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 - Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups
PY - 2022/7/1
Y1 - 2022/7/1
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 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.
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 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.
KW - Age of Onset
KW - Alleles
KW - Alzheimer Disease/epidemiology
KW - Apolipoprotein E2/genetics
KW - Apolipoprotein E4/genetics
KW - Apolipoproteins E/genetics
KW - Female
KW - Genotype
KW - Humans
KW - Male
UR - http://www.scopus.com/inward/record.url?scp=85134221014&partnerID=8YFLogxK
U2 - 10.1001/jamaneurol.2022.1166
DO - 10.1001/jamaneurol.2022.1166
M3 - Journal article
C2 - 35639372
SN - 2168-6149
VL - 79
SP - 652
EP - 663
JO - JAMA Neurology
JF - JAMA Neurology
IS - 7
ER -