Association between lifestyle at different life periods and brain integrity in older adults

Importance Lifestyle factors have been associated with dementia risk and neuroimaging markers of ageing and Alzheimer’s Disease (AD), but the period at which they have the greatest influence remains unclear. Objective To determine the relative influence of lifestyle at different life periods on older adults’ brain health. Design, Setting, and Participants Baseline data from the Age-Well trial were used in this study. Cognitively unimpaired participants aged 65 years and older were recruited in the general population between November 2016 to March 2018 in Caen, France. Analysis took place between June 2022 and September 2023. Exposure(s) The Lifetime of Experiences Questionnaire (LEQ) was used to assess lifestyle during young adulthood (3-30y), midlife (30-65y) and late-life (>65y). For each life period, LEQ score is divided into specific and non-specific subscores. Main Outcome(s) and Measure(s) Multiple regressions were conducted including lifestyle at the three life periods (in the same model) to predict gray matter volume (GMv; from structural MRI), glucose metabolism (FDG-PET), perfusion (Florbetapir-PET, early-acquisition) and amyloid burden (Florbetapir-PET, late-acquisition), both in AD-sensitive regions and voxel-wise, controlling for age and sex. Then, comparisons of correlations between lifestyle at each life period, as well as between specific versus non-specific activities, and neuroimaging outcomes were performed. Results Of the 135 older adults (mean age=69.3±3.79), 61.5% were women. No significant association was found between LEQ scores and AD-sensitive regions. While LEQ-young was not associated with neuroimaging, LEQ-midlife was more strongly associated with GMv, including in the anterior cingulate cortex, and with amyloid burden in the precuneus compared to the other periods. LEQ-late showed stronger associations with perfusion and glucose metabolism than LEQ-young and LEQ-midlife in medial frontal regions. Lower amyloid burden was more strongly correlated with LEQ-midlife specific than non-specific activities (z=-2.0977, p<.05, [95% CI, −0.3985 - −0.0102]) while perfusion was more strongly correlated with LEQ-late non-specific than specific scores (z=2.4369, p<.01, [95% CI, 0.0.415-0.4165]). Conclusions and Relevance Lifestyle at different life periods might have complementary benefits on structural/molecular versus functional markers of brain health in late-life. Interestingly, these associations were found in regions related to reserve/resilience and aging. Trial registration [Clinicaltrials.gov][1] Identifier: [NCT02977819][2] ### Competing Interest Statement Dr. Chetelat reported grants, personal fees, and non-financial support from Institut National de la Sante et de la Recherche Medicale (Inserm), grants from European Union's Horizon 2020 research and innovation programme under grant agreement No 667696 (PI), grants from Fondation d'entreprise MMA des Entrepreneurs du Futur, during the conduct of the study; personal fees from Fondation Entrepreneurs MMA, grants and personal fees from Fondation Alzheimer, grants from Region Normandie, grants from Fondation Recherche Alzheimer, and grants from Association France Alzheimer, outside the submitted work. Dr Gonneaud received funding from the Fondation Alzheimer & Fondation de France (Allocation Jeune Chercheur) and an award from the Rotary Club Lille la Madeleine. ### Funding Statement The Age-Well randomized clinical trial is part of the Medit-Ageing project and is supported by the European Union's Horizon 2020 Research and Innovation Program (grant 667696), Region Normandie (Label d'Excellence), and Fondation d'Entreprise MMA des Entrepreneurs du Futur. Institut National de la Sante et de la Recherche Medicale (Inserm) is the sponsor. The funders and sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Age-Well randomized control trial was approved by ethics committee (Comite de Protection des Personnes Nord-Ouest III, Caen, France; registration number: EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; [ClinicalTrials.gov][3] Identifier: [NCT02977819][2]) and a written informed consent was obtained from each participant prior to examinations I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][3]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data underlying this report are made available on request following a formal data sharing agreement and approval by the consortium and executive committee () [1]: http://Clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02977819&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F31%2F2024.01.31.24302049.atom [3]: http://ClinicalTrials.gov