RT Journal Article
T1 Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.
A1 Le-Guen, Yann
A1 Belloy, Michael E
A1 Grenier-Boley, Benjamin
A1 de-Rojas, Itziar
A1 Castillo-Morales, Atahualpa
A1 Jansen, Iris
A1 Nicolas, Aude
A1 Bellenguez, Céline
A1 Dalmasso, Carolina
A1 Küçükali, Fahri
A1 Eger, Sarah J
A1 Rasmussen, Katrine Laura
A1 Thomassen, Jesper Qvist
A1 Deleuze, Jean-François
A1 He, Zihuai
A1 Napolioni, Valerio
A1 Amouyel, Philippe
A1 Jessen, Frank
A1 Kehoe, Patrick G
A1 van Duijn, Cornelia
A1 Tsolaki, Magda
A1 Sanchez-Juan, Pascual
A1 Sleegers, Kristel
A1 Ingelsson, Martin
A1 Rossi, Giacomina
A1 Hiltunen, Mikko
A1 Sims, Rebecca
A1 van-der-Flier, Wiesje M
A1 Ramirez, Alfredo
A1 Andreassen, Ole A
A1 Frikke-Schmidt, Ruth
A1 Williams, Julie
A1 Ruiz, Agustín
A1 Lambert, Jean-Charles
A1 Greicius, Michael D
A1 Arosio, Beatrice
A1 Benussi, Luisa
A1 Boland, Anne
A1 Borroni, Barbara
A1 Caffarra, Paolo
A1 Daian, Delphine
A1 Daniele, Antonio
A1 Debette, Stéphanie
A1 Dufouil, Carole
A1 Düzel, Emrah
A1 Galimberti, Daniela
A1 Giedraitis, Vilmantas
A1 Grimmer, Timo
A1 Graff, Caroline
A1 Grünblatt, Edna
A1 Hanon, Olivier
A1 Hausner, Lucrezia
A1 Heilmann-Heimbach, Stefanie
A1 Holstege, Henne
A1 Hort, Jakub
A1 Jürgen, Deckert
A1 Kuulasmaa, Teemu
A1 van-der-Lugt, Aad
A1 Masullo, Carlo
A1 Mecocci, Patrizia
A1 Mehrabian, Shima
A1 de-Mendonça, Alexandre
A1 Moebus, Susanne
A1 Nacmias, Benedetta
A1 Nicolas, Gael
A1 Olaso, Robert
A1 Papenberg, Goran
A1 Parnetti, Lucilla
A1 Pasquier, Florence
A1 Peters, Oliver
A1 Pijnenburg, Yolande A L
A1 Popp, Julius
A1 Rainero, Innocenzo
A1 Ramakers, Inez
A1 Riedel-Heller, Steffi
A1 Scarmeas, Nikolaos
A1 Scheltens, Philip
A1 Scherbaum, Norbert
A1 Schneider, Anja
A1 Seripa, Davide
A1 Soininen, Hilkka
A1 Solfrizzi, Vincenzo
A1 Spalletta, Gianfranco
A1 Squassina, Alessio
A1 van-Swieten, John
A1 Tegos, Thomas J
A1 Tremolizzo, Lucio
A1 Verhey, Frans
A1 Vyhnalek, Martin
A1 Wiltfang, Jens
A1 Boada, Merce
A1 García-González, Pablo
A1 Puerta, Raquel
A1 Real, Luis M
A1 Alvarez, Victoria
A1 Bullido, Maria J
A1 Clarimon, Jordi
A1 Garcia-Alberca, Jose Maria
A1 Mir, Pablo
A1 Moreno, Fermin
A1 Pastor, Pau
A1 Piñol-Ripoll, Gerard
A1 Molina-Porcel, Laura
A1 Perez-Tur, Jordi
A1 Rodriguez-Rodriguez, Eloy
A1 Royo, Jose Luis
A1 Sanchez-Valle, Raquel
A1 Dichgans, Martin
A1 Rujescu, Dan
K1 Age of Onset
K1 Alzheimer Disease
K1 Apolipoproteins E
K1 Genotype
K1 Humans
AB 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. To determine whether rare missense variants on APOE are associated with AD risk. 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. 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. 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. 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.
PB American Medical Association
YR 2022
FD 2022-05-31
LK http://hdl.handle.net/10668/22161
UL http://hdl.handle.net/10668/22161
LA en
NO Le Guen Y, Belloy ME, Grenier-Boley B, de Rojas I, Castillo-Morales A, Jansen I, et al. Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease. JAMA Neurol. 2022 Jul 1;79(7):652-663.
DS RISalud
RD Apr 10, 2025