APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers’s disease

APOE stratified genome-wide association studies provide novel insights into the genetic etiology of Alzheimers’s disease Abstract Among the more than 90 identified genetic risk loci for late-onset Alzheimer’s disease (AD) and related dementias, the apolipoprotein E gene (APOE) ɛ2/ɛ3/ɛ4 polymorphisms remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies1–10. Despite this massive signal, the exact mechanisms for how ɛ4 increases and for how ɛ2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11–13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. Such insights may help to understand and overcome side effects, to impact clinical trial enrolment strategies, and to create the scientific basis for targeted mechanism-driven therapies in neurodegenerative diseases. Competing Interest Statement C van Duijn is currently the Research Director Brain Health of the Health Data Research UK (HDR UK) and the UK Dementia Research Institute (UK DRI), working in partnership with Dementias Platform UK (DPUK). Some authors’ participation in this project was part of a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research. M Nalls also owns stock in Character Bio Inc. and Neuron23 Inc. Funding Statement This work was funded by a grant (EADB) from the EU Joint Programme Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Metropole Communaute Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). This work was further funded by grants from the Lundbeck Foundation (R278-2018-804), the Danish Heart Foundation, and the Research Fund at Sygeforsikringen Danmark (2021-0245). Najaf Amin is funded by National Institute on Aging (NIH) and Oxford-GSK Institute of Molecular and Computational Medicine (IMCM). Cornelia M van Duijn is supported by the US National Institute on Aging (NIH), NovoNordisk, the Oxford-GSK Institute of Molecular and Computational Medicine (IMCM), Centre of Artificial Intelligence for Precision Medicines (CAIPM) of the University of Oxford and King Abdul Aziz University, Alzheimer Research UK (ARUK), UK National Institute for Health and Care Research (NIHR) Oxford Research Center (BRC), ZonMW (Delta Dementie) and Alzheimer Nederland. This research was also supported in part by the Intramural Research Program of the NIH, National Institute of Aging (NIA), National Institutes of Health, Department of Health and Human Services; project number ZO1 AG000534, as well as the National Institute of Neurological Disorders and Stroke. 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 datasets used in our study were based on individual-level data in each cohort. Summary statistics from each cohort were meta-analyses and presented in the manuscript. All individual-level data had been de-identified prior to its use in this study. This study is a collaboration between already described cohorts and biobanks. The study was approved by all relevant steering comitees and the individual countries ethical comitees. The individual approvals are described in detail in the Supplementary note. 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. 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 Footnotes Data availability Summary statistics will be made available upon publication through the European Bioinformatics Institute GWAS Catalog (https://www.ebi.ac.uk/gwas/). 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