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. 2022 Jul 1;79(7):652-663.
doi: 10.1001/jamaneurol.2022.1166.

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

Yann Le Guen  1   2 , Michael E Belloy  1 , Benjamin Grenier-Boley  3 , Itziar de Rojas  4   5 , Atahualpa Castillo-Morales  6 , Iris Jansen  7   8 , Aude Nicolas  3 , Céline Bellenguez  3 , Carolina Dalmasso  9   10 , Fahri Küçükali  11   12   13 , Sarah J Eger  1 , Katrine Laura Rasmussen  14   15 , Jesper Qvist Thomassen  14 , Jean-François Deleuze  16 , Zihuai He  1   17 , Valerio Napolioni  18 , Philippe Amouyel  3 , Frank Jessen  9   19   20 , Patrick G Kehoe  21 , Cornelia van Duijn  22   23 , Magda Tsolaki  24 , Pascual Sánchez-Juan  5   25 , Kristel Sleegers  11   12   13 , Martin Ingelsson  26   27   28 , Giacomina Rossi  29 , Mikko Hiltunen  30 , Rebecca Sims  31 , Wiesje M van der Flier  7 , Alfredo Ramirez  9   19   20   32   33 , Ole A Andreassen  34   35 , Ruth Frikke-Schmidt  14   15 , Julie Williams  6   31 , Agustín Ruiz  4   5 , Jean-Charles Lambert  3 , Michael D Greicius  1 ; Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups; Beatrice Arosio  36 , Luisa Benussi  37 , Anne Boland  16 , Barbara Borroni  38 , Paolo Caffarra  39 , Delphine Daian  16 , Antonio Daniele  40   41 , Stéphanie Debette  42   43 , Carole Dufouil  44   45 , Emrah Düzel  46   47 , Daniela Galimberti  48   49 , Vilmantas Giedraitis  26 , Timo Grimmer  50 , Caroline Graff  51 , Edna Grünblatt  52   53   54 , Olivier Hanon  55 , Lucrezia Hausner  56 , Stefanie Heilmann-Heimbach  57 , Henne Holstege  7   58 , Jakub Hort  59   60 , Deckert Jürgen  61 , Teemu Kuulasmaa  30 , Aad van der Lugt  62 , Carlo Masullo  63 , Patrizia Mecocci  64 , Shima Mehrabian  65 , Alexandre de Mendonça  66 , Susanne Moebus  67 , Benedetta Nacmias  68   69 , Gael Nicolas  70 , Robert Olaso  16 , Goran Papenberg  71 , Lucilla Parnetti  72 , Florence Pasquier  73 , Oliver Peters  74   75 , Yolande A L Pijnenburg  7 , Julius Popp  76   77   78 , Innocenzo Rainero  79 , Inez Ramakers  80 , Steffi Riedel-Heller  81 , Nikolaos Scarmeas  82   83 , Philip Scheltens  7 , Norbert Scherbaum  84 , Anja Schneider  19   32 , Davide Seripa  85 , Hilkka Soininen  86 , Vincenzo Solfrizzi  87 , Gianfranco Spalletta  88   89 , Alessio Squassina  90 , John van Swieten  91 , Thomas J Tegos  24 , Lucio Tremolizzo  92 , Frans Verhey  80 , Martin Vyhnalek  59   60 , Jens Wiltfang  93   94   95 , Mercè Boada  4   5 , Pablo García-González  4   5 , Raquel Puerta  4 , Luis M Real  96   97 , Victoria Álvarez  98   99 , María J Bullido  5   100   101 , Jordi Clarimon  5   102 , José María García-Alberca  5   103 , Pablo Mir  5   104 , Fermin Moreno  5   105   106 , Pau Pastor  107   108 , Gerard Piñol-Ripoll  109   110 , Laura Molina-Porcel  111   112 , Jordi Pérez-Tur  5   113   114 , Eloy Rodríguez-Rodríguez  5   115 , Jose Luís Royo  97 , Raquel Sánchez-Valle  116 , Martin Dichgans  117   118   119 , Dan Rujescu  120
Affiliations

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

Yann Le Guen et al. JAMA Neurol. .

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 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 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, 76 195 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 544 384 participants were analyzed in the primary case-control analysis; 312 476 (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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Belloy 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 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.

Figures

Figure 1.
Figure 1.. Association of V236E and R251G With Alzheimer Disease (AD) Risk Across All Cohorts
Forest plots show the results for the non–APOE-stratified analyses adjusted by ε2 and ε4 dosages. eFigure 2 in Supplement 1 presents equivalent forest plots for these 2 variants in the APOE-stratified sensitivity analyses, showing consistent findings. ADGC indicates Alzheimer’s Disease Genetic Consortium; ADSP, Alzheimer’s Disease Sequencing Project; CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; DemGene, Norwegian Dementia Genetics Network; EADB, European Alzheimer’s Disease DNA Biobank; EADI, European Alzheimer’s Disease Initiative; GERAD, Genetic and Environmental Risk in Alzheimer's Disease Consortium; GR@ACE, Genome Research at Fundació Alzheimer Center Barcelona; TOPMed, Trans-Omics for Precision Medicine; WES, whole-exome sequencing; WGS, whole-genome sequencing.
Figure 2.
Figure 2.. Risk Equivalence of APOE ε3/ε3 (V236E) and APOE ε3/ε4 (R251G) to ε2/ε3 Carriers
Alzheimer disease risk per APOE genotype was compared with the APOE ε3/ε3 reference group (ie, odds ratio [OR] for APOE ε3/ε3 equals to 1), meta-analyzing results from the Alzheimer’s Disease Genetic Consortium and Alzheimer’s Disease Sequencing Project cohorts (stages 1 and 2). eFigure 3 in Supplement 1 presents equivalent results at different inclusion cutoffs for European ancestry.
See this image and copyright information in PMC

Comment in

  • doi: 10.1001/jamaneurol.2022.0854

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