Interaction between APOE4 status and lifestyle on brain and cognitive outcomes in cognitively unimpaired older adults

INTRODUCTION APOE4 genotype and lifestyle have been associated with Alzheimer’s disease (AD) risk, but how they interact on neuroimaging and cognitive markers of aging and AD remains unclear. METHODS In 135 cognitively unimpaired older adults from the baseline Age-Well trial, we investigated the interaction between APOE 4 status and cognitive activity, diet and physical activity on cognition and neuroimaging markers of neurodegeneration and amyloid. RESULTS Higher cognitive activity correlated with lower medial temporal lobe (MTL) volume and perfusion in APOE4 -carriers, but increased cognitive performance irrespective of APOE4 status. Higher adherence to the Mediterranean diet correlated with higher MTL metabolism and attention scores in APOE4- carriers. Conversely, physical activity correlated with higher MTL perfusion and lower amyloid in APOE4 -non-carriers only. DISCUSSION Genetics and lifestyle factors act through different mechanisms to help APOE4 -carriers resist or cope with brain alterations and postpone cognitive decline. Our results support the need of personalized lifestyle-based interventions for AD. Trial Registration Information EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; [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. F. Felisatti was funded by the European Union's Horizon 2020 Research and Innovation Program (grant 667696) and the MMA IARD SA. Dr Gonneaud received funding from the Fondation Alzheimer & Fondation de France (Allocation Jeune Chercheur) and an award from the Rotary Club Lille la Madeleine. Dr Marchant reported funding from the EU Joint Programme-Neurodegenerative Disease Research (JPND) grant funded by the UK Medical Research Council (No. MR/TO46171/1) outside the submitted work. Dr. Collette reported grants form F.R.S-FNRS (Belgium), Fond pour la Recherche Alzheimer and King Baudouin Fundation (Belgium), grants from Liege University. Tim Whitfield was funded by The Dunhill Medical Trust (grant number RTF1806\45). Florence Requier is supported by SAO-FRA (Belgium, grant 2020/0026). No other disclosures were reported. ### 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][1] 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][1]. 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 Data is available upon request following a formal data sharing agreement and approval by the consortium and executive committee. The data sharing request form can be downloaded online: silversantestudy.eu/2020/09/25/data-sharing/ [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02977819&atom=%2Fmedrxiv%2Fearly%2F2023%2F07%2F17%2F2023.07.17.23292755.atom