TY - JOUR

T1 - Association of Rare APOE Missense Variants V236E and R251G with Risk of Alzheimer Disease

AU - Le Guen, Yann

AU - Belloy, Michael E.

AU - Grenier-Boley, Benjamin

AU - De Rojas, Itziar

AU - Castillo-Morales, Atahualpa

AU - Jansen, Iris

AU - Nicolas, Aude

AU - Bellenguez, Céline

AU - Dalmasso, Carolina

AU - Küçükali, Fahri

AU - Eger, Sarah J.

AU - Rasmussen, Katrine Laura

AU - Thomassen, Jesper Qvist

AU - Deleuze, Jean François

AU - He, Zihuai

AU - Napolioni, Valerio

AU - Amouyel, Philippe

AU - Jessen, Frank

AU - Kehoe, Patrick G.

AU - Van Duijn, Cornelia

AU - Tsolaki, Magda

AU - Sánchez-Juan, Pascual

AU - Sleegers, Kristel

AU - Ingelsson, Martin

AU - Rossi, Giacomina

AU - Hiltunen, Mikko

AU - Sims, Rebecca

AU - Van Der Flier, Wiesje M.

AU - Ramirez, Alfredo

AU - Andreassen, Ole A.

AU - Frikke-Schmidt, Ruth

AU - Williams, Julie

AU - Ruiz, Agustín

AU - Lambert, Jean Charles

AU - Greicius, Michael D.

AU - Arosio, Beatrice

AU - Benussi, Luisa

AU - Boland, Anne

AU - Borroni, Barbara

AU - Caffarra, Paolo

AU - Daian, Delphine

AU - Daniele, Antonio

AU - Debette, Stéphanie

AU - Dufouil, Carole

AU - Düzel, Emrah

AU - Galimberti, Daniela

AU - Giedraitis, Vilmantas

AU - Grimmer, Timo

AU - Graff, Caroline

AU - Grünblatt, Edna

AU - Hanon, Olivier

AU - Hausner, Lucrezia

AU - Heilmann-Heimbach, Stefanie

AU - Holstege, Henne

AU - Hort, Jakub

AU - Jürgen, Deckert

AU - Kuulasmaa, Teemu

AU - Van Der Lugt, Aad

AU - Masullo, Carlo

AU - Mecocci, Patrizia

AU - Mehrabian, Shima

AU - De Mendonça, Alexandre

AU - Moebus, Susanne

AU - Nacmias, Benedetta

AU - Nicolas, Gael

AU - Olaso, Robert

AU - Papenberg, Goran

AU - Parnetti, Lucilla

AU - Pasquier, Florence

AU - Peters, Oliver

AU - Pijnenburg, Yolande A.L.

AU - Popp, Julius

AU - Rainero, Innocenzo

AU - Ramakers, Inez

AU - Riedel-Heller, Steffi

AU - Scarmeas, Nikolaos

AU - Scheltens, Philip

AU - Scherbaum, Norbert

AU - Schneider, Anja

AU - Seripa, Davide

AU - Soininen, Hilkka

AU - Solfrizzi, Vincenzo

AU - Spalletta, Gianfranco

AU - Squassina, Alessio

AU - Van Swieten, John

AU - Tegos, Thomas J.

AU - Tremolizzo, Lucio

AU - Verhey, Frans

AU - Vyhnalek, Martin

AU - Wiltfang, Jens

AU - Boada, Mercè

AU - García-González, Pablo

AU - Puerta, Raquel

AU - Real, Luis M.

AU - Álvarez, Victoria

AU - Bullido, María J.

AU - Clarimon, Jordi

AU - García-Alberca, José María

AU - Mir, Pablo

AU - Moreno, Fermin

AU - Pastor, Pau

AU - Piñol-Ripoll, Gerard

AU - Molina-Porcel, Laura

AU - Pérez-Tur, Jordi

AU - Rodríguez-Rodríguez, Eloy

AU - Royo, Jose Luís

AU - Sánchez-Valle, Raquel

AU - Dichgans, Martin

AU - Rujescu, Dan

N1 - Publisher Copyright: © 2022 American Medical Association. All rights reserved.

PY - 2022

Y1 - 2022

N2 - 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..

AB - 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..

U2 - 10.1001/jamaneurol.2022.1166

DO - 10.1001/jamaneurol.2022.1166

M3 - Journal article

C2 - 35639372

AN - SCOPUS:85134221014

VL - 79

SP - 652

EP - 663

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

IS - 7

ER -