substantial sample size, diverse population, comprehensive covariate adjustment, and extensive sensitivity analyses further enhance the robustness and internal validity of the findings. Some limitations characterize the present study. First, LFs were assessed at baseline and the associations of LFs with NPD progression could not be assessed. However, the previous study has analyzed participants who attended both the baseline survey and the follow-up resurvey. During a median interval of about 8 years, most individuals did not change their lifestyle risk level 34 . The use of baseline lifestyle data also helps avoid reverse causation resulting from lifestyle changes that occur after disease onset. Second, although we used diagnostic information from multiple sources, some cases of NPDs might still have been missed. Third, this study did not collect information on NPDs treatment, and medication adherence may correlate with adherence to a healthy lifestyle. However, we adjusted for education as a proxy for multiple health-related behaviors, so residual confounding from treatment is unlikely to fully account for the observed associations between LFs and the transition from FNPDs to NPM and subsequent mortality 42 . Fourth, some participants were diagnosed with two NPMs simultaneously in one admission, causing the same diagnosis date for both NPMs. For participants entering multiple disease states on the same date, a 0.5-day interval was assigned to define FNPD onset, which may have introduced minor temporal misclassification. However, alternative interval specifications and exclusion of these individuals did not materially alter the results. Fifth, given the observational design, causality cannot be inferred. Although evidence from Mendelian randomization studies and randomized trials supports a potential causal role of lifestyle factors35,43-45, the underlying mechanisms remain to be clarified. Self-reported exposures and residual confounding may also have influenced the estimates. In this large prospective cohort, unhealthy lifestyle burden was associated with stage-specific transitions across the neuropsychiatric disease spectrum, exerting stronger effects on disease onset and mortality than on NPM accumulation. These findings support a model in which modifiable systemic exposures shape neurobiological vulnerability and long-term survival across neuropsychiatric disorders. Declarations ACKNOWLEDGEMENTS We thank all participants and staff in the UK Biobank for their dedication and contribution to this study. ETHICS AND CONSENT TO PARTICIPATE This study was conducted in accordance with the Declaration of Helsinki. Ethical approval for the UK Biobank study was granted by the North West Multicenter Research Ethics Committee. All participants provided written informed consent at the time of recruitment, agreeing to the collection and use of their biological samples, health data, and linkage to health records for approved research purposes. The UK Biobank has obtained ethics approval from the National Information Governance Board for Health and Social Care and the National Health Service National Research Ethics Service. FUNDING INFORMATION This study was supported by Fundamental research program funding of Ninth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JYZZ286) and the National Natural Science Foundation of China (82571480, 82071282 and 82201572). The funders of the study had no role in study design, data collection, analysis, decision to publish or manuscript preparation. AUTHOR CONTRIBUTIONS J.J.S. and J.R.L. conceived the study and contributed to the interpretation of the results. Concept and design: J.J.S., J.R.L., C.H.C., and X.L. Analyses and drafting of the manuscript: C.H.C., X.L, P.L.L.,Y.Q., S.H.W, and L.Z. Critical revision of the manuscript: Y.N.L., Y.Q., S.H.W. Administrative, technical, or material support: Y.N.L., S.T.. All authors had access to the data in the study and had final responsibility for the decision to submit for publication. CONFLICT OF INTEREST STATEMENT The authors declare no competing interests. AVAILABILITY OF DATA AND MATERIALS https:// www. ukbio bank. ac. uk. The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. References Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the global burden of disease study 2010. Lancet. 2013;382:1575-1586. Collaborators. Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2019;18:459-480. GBD 2016 Parkinson's Disease Collaborators. Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the global burden of disease study 2016. 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Published 2025 Jul 28. doi:10.1177/17562864251356062 Boffetta P. Causation in the presence of weak associations. *Crit Rev Food Sci Nutr*. 2010;50(sup1):13-16. doi:10.1080/10408398.2010.526842 Zhao Y, Yang L, Sahakian BJ, et al. The brain structure, immunometabolic and genetic mechanisms underlying the association between lifestyle and depression. *Nat Ment Health*. 2023;1:736-750. doi:10.1038/s44220-023-00120-1 Firth J, Solmi M, Wootton RE, et al. A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders. World Psychiatry. 2020;19(3):360-380. doi:10.1002/wps.20773 Walburg FS, van Meijel B, Hoekstra T, et al. Effectiveness of a lifestyle intervention for people with a severe mental illness in Dutch outpatient mental health care: a randomized clinical trial. *JAMA Psychiatry*. 2023;80(9):886-894. doi:10.1001/jamapsychiatry.2023.1566 Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files table1.docx Table 1. Hazard ratios (95%CIs) for each transition in transition pattern B by LFs among 317,165 participants. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. Number of events refers to number of cases in each transition. For analyses of dichotomous LFs, three LFs were mutually adjusted. Values shown in bold are statistically significant (P<0.05). Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status. Abbreviations: CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; PD, Parkinson disease; LFs, lifestyle factors. table2.docx Table 2. Hazard ratios (95%CIs) for each transition in transition pattern B by number of high-risk LFs among 317,165 participants. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. When the number of LFs was included as a categorical variable, the reference group was those having no unhealthy LFs. Values shown in bold are statistically significant (P<0.05). Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status. Abbreviations: CI, confidence interval; FNPD, firstneuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; PD, Parkinson disease; LFs, lifestyle factors. table3.docx Table 3. Hazard ratios (95% CIs) for each transition in transition pattern B by dyads of high-risk LFs among 317,165 participants. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status and presence of any other LFs not included in dyad. Abbreviations: CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; PD, Parkinson disease; LFs, lifestyle factors. figureS1.png Figure S1. Flowchart of the study. fiureS2.png Figure S2. Subgroup analysis of associations of the number of LFs with morbidity transitions among 317,163 participants. A: transition from baseline to FNPD; B: transition from FNPD to NPM. CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; LFs, lifestyle factors. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status. figureS3.png Figure S3. Subgroup analysis of associations of the number of LFs with morbidity transitions among 317,163 participants. A: transition from baseline to death; B: transition from FNPD to death; C: transition from NPM to death. CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity;LFs, lifestyle factors. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status. tableS1.docx Table S1. Baseline characteristics of 317,163 participants in the UK Biobank cohort by incident disease status during follow-up. TDI, Townsend deprivation index; BMI, body mass index; NPD, neuropsychiatric diseases; FNPD, first neuropsychiatricdiseases disease; NPM, neuropsychiatric multimorbidity. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as occurring at least two of the above-mentioned diseases. tableS2.docx Table S2. HRs (95% CIs) for incident first neuropsychiatric disease, neuropsychiatric multimorbidity, and all-cause mortality by LFs among 317,163 participants. HR, hazard ratio; CI, confidence interval; LFs, lifestyle factors. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as occurring at least two of the above-mentioned diseases. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, stroke history, hypertension status, diabetes status. For analyses of individual LFs, three LFs were mutually adjusted. For analyses of dyads of LFs, models were additionally adjusted for presence of any other LFs not included in dyad. tableS3.docx Table S3.Sensitivity analysis of associations of individual LFs with transitions of neuropsychiatric diseases among 317,163 participants. CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; LFs, lifestyle factors. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. A series of sensitivity analyses were conducted: (1) calculating the entering date of the prior state using different time intervals (0.5-day, 0.5-year, 1-year, 3-year, 5-year) for participants who entered different states on the same day; (2) excluding participants who entered different states on the same date; (3) additionally adjusting for total cholesterol, triglyceride and C-reactive protein; (5) excluding the events occurring in the first two years follow-up. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status and three LFs were mutually adjusted. tableS4.docx Table S4. Sensitivity analysis of associations of the number of high-risk LFs with transitions of neuropsychiatric diseases among 317,163 participants. CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; LFs, lifestyle factors. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. A series of sensitivity analyses were conducted: (1) calculating the entering date of the prior state using different time intervals (0.5-day, 0.5-year, 1-year, 3-year, 5-year) for participants who entered different states on the same day; (2) excluding participants who entered different states on the same date; (3) additionally adjusting for total cholesterol, triglyceride and C-reactive protein; (5) excluding the events occurring in the first two years follow-up. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 03 May, 2026 Reviewers agreed at journal 17 Apr, 2026 Reviewers agreed at journal 17 Apr, 2026 Reviewers invited by journal 17 Apr, 2026 Editor invited by journal 30 Mar, 2026 Editor assigned by journal 28 Mar, 2026 Submission checks completed at journal 28 Mar, 2026 First submitted to journal 27 Mar, 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. 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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-9242207","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":627838269,"identity":"2ec8d431-4594-42eb-8f0f-826a12449ae7","order_by":0,"name":"Chao-Hua Cong","email":"","orcid":"","institution":"Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chao-Hua","middleName":"","lastName":"Cong","suffix":""},{"id":627838270,"identity":"1cc8e942-39e2-43a5-ae82-1c264d78ac74","order_by":1,"name":"xin li","email":"","orcid":"","institution":"Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"xin","middleName":"","lastName":"li","suffix":""},{"id":627838271,"identity":"65ed1d81-1162-445c-a9f0-cc11c13bc562","order_by":2,"name":"Shu-hong Wang","email":"","orcid":"","institution":"Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shu-hong","middleName":"","lastName":"Wang","suffix":""},{"id":627838272,"identity":"c0758960-010d-47a0-8175-403d66dbcf2b","order_by":3,"name":"Yuan Qiao","email":"","orcid":"","institution":"Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Qiao","suffix":""},{"id":627838273,"identity":"79ecad96-79aa-4a22-b9b4-08d50f2df658","order_by":4,"name":"Lei Zhao","email":"","orcid":"","institution":"Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Zhao","suffix":""},{"id":627838274,"identity":"2d513c67-2242-44a0-a9f0-37d8af5f8c4d","order_by":5,"name":"Pan-Long Li","email":"","orcid":"","institution":"Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pan-Long","middleName":"","lastName":"Li","suffix":""},{"id":627838275,"identity":"b5b7c030-3b63-4a0c-bf35-84f49d382092","order_by":6,"name":"Shan Tian","email":"","orcid":"","institution":"Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shan","middleName":"","lastName":"Tian","suffix":""},{"id":627838276,"identity":"cd733244-1205-4eda-afb1-740f7e1adc40","order_by":7,"name":"Yu-Na Li","email":"","orcid":"","institution":"Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yu-Na","middleName":"","lastName":"Li","suffix":""},{"id":627838277,"identity":"78135e25-ddde-49a3-8eb5-c3d0064ceb75","order_by":8,"name":"Jian-Ren Liu","email":"","orcid":"","institution":"Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jian-Ren","middleName":"","lastName":"Liu","suffix":""},{"id":627838278,"identity":"1b98ad52-65b6-4bbb-af47-b8bb2c11f66c","order_by":9,"name":"Jing-Jing Su","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYBACxmYgIWEAYjIfOJBgYMPDz99AtBa2xAcfKtJkJGccINpCHmPDGWcO2xg0JOBXx9zOe/iFRcEdu/kzEsykedvO8xgwHGD88DEHn8P40iwkDJ4lb7iRkAbUcpvHnLmBWXLmNnxaeMwMJAwOJxtIJBwDa7FsOMDGzEuMFvkZiW1ALed4DA4kENRi/ACoxY7hRjIz0PsHiNJiBgzkwwkGZ54xAgM5mUdyxsFmvH4x7D9j/Fniz2F7+fb8D8CotLPn528++OEjPi0NDGzSEgwMiQ1INjfgUg0G8sCo+fiBgcEer6pRMApGwSgY2QAAc1ZTutf9Ue8AAAAASUVORK5CYII=","orcid":"","institution":"Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jing-Jing","middleName":"","lastName":"Su","suffix":""}],"badges":[],"createdAt":"2026-03-27 08:38:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9242207/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9242207/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107872223,"identity":"2f671fae-e770-4576-b95f-660fa1893ef1","added_by":"auto","created_at":"2026-04-27 07:56:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38861,"visible":true,"origin":"","legend":"\u003cp\u003eNumbers (percentages) of participants in transition pattern A from baseline to first neuropsychiatric disease (FNPD), neuropsychiatric multimorbidity (NPM), and death. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity defined as the occurrence of at least two of the above-mentioned diseases.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/500874fd63be4c2be674baeb.png"},{"id":107873034,"identity":"af650777-9bab-4c57-af6f-597ca7e22000","added_by":"auto","created_at":"2026-04-27 08:01:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":235876,"visible":true,"origin":"","legend":"\u003cp\u003eNumbers (percentages) of participants in transition pattern B from baseline to one of the specific neuropsychiatric diseases, then to neuropsychiatric multimorbidity (NPM), and subsequently to death. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases.\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/544487693e185cfb06dbc124.png"},{"id":107871273,"identity":"09c0d8da-4d5f-4552-a9c7-cff93f64b030","added_by":"auto","created_at":"2026-04-27 07:47:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":135245,"visible":true,"origin":"","legend":"\u003cp\u003eHazardratios (95% CIs) for transition pattern A by lifestyle factors (LFs) (A) and number of LFs (B) among 317,165 participants. CI, confidence interval; \u0026nbsp;FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above mentioned diseases. Number of cases refers to number of cases in each transition with the corresponding exposure. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/467ced9992701d8d3881e88d.png"},{"id":108006135,"identity":"2296b1d7-2afc-47e4-a654-5f59641d7b31","added_by":"auto","created_at":"2026-04-28 12:53:54","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":77407,"visible":true,"origin":"","legend":"\u003cp\u003eHazard ratios (95%CIs) for transition pattern A by dyads of LFs among 317,165 participants. CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; LFs, lifestyle factors. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status and presence of any other LFs not included in the dyad.\u003c/p\u003e","description":"","filename":"fiure4.png","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/fe5ee7c1e20be4316499454e.png"},{"id":108185122,"identity":"c95499c9-8cf4-433e-8a20-e495dae7c739","added_by":"auto","created_at":"2026-04-30 09:05:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":601269,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/9dbf7240-573f-4208-b6df-7f09f7348a0e.pdf"},{"id":107872087,"identity":"89e388aa-0eae-4973-ae35-30377f6f5f4d","added_by":"auto","created_at":"2026-04-27 07:55:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14561,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Hazard ratios (95%CIs) for each transition in transition pattern B by LFs among 317,165 participants. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. Number of events refers to number of cases in each transition. For analyses of dichotomous LFs, three LFs were mutually adjusted. Values shown in bold are statistically significant (P\u0026lt;0.05). Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status. Abbreviations: CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; PD, Parkinson disease; LFs, lifestyle factors.\u003c/p\u003e","description":"","filename":"table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/17a84e3cb100f8cd3a100b10.docx"},{"id":107872187,"identity":"5ddab042-9144-4ae5-8a68-bc340d1975ca","added_by":"auto","created_at":"2026-04-27 07:56:00","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":15555,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Hazard ratios (95%CIs) for each transition in transition pattern B by number of high-risk LFs among 317,165 participants. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. When the number of LFs was included as a categorical variable, the reference group was those having no unhealthy LFs. Values shown in bold are statistically significant (P\u0026lt;0.05). Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status. Abbreviations: CI, confidence interval; FNPD, firstneuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; PD, Parkinson disease; LFs, lifestyle factors.\u003c/p\u003e","description":"","filename":"table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/509788d8470b13c6c3cbc74a.docx"},{"id":108006334,"identity":"588620e2-86dd-437a-9aad-3cb7d0e5a462","added_by":"auto","created_at":"2026-04-28 12:55:12","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":14823,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Hazard ratios (95% CIs) for each transition in transition pattern B by dyads of high-risk LFs among 317,165 participants. Neuropsychiatric diseases included dementia, Parkinson disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status and presence of any other LFs not included in dyad. Abbreviations: CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; PD, Parkinson disease; LFs, lifestyle factors.\u003c/p\u003e","description":"","filename":"table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/80838d17efcc58222d2323ea.docx"},{"id":107871204,"identity":"a5316217-5e9a-4522-a9ae-888ce9307c21","added_by":"auto","created_at":"2026-04-27 07:47:13","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":65677,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S1. \u003c/strong\u003eFlowchart of the study.\u003c/p\u003e","description":"","filename":"figureS1.png","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/3a738b7c97c374906f7f14fb.png"},{"id":107871247,"identity":"ea7d4a15-0355-4334-bd2c-1a0c8d2ca181","added_by":"auto","created_at":"2026-04-27 07:47:48","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":85375,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S2. \u003c/strong\u003eSubgroup analysis of associations of the number of LFs with morbidity transitions among 317,163 participants.\u003c/p\u003e\n\u003cp\u003eA: transition from baseline to FNPD; B: transition from FNPD to NPM.\u003c/p\u003e\n\u003cp\u003eCI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; LFs, lifestyle factors.\u003c/p\u003e\n\u003cp\u003eNeuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases.\u003c/p\u003e\n\u003cp\u003eModels were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status.\u003c/p\u003e","description":"","filename":"fiureS2.png","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/41238548a317bc3c0a26c447.png"},{"id":108180978,"identity":"43533f6f-f30b-4c91-8bdb-5b14b21e736d","added_by":"auto","created_at":"2026-04-30 08:55:54","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":99561,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S3. \u003c/strong\u003eSubgroup analysis of associations of the number of LFs with morbidity transitions among 317,163 participants.\u003c/p\u003e\n\u003cp\u003eA: transition from baseline to death; B: transition from FNPD to death; C: transition from NPM to death.\u003c/p\u003e\n\u003cp\u003eCI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity;LFs, lifestyle factors.\u003c/p\u003e\n\u003cp\u003eNeuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases.\u003c/p\u003e\n\u003cp\u003eModels were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status.\u003c/p\u003e","description":"","filename":"figureS3.png","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/ddcb0dfc1ed866b596513f8e.png"},{"id":107871339,"identity":"c9f7a63f-e44c-467d-bd36-9de4fef74d25","added_by":"auto","created_at":"2026-04-27 07:48:25","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":21207,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S1. \u003c/strong\u003eBaseline characteristics of 317,163 participants in the UK Biobank cohort by incident disease status during follow-up. TDI, Townsend deprivation index; BMI, body mass index; NPD, neuropsychiatric diseases; FNPD, first neuropsychiatricdiseases disease; NPM, neuropsychiatric multimorbidity. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as occurring at least two of the above-mentioned diseases.\u003c/p\u003e","description":"","filename":"tableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/cdc52d12bac4f4ae9562facb.docx"},{"id":108181014,"identity":"ede15c64-e116-460d-a46c-71c6f10a8293","added_by":"auto","created_at":"2026-04-30 08:56:14","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":19296,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S2. \u003c/strong\u003eHRs (95% CIs) for incident first neuropsychiatric disease, neuropsychiatric multimorbidity, and all-cause mortality by LFs among 317,163 participants. HR, hazard ratio; CI, confidence interval; LFs, lifestyle factors. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as occurring at least two of the above-mentioned diseases. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, stroke history, hypertension status, diabetes status. For analyses of individual LFs, three LFs were mutually adjusted. For analyses of dyads of LFs, models were additionally adjusted for presence of any other LFs not included in dyad.\u003c/p\u003e","description":"","filename":"tableS2.docx","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/eadedfc857ef59c37cafb430.docx"},{"id":108181087,"identity":"d77f9ac9-7316-47c9-b6fa-7673b4dcde96","added_by":"auto","created_at":"2026-04-30 08:57:12","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":21046,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S3.\u003c/strong\u003eSensitivity analysis of associations of individual LFs with transitions of neuropsychiatric diseases among 317,163 participants. CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; LFs, lifestyle factors. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. A series of sensitivity analyses were conducted: (1) calculating the entering date of the prior state using different time intervals (0.5-day, 0.5-year, 1-year, 3-year, 5-year) for participants who entered different states on the same day; (2) excluding participants who entered different states on the same date; (3) additionally adjusting for total cholesterol, triglyceride and C-reactive protein; (5) excluding the events occurring in the first two years follow-up. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status and three LFs were mutually adjusted.\u003c/p\u003e","description":"","filename":"tableS3.docx","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/f138ceb2a5ba82d9a8438610.docx"},{"id":107871246,"identity":"0a43a1cb-b97b-45e6-a7b7-205d689f3d8d","added_by":"auto","created_at":"2026-04-27 07:47:48","extension":"docx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":24170,"visible":true,"origin":"","legend":"\u003cp\u003eTable S4. Sensitivity analysis of associations of the number of high-risk LFs with transitions of neuropsychiatric diseases among 317,163 participants. CI, confidence interval; FNPD, first neuropsychiatric disease; HR, hazard ratio; NPM, neuropsychiatric multimorbidity; LFs, lifestyle factors. Neuropsychiatric diseases included dementia, Parkinson's disease, anxiety, depression and sleep disorders. Neuropsychiatric multimorbidity is defined as the occurrence of at least two of the above-mentioned diseases. A series of sensitivity analyses were conducted: (1) calculating the entering date of the prior state using different time intervals (0.5-day, 0.5-year, 1-year, 3-year, 5-year) for participants who entered different states on the same day; (2) excluding participants who entered different states on the same date; (3) additionally adjusting for total cholesterol, triglyceride and C-reactive protein; (5) excluding the events occurring in the first two years follow-up. Models were adjusted for age, sex, race, Townsend deprivation index, household income, education, employment status, body mass index, healthy diet score, healthy drinking, prior stroke, hypertension status, diabetes status.\u003c/p\u003e","description":"","filename":"tableS4.docx","url":"https://assets-eu.researchsquare.com/files/rs-9242207/v1/4afb8541b29273b05e83b11d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between unhealthy lifestyle and dynamic transitions of neuropsychiatric disorders: A longitudinal trajectory analysis in UK Biobank","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeurological and psychiatric diseases (NPDs) are increasingly recognised as major causes of death and disability\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e, affecting approximately 450\u0026nbsp;million people worldwide\u003csup\u003e4\u003c/sup\u003e. NPDs are typically intercorrelated and tend to co-exist in individuals\u003csup\u003e5\u0026ndash;8\u003c/sup\u003e, due to shared risk factors and pathophysiology\u003csup\u003e9\u0026ndash;10\u003c/sup\u003e, termed neuropsychiatric multimorbidity (NPM). Compared with isolated NPDs, NMP is suggested to be associated with poorer quality of life, worse health outcomes and higher healthcare costs\u003csup\u003e11\u0026ndash;12\u003c/sup\u003e. Therefore, it is critical to identify the risk factors that drive the onset and progression of NPDs to NPM and to implement early preventive interventions.\u003c/p\u003e \u003cp\u003eUnhealthy lifestyle factors (LFs) such as smoking\u003csup\u003e13\u0026ndash;15\u003c/sup\u003e,unhealthy sleep duration\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e, physical inactivity\u003csup\u003e19\u0026ndash;21\u003c/sup\u003e are well-recognized risk factors for single NPD. However, their potential influence on the dynamic transitions of NPDs remains poorly understood. Although LFs may influence every stage of the NPD trajectory\u0026mdash;from a healthy state to a single NPD, then to NPM, and ultimately to death\u0026mdash;previous works have examined only the first transition (health\u0026rarr;single NPD). This narrow focus underestimates the overall impact of LFs on the dynamic course of these disorders and obscures the roles that LFs might play at later stages of progression. Clarifying how LFs relates to the incidence, progression, and prognosis of NPDs would extend current knowledge of lifestyle\u0026ndash;NPD links and inform targeted prevention and intervention strategies. Moreover, since the etiological pathways underlying individual NPDs are distinct, whether LFs are differentially associated with disease specific transitions remains to be elucidated.\u003c/p\u003e \u003cp\u003eTherefore, we aimed to examine the associations of single and combined LFs with NPDs, NPM and death in the large UK Biobank cohort. Importantly, we used multi-state model to investigate the potentially different impacts of LFs on transitions from free of NPD to first neuropsychiatric disease (FNPD), subsequently to NPM and further to death. In line with previous study\u003csup\u003e22\u003c/sup\u003e, we limited NPDs to dementia, Parkinson disease, anxiety, depression and sleep disorders. Because of the large number of cases, we further examined the role of LFs in all possible transitions between healthy and individual NPDs, as well as individual NPDs to NPM and death.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThe UK Biobank is a prospective, population-based cohort that recruited over 500,000 participants aged 40 to 70 years from England, Scotland, and Wales between 2006 and 2010\u003csup\u003e23\u003c/sup\u003e. Participants completed touchscreen and nurse-led questionnaires, underwent physical measurements, and provided biological samples at recruitment. This study was conducted in accordance with the Declaration of Helsinki. Ethical approval was granted by the North West Multicenter Research Ethics Committee, and all participants provided written informed consent. Of the participants in the UK Biobank study, we excluded those with a prior diagnosis of dementia, anxiety, depression and Parkinson disease (n\u0026thinsp;=\u0026thinsp;69,461), those without complete data on smoking, sleep duration and physical activity (n\u0026thinsp;=\u0026thinsp;87,693), those with a diagnosis of cancer (n\u0026thinsp;=\u0026thinsp;28,053). Ultimately, 317,163 participants constituted the study population for the association analyses (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Prevalent neuropsychiatric diseases were identified based on self-reported medical conditions, primary care data and hospital inpatient records.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDefinition of high-risk lifestyle factors\u003c/h3\u003e\n\u003cp\u003eWe considered three modifiable LFs\u0026mdash;smoking, sleep duration, and physical activity. Alcohol consumption was not included in the LFs because its impact on neuropsychiatric disorders and mortality varies depending on the type of beverage, dosage, duration, genetic predisposition, and baseline health status\u003csup\u003e24\u0026ndash;26\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFor smoking status, we assigned current smokers to the high-risk group\u003csup\u003e13\u003c/sup\u003e. Because both short and long sleep duration have been associated with a higher risk of dementia\u003csup\u003e27\u0026ndash;28\u003c/sup\u003e, sleep duration of less than 7 hours or more than 9 hours per day was classified as unhealthy category. Insufficient physical activity was defined as less than 150 minutes per week of moderate-intensity activity, or less than 75 minutes per week of vigorous-intensity activity, or an equivalent combination of both\u003csup\u003e29\u003c/sup\u003e. The number of high-risk LFs was counted, ranging from 0 to 3.\u003c/p\u003e\n\u003ch3\u003eAscertainment of outcome\u003c/h3\u003e\n\u003cp\u003eIn the UK Biobank cohort, five NPDs were identified based on diagnostic codes from the 10th revision of the International Classification of Diseases (ICD 10): dementia (F00-F03, G30), PD (G20-G23), anxiety (F40-F43), depression (F32-F34, F38-F39) and sleep disorders (F51, G47). These diseases were selected due to their close relationships with LFs in previous studies, as well as their relatively high prevalence in the population\u003csup\u003e13,30\u003c/sup\u003e. Incident deaths were ascertained via linkage to the NHS Information Centre (England and Wales) and the NHS Central Register (Scotland). NPM was defined as co-occurrence of at least two of the above NPDs.\u003c/p\u003e\n\u003ch3\u003eCovariates\u003c/h3\u003e\n\u003cp\u003eCovariates for this analysis were collected via questionnaire or face-to-face interview and comprised age, sex, ethnicity (white or other), education (college/university degree or other), employment status (currently working, retired, or other), annual household income (high: \u0026ge; \u0026pound;52,000; medium: \u0026pound;18,000\u0026ndash;\u0026pound;51,999; low: \u0026lt; \u0026pound;18,000), the Townsend Deprivation Index (TDI; a lower score indicates higher socioeconomic status), body mass index (BMI), healthy drinking, healthy diet score, diabetes, prior stroke and high blood pressure. BMI was calculated by dividing weight (kg) by height squared (m\u003csup\u003e2\u003c/sup\u003e). Healthy drinking was defined as moderate alcohol intake: \u0026le; 1 drink (14 g)/day for women and \u0026le;\u0026thinsp;2 drinks (28 g)/day for men\u003csup\u003e31\u003c/sup\u003e. The diet score (0\u0026ndash;5) awarded 1 point for each of the following: vegetable intake\u0026thinsp;\u0026ge;\u0026thinsp;median, fruit intake\u0026thinsp;\u0026ge;\u0026thinsp;median, fish intake\u0026thinsp;\u0026ge;\u0026thinsp;median, red meat\u0026thinsp;\u0026lt;\u0026thinsp;median, and processed red meat\u0026thinsp;\u0026lt;\u0026thinsp;median\u003csup\u003e32\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n \u003cp\u003eBaseline characteristics of the analytic sample were summarized as percentage for categorical variables and mean (SD) for continuous variables. Multiple imputations by chained equation (MICE) method were used to handle missing covariates. Follow-up time was calculated from enrolment to the date of outcome diagnosis, death, or the censoring date (January 30, 2022), whichever came first. Models were adjusted for age, sex, education, ethnicity, TDI, BMI, household income, employment status, healthy drinking, healthy diet score, hypertension, diabetes status and stroke history.\u003c/p\u003e \u003cp\u003eWe employed Cox proportional hazards regression to quantify the hazard ratios (HRs) and corresponding 95% CIs for associations between LFs (separately or jointly) and FNPDs, NPM and all-cause mortality. In evaluating individual LFs, all other LFs were mutually adjusted. For combined exposure analyses, the number of LFs was included as a categorical variable. To determinethe HR for the events per one-factor increase in LFs, the number of LFs was fitted as an ordinal variable in a separate model. We further explored specific two LFs combinations, controlling for relevant confounders and any lifestyle components not comprising the dyad being tested.\u003c/p\u003e\u003cp\u003eTo evaluate how individual and combined LFs influence temporal progression from free of NPDs to FNPD, NPM, and death, we used multi-state model. This analytical approach extends competing risks methodology to delineate factor-specific effects across distinct disease trajectory phases\u003csup\u003e33\u003c/sup\u003e. We specified five transitions based on the natural history of NPM and prior research\u003csup\u003e22\u003c/sup\u003e (Transition Pattern A, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e): healthy baseline to FNPD; FNPD to NPM; baseline healthy to all-cause mortality; FNPD to death and NPM to death. The date of NPM was defined as the date of second NPD diagnosis. When participants entered multiple states simultaneously (n\u0026thinsp;=\u0026thinsp;1,858), we temporally ordered these events by assigning antecedent states entry dates 0.5 days prior to subsequent states\u003csup\u003e34\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe also used the multi-state model with the same setting to analyse the effects of LFs on different pathways from baseline to NPM, and to the absorbing state\u0026mdash;death. We divided the NPDs into five individual diseases, i.e., dementia, PD, anxiety, depression and sleep disorders, resulting in 17 transitions (transition pattern B, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In this disease-specific analysis, NPM was redefined as having two of five individual diseases. Because the temporal sequence of disease occurrence could not be ascertained if a participant was diagnosed with at least two of dementia, PD, anxiety, depression and sleep disorders on the same date, we excluded them, leaving 315,305 participants in this analysis.\u003c/p\u003e \u003cp\u003eThe multistate analyses of the transition pattern A were further stratified according to sex, age, employment, education and healthy drinking. The interactions were tested by using the likelihood ratio test comparing models with and without a cross-product term.\u003c/p\u003e \u003cp\u003eWe conducted several sensitivity analyses for the multi-state model of transition pattern A: (i) for participants who transitioned to multiple disease states simultaneously, we varied the entry time of the prior state using intervals of 0.5, 1, 3, and 5 years; (ii) we omitted participants with concurrent transitions to different states; (iii) models were further adjusted for lipid profiles (total cholesterol and triglycerides) and inflammatory markers (C-reactive protein); and (iv) events occurring during the initial 2-year follow-up were excluded.\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using R software (version 4.2.2). The multi-state models were constructed using the \u0026lsquo;mstate\u0026rsquo; package. Two-tailed P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated statistical significance.\u003c/p\u003e "},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eDescriptive analysis\u003c/h2\u003e \u003cp\u003eA total of 317,163 participants with complete data were included in this study; the mean age at baseline was 56.0 [SD 8.1] years, and 48.5% were male. During a median follow-up of 12.6 years, 35,010 participants (11.0%) experienced at least one NPD (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Of all incident NPDs patients, 5,865 (16.8%) developed NPM, and afterward, 20,932 died from any causes; 16,878 died without experiencing NPDs. In the separate analysis for individual diseases (transition pattern B; 1,858 participants were excluded), 3,893 participants (1.2% of the baseline healthy participants) had dementia, 1,743 (0.5%) had PD, 13,147 (4.2%) had anxiety, 11,985 (3.8%) had depression and 6,648 (2.1%) had sleep disorders, and 791 (20.5%), 518 (29.7%), 3,096 (23.3%), 3,097 (25.8%) and 796 (12.0%) of them developed NPM later respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Compared with cases whose FNPD was PD, anxiety, depression, or sleep disorders, cases whose FCMD was dementia were more likely to die afterwards, with 1,963 (50.4%) died during follow-up. Participants who experienced one or more NPDs were more likely to be older and to have a higher degree of socioeconomic deprivation, lower education levels, higher BMI and to have hypertension and prior stroke than survivors free of NPDs (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCox regression analyses\u003c/h3\u003e\n\u003cp\u003eAll three high-risk LFs were associated with an increased risk of FNPD, NPM, and all-cause death (Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e). Unhealthy sleep showed the strongest associations with FCMD and NPM [HRs (95%CIs):1.12 (1.09,1.15), 1.11 (1.05,1.18)], whereas smoking exhibited the strongest association with mortality [HR (95% CI): 2.29 (2.21, 2.38)]. Upward trends were observed for risks of FNPD, NPM, and death with an increasing number of high-risk LFs; the corresponding HRs (95% CIs) per one-factor increase was 1.08 (1.07, 1.10), 1.06 (1.03, 1.10), and 1.36 (1.33, 1.38), respectively. Individuals with concurrent smoking and unhealthy sleep had the highest risk of FNPD, NPM and death (HRs (95% CIs): 1.21 (1.14, 1.27), 1.20 (1.05, 1.38), and 2.41 (2.28, 2.55)). In general, the associations for transition to FNPD and death were slightly stronger than those for transition to NPM.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMulti-state analyses\u003c/h2\u003e \u003cp\u003eConsistent with Cox regression results, multi-state modeling revealed comparable findings for baseline to FNPD progression while delineating distinct temporal contributions of high-risk LFs to NPM development (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Smoking, unhealthy sleep patterns, and physical inactivity exerted more pronounced effects on FNPD incidence than on subsequent NPM acquisition. Except for unhealthy sleep, the remaining two LFs demonstrated comparable HR for mortality risk regardless of whether participants transitioned from FNPD or NPM. Notably, smoking exhibited stronger associations with mortality outcomes (from healthy baseline, FNPD, or NPM) than with non-fatal disease progression.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCombined LFs demonstrated dose-response relationships with all five state progressions (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The number of high-risk LFs exhibited stronger associations with initial FNPD development than with subsequent NPM progression, while mortality risk estimates were comparable regardless of whether death followed FNPD or NPM. Specifically, each additional risk factor conferred adjusted HR (95% CIs) of 1.08 (1.07, 1.10) for baseline to FNPD progression, 1.04 (1.00, 1.16) for FNPD to NPM conversion, and 1.34 (1.32, 1.37), 1.23 (1.18, 1.28), and 1.26 (1.15, 1.39) for mortality from baseline, FNPD, and NPM, respectively. Among pairwise combinations, the \"smoking plus unhealthy sleep\" dyad conferred the highest risk for both incident FNPD and disease progression. Notably, any pair involving smoking demonstrated uniformly strong associations with fatal outcomes across all baseline health states (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eStratification by specific disease (dementia, PD, anxiety, depression, and sleep disorders) revealed that smoking exhibited preferential associations with mortality, dementia, and sleep disorders relative to PD, anxiety, or depression (Table\u0026nbsp;1). Unhealthy sleep demonstrated attenuated effects on progression from FCMD to NMP compared with other trajectories. Physical inactivity specifically elevated PD and sleep disorder risks, concurrently increasing mortality likelihood from baseline or depression/sleep disorder states. Joint exposure analyses further indicated dose-response gradients across all transitions except progression to NPM (Table\u0026nbsp;2). For incident disease development, dementia and sleep disorders manifested the strongest susceptibility to most lifestyle dyads, though their influences on subsequent NPM and mortality varied markedly by specific disease type (Table\u0026nbsp;3).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity and stratified analyses\u003c/h2\u003e \u003cp\u003eResults remained robust across sensitivity analyses (Tables S3 and S4). While stratified analyses detected several significant interactions, most lacked clinical relevance (Figures \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e and S4). Age demonstrated significant effect modification on lifestyle factor-disease trajectories, albeit with inconsistent directions across transitions. Females exhibited heightened vulnerability to FNPD-related mortality compared with males. Obesity conferred divergent risks: elevated for baseline-to -FNPD progression but attenuated for FNPD-to-death transition. Education and healthy drinking showed limited modifying effects, influencing only one of five trajectories.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this large-scale prospective cohort study of over 317,000 participants from the UK Biobank, we comprehensively evaluated the associations between modifiable unhealthy LFs and dynamic transitions across the NPD trajectory\u0026mdash;from a disease-free state to FNPD, subsequently to NPM, and ultimately to death\u0026mdash;using multi-state modeling. Several key findings emerged. First, unhealthy LFs were significantly associated with nearly all transition stages in the NPD continuum. Second, the magnitude of associations differed across stages, with stronger effects observed for the transition from healthy status to FNPD than from FNPD to NPM. Third, lifestyle burden demonstrated a graded relationship with both morbidity and mortality transitions. Finally, when specific NPDs were examined separately, the influence of individual and combined LFs varied substantially across disease types and transition pathways. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; The adverse effects of LFs on the incidence of neurological or psychiatric disorders have been previously demonstrated\u003csup\u003e35-38\u003c/sup\u003e. Findings from aprospective cohort of 50,000 UK participants revealed hazardous impacts of smoking or sleep characteristics on developing dementia, PD, major depression and anxiety. A study conducted in the cohort of 106,527 Norwegian participants found that sleep and physical activity were associated with both depression and anxiety. Compared with participants who slept 7\u0026ndash;8 h and exercised \u0026ge;3 times/week, the HRs (95% CIs) for those with slept \u0026le;5 h and were almost physically inactive were 1.97 (1.83, 2.25) and 1.74 (1.63,1.87) for depression and anxiety, respectively. Moreover, several studies have reported that unhealthy LFs elevate the risk of depression and anxiety in individuals with PD, which suggests that LFs may play a role in the transition from FNPD to NPM. Nevertheless, some limitations in previous studies merit consideration. First, these studies merely analyse the association between LFs and a single-disease stage. It is difficult to ascertain whether lifestyle factors exert stage-specific effects across the neuropsychiatric trajectory\u0026mdash;from healthy to FNPD, from FNPD to NPM, and from NPM to death\u0026mdash;when these transitions are analyzed separately. Moreover, because lifestyle factors are strongly associated with mortality, death constitutes a competing event that precludes subsequent progression to NPM. Treating death as non-informative censoring in conventional Cox models may violate the independent censoring assumption and bias risk estimates, thereby obscuring the true stage-specific associations\u003csup\u003e39\u003c/sup\u003e.Third, although neurological and psychiatric disorders are closely interrelated, the potential role of LFs in the development of their multimorbidity is typically overlooked and demands further clarification.\u003c/p\u003e\n\u003cp\u003eBy applying a multi-state framework that explicitly models intermediate disease states and competing mortality risk, our study extends existing literature in several important ways. We demonstrate that LFs influence not only primary disease incidence but also subsequent multimorbidity accumulation and survival outcomes. Importantly, the relative contribution of LFs was more pronounced in the early transition (healthy to FNPD) than in later progression (FNPD to NPM), suggesting that lifestyle exposures may exert stronger etiological effects in disease initiation than in disease clustering.\u003c/p\u003e\n\u003cp\u003eIn addition to LFs, a range of other factors affect the progression from FNPD to NPM. They may cover up the relative importance of LFs in determining the risk of developing NPM, to some extent. A study conducted in the cohort of 402,950 UK participants concluded that cardiometabolic multimorbidity accelerates progression from FNPD to NPM\u003csup\u003e22\u003c/sup\u003e. Anemia, hypothyroidism, social isolation, and hearing loss markedly increase the probability of neuropsychiatric symptoms in Alzheimer\u0026rsquo;s disease, while dopaminergic medications significantly raise the risk of hallucinations and delusions in Parkinson\u0026rsquo;s disease\u003csup\u003e41-42\u003c/sup\u003e. Nonetheless, LFs remained critical determinants of NPM onset. Our findings corroborate their established role in primary disease prevention while highlighting potential for secondary intervention to prevent NPM progression. Amidst ageing populations facing escalating multimorbidity and polypharmacy, behavioral modifications offer a cost-effective strategy to attenuate medication burden and healthcare costs.\u003c/p\u003e\n\u003cp\u003ePrevious studies showed a cumulative effect of LFs on the incidence of dementia, PD, depression and anxiety disorders\u003csup\u003e13,16,35\u003c/sup\u003e.\u0026nbsp;In this study, we have extended these findings from a single disease to multimorbidity. Participants with three high-risk LFs were roughly 25% more likely to develop both FNPD and NPM than those with only one, underscoring the vast preventive potential of lifestyle interventions across the entire disease trajectory. Stratified analysis further showed that LFs had a greater impact on the risk of transition to death among middle-aged participants compared with older adults. It is probably due to the relatively higher baseline hazard for older participants and the those most vulnerable to death have already died before enrollment (survival effect), leaving a healthier, lower-risk elderly cohort. Greater residual lifespan and modifiable risk burden in middle-aged individuals, allowing lifestyle changes to exert a larger relative effect on delayed mortality. These findings indicate greater significance in strengthening lifestyle interventions among younger adults.\u003c/p\u003e\n\u003cp\u003eUnlike previous studies constrained by limited sample sizes, our investigation enabled comprehensive delineation of LFs roles across the complete disease spectrum\u0026mdash;encompassing transitions from health to five specific disease, their subsequent progression to NPM, and ultimate mortality. Results indicate that single LF manifest distinct influences at different disease stages. Smoking, for instance, increased the risk of almost all morbidity outcomes yet showed no significant association with incident NPM in patients with FNPDs. Moreover, even within the same transition stage, individual LFs influenced disease-specific pathways differently. For example, physical inactivity was linked more strongly to incident PD and sleep disorders than to dementia, anxiety or depression. In contrast, our study observed that unhealthy sleep played roles in basically all transitions to death, suggesting a universal benefit of healthy sleep.\u003c/p\u003e\n\u003cp\u003eThe present study provides evidence from a large-scale, uniquely UK-based cohort\u0026mdash;a well-represented population operating under the same health-care system as most developed countries where previous research was conducted. The principal strength of this study is the application of multi-state modeling, which enabled stage-specific estimation of LFs effects across the neuropsychiatric trajectory while accounting for competing mortality risk. Leveraging a large prospective cohort with over 12 years of follow-up, we were able to model transitions from health to individual FNPDs, subsequent NPM, and death. The substantial sample size, diverse population, comprehensive covariate adjustment, and extensive sensitivity analyses further enhance the robustness and internal validity of the findings.\u003c/p\u003e\n\u003cp\u003eSome limitations characterize the present study. First, LFs were assessed at baseline and the associations of LFs with NPD progression could not be assessed. However, the previous study has analyzed participants who attended both the baseline survey and the follow-up resurvey. During a median interval of about 8 years, most individuals did not change their lifestyle risk level\u003csup\u003e34\u003c/sup\u003e. The use of baseline lifestyle data also helps avoid reverse causation resulting from lifestyle changes that occur after disease onset. Second, although we used diagnostic information from multiple sources, some cases of NPDs might still have been missed. Third, this study did not collect information on NPDs treatment, and medication adherence may correlate with adherence to a healthy lifestyle. However, we adjusted for education as a proxy for multiple health-related behaviors, so residual confounding from treatment is unlikely to fully account for the observed associations between LFs and the transition from FNPDs to NPM and subsequent mortality\u003csup\u003e42\u003c/sup\u003e. Fourth, some participants were diagnosed with two NPMs simultaneously in one admission, causing the same diagnosis date for both NPMs. For participants entering multiple disease states on the same date, a 0.5-day interval was assigned to define FNPD onset, which may have introduced minor temporal misclassification. However, alternative interval specifications and exclusion of these individuals did not materially alter the results. Fifth, given the observational design, causality cannot be inferred. Although evidence from Mendelian randomization studies and randomized trials supports a potential causal role of lifestyle factors35,43-45, the underlying mechanisms remain to be clarified. Self-reported exposures and residual confounding may also have influenced the estimates.\u003c/p\u003e\n\u003cp\u003eIn this large prospective cohort, unhealthy lifestyle burden was associated with stage-specific transitions across the neuropsychiatric disease spectrum, exerting stronger effects on disease onset and mortality than on NPM accumulation. These findings support a model in which modifiable systemic exposures shape neurobiological vulnerability and long-term survival across neuropsychiatric disorders.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all participants and staff in the UK Biobank for their dedication and contribution to this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS AND CONSENT TO PARTICIPATE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki. Ethical approval for the UK Biobank study was granted by the North West Multicenter Research Ethics Committee. All participants provided written informed consent at the time of recruitment, agreeing to the collection and use of their biological samples, health data, and linkage to health records for approved research purposes. The UK Biobank has obtained ethics approval from the National Information Governance Board for Health and Social Care and the National Health Service National Research Ethics Service. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING INFORMATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Fundamental research program funding of Ninth People\u0026apos;s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JYZZ286) and the National Natural Science Foundation of China (82571480, 82071282 and 82201572). The funders of the study had no role in study design, data collection, analysis, decision to publish or manuscript preparation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.J.S. and J.R.L. conceived the study and contributed to the interpretation of the results. Concept and design: J.J.S., J.R.L., C.H.C., and X.L. Analyses and drafting of the manuscript: C.H.C., X.L, P.L.L.,Y.Q., S.H.W, and L.Z. Critical revision of the manuscript: Y.N.L., Y.Q., S.H.W. Administrative, technical, or material support: Y.N.L., S.T.. All authors had access to the data in the study and had final responsibility for the decision to submit for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ehttps:// www. ukbio bank. ac. uk. The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eWhiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the global burden of disease study 2010. Lancet. 2013;382:1575-1586.\u003c/li\u003e\n \u003cli\u003eCollaborators. 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A meta-review of \u0026quot;lifestyle psychiatry\u0026quot;: the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders.\u0026nbsp;World Psychiatry. 2020;19(3):360-380. doi:10.1002/wps.20773\u003c/li\u003e\n \u003cli\u003eWalburg FS, van Meijel B, Hoekstra T, et al. Effectiveness of a lifestyle intervention for people with a severe mental illness in Dutch outpatient mental health care: a randomized clinical trial. *JAMA Psychiatry*. 2023;80(9):886-894. doi:10.1001/jamapsychiatry.2023.1566\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"neuropsychiatric disorders, multimorbidity, progression, lifestyle, prospective cohort study","lastPublishedDoi":"10.21203/rs.3.rs-9242207/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9242207/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe potential difference in the impacts of unhealthy lifestyle factors (LFs) on progression from healthy to first neurological and psychiatric disorders (NPDs), subsequently to neuropsychiatric multimorbidity (NPM), and further to death is unclear. We aimed to evaluate the associations between unhealthy lifestyle and dynamic transitions of NPDs.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eThis prospective study included 317,163 participants from the UK Biobank cohort. NPM was defined as the coexistence of at least two NPDs, including dementia, Parkinson disease, anxiety, depression and sleep disorders. We used multi-state model to analyse the impacts of unhealthy LFs (current smoking, unhealthy sleep duration and physical inactivity) on the progression of NPDs.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eDuring a median follow-up of 12.85 years, 35,010 participants developed at least one NPD, 5,865 developed NPM and 20,932 died afterwards. Unhealthy LFs played crucial but different roles in all transitions from healthy to NPD, to NPM, and then to death. The hazard ratios (95% confidence intervals) per one-factor increase were 1.08 (1.07, 1.10) and 1.04 (1.00, 1.16) for transitions from healthy to NPD, and from first NPD to NPM, and 1.34 (1.32, 1.37), 1.23 (1.18, 1.28) and 1.26 (1.15, 1.39) for mortality risk from healthy, NPD and NPM, respectively. When we further divided NPD into dementia, Parkinson disease, anxiety, depression and sleep disorders, the associations of single and combined unhealthy LFs with NPD transitions varied depending on disease types and specific combinations of unhealthy LFs, even within the same transition stage.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eUnhealthy LFs play important roles in nearly all transitions of NPD progression, highlighting the significance of LFs management for the prevention and control of NPDs.\u003c/p\u003e","manuscriptTitle":"Association between unhealthy lifestyle and dynamic transitions of neuropsychiatric disorders: A longitudinal trajectory analysis in UK Biobank","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-26 17:12:29","doi":"10.21203/rs.3.rs-9242207/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-03T11:00:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"209496768562652437834541709114717745929","date":"2026-04-17T20:21:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"40898102967985030697558024049822307939","date":"2026-04-17T15:28:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-17T11:40:01+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-30T20:39:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-28T08:06:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-28T08:05:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Public Health","date":"2026-03-27T08:20:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-public-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pubh","sideBox":"Learn more about [BMC Public Health](http://bmcpublichealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pubh/default.aspx","title":"BMC Public Health","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9bce63c5-7108-4f19-bb9c-d4eadf9897a6","owner":[],"postedDate":"April 26th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-03T11:00:02+00:00","index":42,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-26T17:12:29+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-26 17:12:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9242207","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9242207","identity":"rs-9242207","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}