Association of Rare APOE Missense Variants V236E and R251G with Risk of Alzheimer Disease

Yann Le Guen*, Michael E. Belloy, Benjamin Grenier-Boley, Itziar De Rojas, Atahualpa Castillo-Morales, Iris Jansen, Aude Nicolas, Céline Bellenguez, Carolina Dalmasso, Fahri Küçükali, Sarah J. Eger, Katrine Laura Rasmussen, Jesper Qvist Thomassen, Jean François Deleuze, Zihuai He, Valerio Napolioni, Philippe Amouyel, Frank Jessen, Patrick G. Kehoe, Cornelia Van DuijnMagda Tsolaki, Pascual Sánchez-Juan, Kristel Sleegers, Martin Ingelsson, Giacomina Rossi, Mikko Hiltunen, Rebecca Sims, Wiesje M. Van Der Flier, Alfredo Ramirez, Ole A. Andreassen, Ruth Frikke-Schmidt, Julie Williams, Agustín Ruiz, Jean Charles Lambert, Michael D. Greicius, Beatrice Arosio, Luisa Benussi, Anne Boland, Barbara Borroni, Paolo Caffarra, Delphine Daian, Antonio Daniele, Stéphanie Debette, Carole Dufouil, Emrah Düzel, Daniela Galimberti, Vilmantas Giedraitis, Timo Grimmer, Caroline Graff, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Henne Holstege, Jakub Hort, Deckert Jürgen, Teemu Kuulasmaa, Aad Van Der Lugt, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Alexandre De Mendonça, Susanne Moebus, Benedetta Nacmias, Gael Nicolas, Robert Olaso, Goran Papenberg, Lucilla Parnetti, Florence Pasquier, Oliver Peters, Yolande A.L. Pijnenburg, Julius Popp, Innocenzo Rainero, Inez Ramakers, Steffi Riedel-Heller, Nikolaos Scarmeas, Philip Scheltens, Norbert Scherbaum, Anja Schneider, Davide Seripa, Hilkka Soininen, Vincenzo Solfrizzi, Gianfranco Spalletta, Alessio Squassina, John Van Swieten, Thomas J. Tegos, Lucio Tremolizzo, Frans Verhey, Martin Vyhnalek, Jens Wiltfang, Mercè Boada, Pablo García-González, Raquel Puerta, Luis M. Real, Victoria Álvarez, María J. Bullido, Jordi Clarimon, José María García-Alberca, Pablo Mir, Fermin Moreno, Pau Pastor, Gerard Piñol-Ripoll, Laura Molina-Porcel, Jordi Pérez-Tur, Eloy Rodríguez-Rodríguez, Jose Luís Royo, Raquel Sánchez-Valle, Martin Dichgans, Dan Rujescu

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

Importance: The APOE ϵ2 and APOE ϵ4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD - particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants - remain poorly understood. Identifying missense variants in addition to APOE ϵ2 and APOE ϵ4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. Objective: To determine whether rare missense variants on APOE are associated with AD risk. Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37409 nonunique participants of European or admixed European ancestry, with 11868 individuals with AD and 11934 controls passing analysis inclusion criteria. In stages 2 and 3, 475473 participants were considered across 8 cohorts, of which 84513 individuals with AD and proxy-AD and 328372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. Results: A total of 544384 participants were analyzed in the primary case-control analysis; 312476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ϵ4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ϵ3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ϵ4 on the APOE gene, which mitigates the ϵ4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ϵ3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE..

Original languageEnglish
Pages (from-to)652-663
Number of pages12
JournalJAMA Neurology
Volume79
Issue number7
Early online date31 May 2022
DOIs
Publication statusPublished - Jul 2022

Bibliographical note

Funding Information:
reported grants from Alzheimer’s Association during the conduct of the study. Dr Küçükali reported grants from the Research Foundation Flanders and grants from The University of Antwerp Research Fund during the conduct of the study. Dr Borroni reported personal fees from Alector, Wave Life Sciences, and Denali outside the submitted work. Dr Debette reported grants from Leducq Foundation, European Research Council Starting Grant, French National Research Agency, Horizon 2020, and EU Joint Programme— Neurodegenerative Disease Research during the conduct of the study. Dr Dufouil reported grants from Fondation Plan Alzheimer, French Ministry of Research, GE Healthcare, and Avid Radiopharmaceuticals/Lilly during the conduct of the study. Dr Düzel reported grants from German Research Foundation, German Federal Ministry of Education and Research, and Human Brain Project as well as personal fees from Roche, Biogen, and neotiv GmbH outside the submitted work. Dr Grimmer reported personal fees from AbbVie, Alector, Anavex, Biogen, Eli Lilly, Functional Neuromodulation, Grifols, Iqvia, Life Molecular Imaging, Novo Nordisk, Noselab, NuiCare, Roche Diagnostics, Roche Pharma, Schwabe, Toyama, UCB, and Vivoryon outside the submitted work. Dr Graff reported grants from Swedish Medical Research Council, ALF Medicine Region Stockholm, Swedish Demensfonden, Alzheimer Foundation, Karolinska Institutet StratNeuro, and Swedish Brain Foundation during the conduct of the study. Dr Hanon reported personal fees from Bayer, Servier, Pfizer, AstraZeneca, Bristol Myers Squibb, and Boehringer outside the submitted work. Dr Heilmann-Heimbach reported personal fees from Life & Brain GmbH during the conduct of the study. Dr Hort reported stock options from Alzheon outside the submitted work. Dr Jürgen reported grants from Vogel Foundation during the conduct of the study; grants from German Research Foundation, German Federal Ministry of Education and Research, Bavarian Secretary of Commerce, and European Union outside the submitted work. Dr Boada reported personal fees from Grifols, Araclon Biotech, Roche, Biogen, Lilly, Merck, Zambon, Novo Nordisk, Bioiberica, Eisai, Servier, and Schwabe as well as grants from Grifols, La Caixa, Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas, and European Federation of Pharmaceutical Industries and Associations outside the submitted work. Dr Moreno reported grants from Instituto de Salud Carlos III and Tau Consortium outside the submitted work. Dr Peters reported grants from Roche, Biogen, Eisai, and Vivoryon as well as personal fees from Roche, Biogen, Eisai, and Griffols outside the submitted work. Dr Popp reported grants from Swiss National Research Foundation during the conduct of the study. Dr Molina-Porcel reported institutional research fees from Biogen outside the submitted work. Dr Ramakers reported grants from Janssen Pharmaceuticals outside the submitted work. Dr Scarmeas reported grants from Alzheimer’s Association, European Social Fund, European Strategic Partnership Agreement Program and Ministry for Health Greece during the conduct of the study. Dr Scheltens reported part-time employment from Lump Sum; grants from Alzheimer’s Drug Discovery Foundation and Cure Alzheimer; is a principal investigator for UCB, Toyama, and Alzheon; and serves on the steering committee of Vivoryon and NOVO outside the submitted work. Dr Schneider reported grants from Cure Alzheimer Foundation, Verum Foundation, and MjFF Foundation outside the submitted work. Dr Spalletta reported grants from Italian Ministry of Health during the conduct of the study. Dr Sánchez-Valle reported personal fees from Wave Pharmaceuticals and Ionis-Biogen as well as grants from Biogen and Sage Pharmaceuticals outside the submitted work. Dr Wiltfang reported personal fees from Abbott, Biogen, Boehringer-Ingelheim, Immungenetics, Janssen, Lilly, Merck Sharp & Dohme, Pfizer, Roche Pharma, Actelion, Amgen, Beejing Yibai Science and Technology, and Roboscreen outside the submitted work; and had a patent for PCT/EP 2011 001724 issued and a patent for PCT/EP 2015 052945 issued. Dr Amouyel reported personal fees from Fondation Alzheimer and Genoscreen Biotech outside the submitted work. Dr Jessen reported grants from German Center for Neurodegenerative Diseases (DZNE) during the conduct of the study. Dr Sleegers reported grants from Alzheimer Research Foundation Belgium, Research Foundation Flanders, and University of Antwerp Research Fund during the conduct of the study. Dr Ingelsson reported personal fees from BioArctic AB. Dr van der Flier reported grants from Netherlands Organisation for Health Research and Development (ZonMW) European Alzheimer’s Disease DNA Biobank during the conduct of the study; grants from Alzheimer Nederland, Hersenstichting, CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA, Novartis-NL, Life-MI, Avid Radiopharmaceuticals, Roche BV, Fujifilm, Combinostics, Gieskes-Strijbis, Dioraphte, Edwin Bouw, Equilibrio, and Pasman outside the submitted work; has performed contract research for Biogen MA and Boehringer Ingelheim; has been an invited speaker at Boehringer Ingelheim, Biogen MA, Danone, Eisai, WebMD Neurology (Medscape), and Springer Healthcare; is consultant to Oxford Health Policy Forum CIC, Roche, and Biogen MA; participated in advisory boards of Biogen MA and Roche; was associate editor of Alzheimer, Research

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and Therapy in 2020/2021; and is associate editor at Brain. Dr Ramirez reported grants from Bundesministerium für Bildung und Forschung and German Research Foundation (Deutsche Forschungsgemeinschaft) during the conduct of the study. Dr Andreassen reported grants from KG Jebsen Stiftelsen, South East Norway Health Authority, Research Council of Norway, and European Union Horizon 2020 during the conduct of the study as well as personal fees from HealthLytix, Lundbeck, and Sunovion outside the submitted work. Dr Ruiz reported grants from Grifols, Fundación Bancaria La Caixa, Instituto de Salud Carlos III, Joint Programming for Neurological Disease—Precision Medicine Program, European Union Innovative Medicine Initiative, and EuroNanoMed, personal fees from Landsteiner Genmed; nonfinancial support from Araclon Biotech and Prevail Therapeutics; and has contracts with Roche, Cortexyme, Janssen outside the submitted work. Dr Greicius reported grants from the National Institutes of Health during the conduct of the study. No other disclosures were reported.

Funding Information:
Funding/Support: This work was supported by the National Institute of Health and National Institute of Aging grants AG060747 (Dr Greicius), AG066206 (Dr He), AG066515 (Drs He and Greicius), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant agreement No. 890650; Dr Le Guen), the Alzheimer’s Association (AARF-20-683984; Dr Belloy), and the Iqbal Farrukh and Asad Jamal Fund, a grant from the EU Joint Programme–Neurodegenerative Disease Research (European Alzheimer DNA BioBank, European Alzheimer’s disease DNA Biobank; Joint Programming for Neurological Disease). Inserm UMR1167 is also funded by the Inserm, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine, and the French government’s LabEx DISTALZ program (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer’s Disease).

Funding Information:
Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

Funding Information:
The Alzheimer’s Disease Sequencing Project (ADSP) is comprised of two Alzheimer’s Disease (AD) genetics consortia and three National Human Genome Research Institute (NHGRI) funded Large Scale Sequencing and Analysis Centers (LSAC). The two AD genetics consortia are the Alzheimer’s Disease Genetics Consortium (ADGC) funded by NIA (U01 AG032984), and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) funded by NIA (R01 AG033193), the National Heart, Lung, and Blood Institute (NHLBI), other National Institute of Health (NIH) institutes and other foreign governmental and non-governmental organizations. The Discovery Phase analysis of sequence data is supported through UF1AG047133 (to Drs. Schellenberg, Farrer, Pericak-Vance, Mayeux, and Haines); U01AG049505 to Dr. Seshadri; U01AG049506 to Dr. Boerwinkle; U01AG049507 to Dr. Wijsman; and U01AG049508 to Dr. Goate and the Discovery Extension Phase analysis is supported through U01AG052411 to Dr. Goate, U01AG052410 to Dr. Pericak-Vance and U01 AG052409 to Drs. Seshadri and Fornage.

Funding Information:
The ADGC cohorts include: Adult Changes in Thought (ACT) (UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657), the Alzheimer’s Disease Centers (ADC) ( P30 AG019610, P30 AG013846, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P50 AG005134, P50 AG016574, P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P50 AG016570, P50 AG005131, P50 AG023501, P30 AG035982, P30 AG028383, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P50 AG005136, P50 AG033514, P50 AG005681, and P50 AG047270), the Chicago Health and Aging Project (CHAP) (R01 AG11101, RC4 AG039085, K23 AG030944), Indianapolis Ibadan (R01 AG009956, P30 AG010133), the Memory and Aging Project (MAP) ( R01 AG17917), Mayo Clinic (MAYO) (R01 AG032990, U01 AG046139, R01 NS080820, RF1 AG051504, P50 AG016574), Mayo Parkinson’s Disease controls (NS039764, NS071674, 5RC2HG005605), University of Miami (R01 AG027944, R01 AG028786, R01 AG019085, IIRG09133827, A2011048), the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology Study (MIRAGE) (R01 AG09029, R01 AG025259), the National Cell Repository for Alzheimer’s Disease (NCRAD) (U24 AG21886), the National Institute on Aging Late Onset Alzheimer's Disease Family Study (NIA-LOAD) (R01 AG041797), the Religious Orders Study (ROS) (P30 AG10161, R01 AG15819), the Texas Alzheimer’s Research and Care Consortium (TARCC) (funded by the Darrell K Royal Texas Alzheimer's Initiative), Vanderbilt University/Case Western Reserve University (VAN/CWRU) (R01 AG019757, R01 AG021547, R01 AG027944, R01 AG028786, P01 NS026630, and Alzheimer’s Association), the Washington Heights-Inwood Columbia Aging Project (WHICAP) (RF1 AG054023), the University of Washington Families (VA Research Merit Grant, NIA: P50AG005136, R01AG041797, NINDS: R01NS069719), the Columbia University HispanicEstudio Familiar de Influencia Genetica de Alzheimer (EFIGA) (RF1 AG015473), the University of Toronto (UT) (funded by Wellcome Trust, Medical Research Council, Canadian Institutes of Health Research), and Genetic Differences (GD) (R01 AG007584). The CHARGE cohorts are supported in part by National Heart, Lung, and Blood Institute (NHLBI) infrastructure grant HL105756 (Psaty), RC2HL102419 (Boerwinkle) and the neurology working group is supported by the National Institute on Aging (NIA) R01 grant AG033193.

Funding Information:
The CHARGE cohorts participating in the ADSP include the following: Austrian Stroke Prevention Study (ASPS), ASPS-Family study, and the Prospective Dementia Registry-Austria (ASPS/PRODEM-Aus), the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Erasmus Rucphen Family Study (ERF), the Framingham Heart Study (FHS), and the Rotterdam Study (RS). ASPS is funded by the Austrian Science Fond (FWF) grant number P20545-P05 and P13180 and the Medical University of Graz. The ASPS-Fam is funded by the Austrian Science Fund (FWF) project I904),the EU Joint Programme - Neurodegenerative Disease Research (JPND) in frame of the BRIDGET project (Austria, Ministry of Science) and the Medical University of Graz and the Steiermärkische Krankenanstalten Gesellschaft. PRODEM-Austria is supported by the Austrian Research Promotion agency (FFG) (Project No. 827462) and by the Austrian National Bank (Anniversary Fund, project 15435. ARIC research is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). Neurocognitive data in ARIC is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD), and with previous brain MRI examinations funded by R01-HL70825 from the NHLBI. CHS research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629, R01AG15928, and R01AG20098 from the NIA. FHS research is supported by NHLBI contracts N01-HC-25195 and HHSN268201500001I. This study was also supported by additional grants from the NIA (R01s AG054076, AG049607 and AG033040 and NINDS (R01 NS017950). The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community's Seventh Framework Programme (FP7/2007-2013)/grant agreement HEALTH-F4-2007-201413 by the European Commission under the programme "Quality of Life and Management of the Living Resources" of 5th Framework Programme (no. QLG2-CT-2002-01254). High-throughput analysis of the ERF data was supported by a joint grant from the Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the municipality of Rotterdam. Genetic data sets are also supported by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project 050-060-810. All studies are grateful to their participants, faculty and staff. The content of these manuscripts is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the U.S. Department of Health and Human Services.

Funding Information:
Biological samples and associated phenotypic data used in primary data analyses were stored at Study Investigators institutions, and at the National Cell Repository for Alzheimer’s Disease (NCRAD, U24AG021886) at Indiana University funded by NIA. Associated Phenotypic Data used in primary and secondary data analyses were provided by Study Investigators, the NIA funded Alzheimer’s Disease Centers (ADCs), and the National Alzheimer’s Coordinating Center (NACC, U01AG016976) and the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by NIA This research was supported in part by the Intramural Research Program of the National Institutes of health, National Library of Medicine. Contributors to the Genetic Analysis Data included Study Investigators on projects that were individually funded by NIA, and other NIH institutes, and by private U.S. organizations, or foreign governmental or nongovernmental organizations.

Funding Information:
Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Funding Information:
The Alzheimer’s Disease Genetics Consortium (ADGC) supported sample preparation, whole exome sequencing and data processing through NIA grant U01AG032984. Sequencing data generation and harmonization is supported by the Genome Center for Alzheimer’s Disease, U54AG052427, and data sharing is supported by NIAGADS, U24AG041689. Samples from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. NIH grants supported enrollment and data collection for the individual studies including: GenerAAtions R01AG20688 (PI M. Daniele Fallin, PhD); Miami/Duke R01 AG027944, R01 AG028786 (PI Margaret A. Pericak-Vance, PhD); NC A&T P20 MD000546, R01 AG28786-01A1 (PI Goldie S. Byrd, PhD); Case Western (PI Jonathan L. Haines, PhD); MIRAGE R01 AG009029 (PI Lindsay A. Farrer, PhD); ROS P30AG10161, R01AG15819, R01AG30146, TGen (PI David A. Bennett, MD); MAP R01AG17917, R01AG15819, TGen (PI David A. Bennett, MD). The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P30 AG062428-01 (PI James Leverenz, MD) P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P30 AG062421-01 (PI Bradley Hyman, MD, PhD), P30 AG062422-01 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI Robert Vassar, PhD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P30 AG062429-01(PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P30 AG062715-01 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD).

Funding Information:
This work was supported by grants from the National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501 and R01AG057777). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

Funding Information:
This work was partially supported by grant funding from NIH R01 AG039700 and NIH P50 AG005136. Subjects and samples used here were originally collected with grant funding from NIH U24 AG026395, U24 AG021886, P50 AG008702, P01 AG007232, R37 AG015473, P30 AG028377, P50 AG05128, P50 AG16574, P30 AG010133, P50 AG005681, P01 AG003991, U01MH046281, U01 MH046290 and U01 MH046373. The funders had no role in study design, analysis or preparation of the manuscript. The authors declare no competing interests.

Funding Information:
This work was supported by the National Institutes of Health (R01 AG027944, R01 AG028786 to MAPV, R01 AG019085 to JLH, P20 MD000546); a joint grant from the Alzheimer’s Association (SG-14-312644) and the Fidelity Biosciences Research Initiative to MAPV; the BrightFocus Foundation (A2011048 to MAPV). NIA-LOAD Family-Based Study supported the collection of samples used in this study through NIH grants U24 AG026395 and R01 AG041797 and the MIRAGE cohort was supported through the NIH grants R01 AG025259 and R01 AG048927. We thank contributors, including the Alzheimer’s disease Centers who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. Study design: HNC, BWK, JLH, MAPV; Sample collection: MLC, JMV, RMC, LAF, JLH, MAPV; Whole exome sequencing and Sanger sequencing: SR, PLW; Sequencing data analysis: HNC, BWK, KLHN, SR, MAK, JRG, ERM, GWB, MAPV; Statistical analysis: BWK, KLHN, JMJ, MAPV; Preparation of manuscript: HNC, BWK. The authors jointly discussed the experimental results throughout the duration of the study. All authors read and approved the final manuscript.

Funding Information:
Data collection and sharing for this project was supported by the Washington Heights-Inwood Columbia Aging Project (WHICAP, PO1AG07232, R01AG037212, RF1AG054023) funded by the National Institute on Aging (NIA) and by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number UL1TR001873. This manuscript has been reviewed by WHICAP investigators for scientific content and consistency of data interpretation with previous WHICAP Study publications. We acknowledge the WHICAP study participants and the WHICAP research and support staff for their contributions to this study.

Funding Information:
Mayo RNAseq Study-Study data were provided by the following sources: The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Ertekin-Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium) and the Michael J. Fox Foundation for Parkinson's Research ROSMAP-We are grateful to the participants in the Religious Order Study, the Memory and Aging Project. This work is supported by the US National Institutes of Health [U01 AG046152, R01 AG043617, R01 AG042210, R01 AG036042, R01 AG036836, R01 AG032990, R01 AG18023, RC2 AG036547, P50 AG016574, U01 ES017155, KL2 RR024151, K25 AG041906-01, R01 AG30146, P30 AG10161, R01 AG17917, R01 AG15819, K08 AG034290, P30 AG10161 and R01 AG11101.

Funding Information:
Mount Sinai Brain Bank (MSBB)-This work was supported by the grants R01AG046170, RF1AG054014, RF1AG057440 and R01AG057907 from the NIH/National Institute on Aging (NIA). R01AG046170 is a component of the AMP-AD Target Discovery and Preclinical Validation Project. Brain tissue collection and characterization was supported by NIH HHSN271201300031C.

Funding Information:
This study was supported by the National Institute on Aging (NIA) grants AG030653, AG041718, AG064877 and P30-AG066468.

Funding Information:
We would like to thank study participants, their families, and the sample collectors for their invaluable contributions. This research was supported in part by the National Institute on Aging grant U01AG049508 (PI Alison M. Goate). This research was supported in part by Genentech, Inc. (PI Alison M. Goate, Robert R. Graham).

Funding Information:
The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by these NIA-funded ADCs: P30 AG013846 (PI Neil Kowall, MD), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG005131 (PI Douglas Galasko, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG005681 (PI John Morris, MD), P30 AG028377 (Kathleen Welsh-Bohmer, PhD), and P50 AG008671 (PI Henry Paulson, MD, PhD).

Funding Information:
Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible.

Funding Information:
The Alzheimer's Disease Genetics Consortium supported the collection of samples used in this study through National Institute on Aging (NIA) grants U01AG032984 and RC2AG036528.

Funding Information:
We acknowledge the generous contributions of the Cache County Memory Study participants. Sequencing for this study was funded by RF1AG054052 (PI: John S.K. Kauwe) The NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is supported by a collaborative agreement from the National Institute on Aging, U24AG041689.

Funding Information:
NG00047: The NIA supported this work through grants U01-AG032984, RC2-AG036528, U01-AG016976 (Dr Kukull); U24 AG026395, U24 AG026390, R01AG037212, R37 AG015473 (Dr Mayeux); K23AG034550 (Dr Reitz); U24-AG021886 (Dr Foroud); R01AG009956, RC2 AG036650 (Dr Hall); UO1 AG06781, UO1 HG004610 (Dr Larson); R01 AG009029 (Dr Farrer); 5R01AG20688 (Dr Fallin); P50 AG005133, AG030653 (Dr Kamboh); R01 AG019085 (Dr Haines); R01 AG1101, R01 AG030146, RC2 AG036650 (Dr Evans); P30AG10161, R01AG15819, R01AG30146, R01AG17917, R01AG15819 (Dr Bennett); R01AG028786 (Dr Manly); R01AG22018, P30AG10161 (Dr Barnes); P50AG16574 (Dr Ertekin-Taner, Dr Graff-Radford), R01 AG032990 (Dr Ertekin-Taner), KL2 RR024151 (Dr Ertekin-Taner); R01 AG027944, R01 AG028786 (Dr Pericak-Vance); P20 MD000546, R01 AG28786-01A1 (Dr Byrd); AG005138 (Dr Buxbaum); P50 AG05681, P01 AG03991, P01 AG026276 (Dr Goate); and P30AG019610, P30AG13846, U01-AG10483, R01CA129769, R01MH080295, R01AG017173, R01AG025259, R01AG33193, P50AG008702, P30AG028377, AG05128, AG025688, P30AG10133, P50AG005146, P50AG005134, P01AG002219, P30AG08051, MO1RR00096, UL1RR029893, P30AG013854, P30AG008017, R01AG026916, R01AG019085, P50AG016582, UL1RR02777, R01AG031581, P30AG010129, P50AG016573, P50AG016575, P50AG016576, P50AG016577, P50AG016570, P50AG005131, P50AG023501, P50AG019724, P30AG028383, P50AG008671, P30AG010124, P50AG005142, P30AG012300, AG010491, AG027944, AG021547, AG019757, P50AG005136 (Alzheimer Disease GeneticsConsortium [ADGC]). We thank Creighton Phelps, Stephen Synder, and Marilyn Miller from the NIA, who are ex-officio members of the ADGC. Support was also provided by the Alzheimer's Association (IIRG-08-89720 [Dr Farrer] and IIRG-05-14147 [Dr Pericak-Vance]), National Institute of Neurological Disorders and Stroke grant NS39764, National Institute of Mental Health grant MH60451, GlaxoSmithKline, and the Office of Research and Development, Biomedical Laboratory Research Program, US Department of Veterans Affairs Administration. For the ADGC, biological samples and associated phenotypic data used in primary data analyses were stored at principal investigators' institutions and at the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University, funded by the NIA. Associated phenotypic data used in secondary data analyses were stored at the National Alzheimer's Coordinating Center and at the NIA Alzheimer's Disease Data Storage Site at the University of Pennsylvania, funded by the NIA. Contributors to the genetic analysis data included principal investigators on projects ndividually funded by the NIA, other NIH institutes, or private entities.

Funding Information:
We thank all Minority Aging Research Study and Latino Core participants and the Rush Alzheimer’s Disease Center staff. This database was funded by the NIH/NIA grants R01AG22018 (MARS) and P30AG 072975 (ADC).

Funding Information:
We thank the staff and participants of the CCHS and CGPS for their important contributions. This work was supported by the Research Council at Rigshospitalet and the Lundbeck Foundation (grant #R278-2018-804).

Funding Information:
The work for this manuscript was further supported by the CoSTREAM project (www.costream.eu)

Funding Information:
We would like to thank patients, controls and researchers who participated in GR@ACE/DEGESCO project. I. de Rojas is supported by national grant from the Instituto de Salud Carlos III FI20/00215. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National Rௗ+ௗDௗ+ௗI Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER— “Una manera de hacer Europa”). Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee.

Funding Information:
This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease) including funding from MEL (Metropole européenne de Lille), ERDF (European Regional Development Fund) and Conseil Régional Nord Pas de Calais. This work was supported by INSERM, the National Foundation for Alzheimer’s disease and related disorders, the Institut Pasteur de Lille and the Centre National de Recherche en Génomique Humaine, CEA, the JPND PERADES, the Laboratory of Excellence GENMED (Medical Genomics) grant no. ANR-10-LABX-0013 managed by the National Research Agency (ANR) part of the Investment for the Future program, and the FP7 AgedBrainSysBio. The Three-City Study was performed as part of collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Agence Nationale de la Recherche, ANR supported the COGINUT and COVADIS projects. Fondation de France and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Lille Génopôle received an unconditional grant from Eisai. The Three-city biological bank was developed and maintained by the laboratory for genomic analysis LAG-BRC - Institut Pasteur de Lille.

Funding Information:
We thank all individuals who participated in this study. Cardiff University was supported by the Wellcome Trust, Alzheimer’s Society (AS; grant RF014/164), the Medical Research Council (MRC; grants G0801418/1, MR/K013041/1, MR/L023784/1), the European Joint Programme for Neurodegenerative Disease (JPND, grant MR/L501517/1), Alzheimer’s Research UK (ARUK, grant ARUK-PG2014-1), Welsh Assembly Government (grant SGR544:CADR), a donation from the Moondance Charitable Foundation, UK Dementia’s Platform (DPUK, reference MR/L023784/1), and the UK Dementia Research Institute at Cardiff. Cambridge University acknowledges support from the MRC. ARUK supported sample collections at the Kings College London, the South West Dementia Bank, Universities of Cambridge, Nottingham, Manchester and Belfast. King’s College London was supported by the NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at the South London and Maudsley NHS Foundation Trust and Kings College London and the MRC. Alzheimer’s Research UK (ARUK) and the Big Lottery Fund provided support to Nottingham University. Ulster Garden Villages, AS, ARUK, American Federation for Aging Research, NI R&D Office and the Royal College of Physicians/Dunhill Medical Trust provided support for Queen’s University, Belfast. The University of Southampton acknowledges support from the AS. The MRC and Mercer’s Institute for Research on Ageing supported the Trinity College group. DCR is a Wellcome Trust Principal Research fellow. The South West Dementia Brain Bank acknowledges support from Bristol Research into Alzheimer’s and Care of the Elderly. The Charles Wolfson Charitable Trust supported the OPTIMA group. Washington University was funded by NIH grants, Barnes Jewish Foundation and the Charles and Joanne Knight Alzheimer’s Research Initiative. Patient recruitment for the MRC Prion Unit/UCL Department of Neurodegenerative Disease collection was supported by the UCLH/UCL Biomedical Research Centre and their work was supported by the NIHR Queen Square Dementia BRU, the Alzheimer’s Research UK and the Alzheimer’s Society. LASER-AD was funded by Lundbeck SA. The AgeCoDe study group was supported by the German Federal Ministry for Education and Research grants 01 GI 0710, 01 GI 0712, 01 GI 0713, 01 GI 0714, 01 GI 0715, 01 GI 0716, 01 GI 0717. Genotyping of the Bonn case-control sample was funded by the German centre for Neurodegenerative Diseases (DZNE), Germany. The GERAD Consortium also used samples ascertained by the NIMH AD Genetics Initiative. HH was supported by a grant of the Katharina-Hardt-Foundation, Bad Homburg vor der Höhe, Germany. The KORA F4 studies were financed by Helmholtz Zentrum München; German Research Center for Environmental Health; BMBF; German National Genome Research Network and the Munich Center of Health Sciences. The Heinz Nixdorf Recall cohort was funded by the Heinz Nixdorf Foundation (Dr. Jur. G.Schmidt, Chairman) and BMBF. We acknowledge use of genotype data from the 1958 Birth Cohort collection and National Blood Service, funded by the MRC and the Wellcome Trust which was genotyped by the Wellcome Trust Case Control Consortium and the Type-1 Diabetes Genetics Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Human Genome Research Institute, National Institute of Child Health and Human Development and Juvenile Diabetes Research Foundation International. The project is also supported through the following funding organisations under the aegis of JPND - www.jpnd.eu (United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)) and through the Motor Neurone Disease Association. This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Prof Jens Wiltfang is supported by an Ilídio Pinho professorship and iBiMED (UID/BIM/04501/2013), at the University of Aveiro, Portugal.

Funding Information:
The project has received funding from The Research Council of Norway (RCN) Grant Nos. 213837, 223273, 225989, 248778, and 251134 and EU JPND Program RCN Grant Nos. 237250, 311993, the South-East Norway Health Authority Grant No. 2013-123, the Norwegian Health Association, and KG Jebsen Foundation. The RCN FRIPRO Mobility grant scheme (FRICON) is co-funded by the European Union’s Seventh Framework Programme for research, technological development and demonstration under Marie Curie grant agreement No 608695. European Community’s grant PIAPP-GA-2011-286213 PsychDPC.

Funding Information:
The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P30 AG062428-01 (PI James Leverenz, MD) P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P30 AG062421-01 (PI Bradley Hyman, MD, PhD), P30 AG062422-01 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI Robert Vassar, PhD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P30 AG062429-01(PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P30 AG062715-01 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD). The genotypic and associated phenotypic data used in the study “Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer’s Disease (GenADA)” were provided by the GlaxoSmithKline, R&D Limited. ROSMAP study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute. The AddNeuroMed data are from a public-private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an Integrated Project funded by the European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5. Clinical leads responsible for data collection are Iwona Káoszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse), imaging leads are Andy Simmons (London), Lars-Olad Wahlund (Stockholm) and Christian Spenger (Zurich) and bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London).

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© 2022 American Medical Association. All rights reserved.

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