Rare missense variant (R251G) on APOE counterbalances the Alzheimer’s disease risk associated with APOE‐ε4
Authors: Guen Yann Le , Belloy Michael E , Grenier‐Boley Benjamin , de Rojas Itziar , Castillo Atahualpa , Jansen Iris E , Nicolas Aude , Bellenguez Céline , Dalmasso Carolina , Küçükali Fahri , Eger Sarah J , Álvarez‐Martínez Victoria , Arosio Beatrice , Benussi Luisa , Boland Anne , Borroni Barbara , Bullido María J. , Caffarra Paolo , Clarimón Jordi , Daian Delphine , Daniele Antonio , Debette Stéphanie , Deleuze Jean‐François , Dichgans Martin , Dufouil Carole , Duzel Emrah , Galimberti Daniela , García‐Alberca Jose María , García‐González Pablo , Giedraitis Vilmantas , Grimmer Timo , Graff Caroline , Grunblatt Edna , Hanon Olivier , Hausner Lucrezia , Heilmann‐Heimbach Stefanie , Holstege Henne , Hort Jakub , Jurgen Deckert , Kuulasmaa Teemu , van der Lugt Aad , Masullo Carlo , Mecocci Patrizia , Mehrabian Shima , de Mendonça Alexandre , Boada Mercè , Mir Pablo , Moebus Susanne , Moreno Fermin , Nacmias Benedetta , Nicolas Gaël , Papenberg Goran , Parnetti Lucilla , Pasquier Florence , Pastor Pau , Peters Oliver , Pijnenburg Yolande A.L. , Piñol‐Ripoll Gerard , Popp Julius , Molina Laura , Puerta Raquel , Pérez‐Tur Jordi , Rainero Innocenzo , Ramakers Inez H.G.B. , Rasmussen Katrine Laura , Real Luis Miguel , Riedel‐Heller Steffi G. , Rodríguez Eloy Rodríguez , Royo José Luís , Rujescu Dan , Scarmeas Nikolaos , Scheltens Philip , Scherbaum Norbert , Schneider Anja , Seripa Davide , Soininen Hilkka , Solfrizzi Vincenzo , Spalletta Gianfranco , Squassina Alessio , van Swieten John C , Sanchez‐Valle Raquel , Tegos Thomas , Thomassen Jesper Qvist , Tremolizzo Lucio , Verhey Frans R.J. , Vyhnalek Martin , Wiltfang Jens , He Zihuai , Napolioni Valerio , Amouyel Philippe , Jessen Frank , Kehoe Patrick G , van Duijn Cornelia M , Tsolaki Magda , Sanchez‐Juan Pascual , Sleegers Kristel , Ingelsson Martin , Rossi Giacomina , Hiltunen Mikko , Sims Rebecca , van der Flier Wiesje M. , Ramirez Alfredo , Andreassen Ole , Frikke‐Schmidt Ruth , Williams Julie , Ruiz Agustin , Lambert Jean‐Charles , Greicius Michael D 
Published: December 2022

AbstractBackgroundDespite decades of research, the mechanisms linking APOE to Alzheimer’s disease (AD) remain poorly understood. Finding additional risk variants at the APOE locus, beyond the common APOE‐ε2 and APOE‐ε4 alleles, may help elucidate how APOE is involved in the disease.MethodAssociation 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+3) (Table 1). Stage 1 included 37,409 non‐unique participants of European or Admixed‐European ancestry, with 11,868 cases and 11,934 controls passing analysis inclusion criteria. In Stages 2+3, 475,473 participants were considered across 8 cohorts, of which 56,029 cases, 28,484 proxy‐AD cases, and 328,372 healthy‐controls passed inclusion criteria, and were of European ancestry.ResultTwo missense variants were associated with a two to three‐fold decreased AD risk: R251G (odds ratio, 0.44; 95% confidence interval [CI], 0.33‐0.59; P = 4.7×10‐8) and V236E (odds ratio, 0.37; 95% CI, 0.25‐0.56; P = 1.9×10‐6) (Table 2, Figures 1, 2). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared to non‐carriers (Table 3).ConclusionWe identified a novel variant associated with AD, R251G, which mitigates the ε4 associated AD risk, and confirmed the protective effect of the V236E variant. The location of the 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 have the potential to identify novel pathways for drug development.