APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.
Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.
Authors
Thomassen Thomassen, Leonard Leonard, Ulms Ulms, Grenier-Boley Grenier-Boley, Heikkinen Heikkinen, Garcia-González Garcia-González, Castillo-Morales Castillo-Morales, Kikuchi Kikuchi, Gim Gim, Cao Cao, Küçükali Küçükali, Amin Amin, Yoon Yoon, de Rojas de Rojas, Alvarez Jerez Alvarez Jerez, Alvarez Alvarez, Arosio Arosio, Bellenguez Bellenguez, Bergh Bergh, Billingsley Billingsley, Blauwendraat Blauwendraat, Boada Boada, Borroni Borroni, BossĂą BossĂą, Bullido Bullido, Daniele Daniele, Carracedo Carracedo, de Mendonça de Mendonça, Cookson Cookson, Deckert Deckert, Dichgans Dichgans, Djurovic Djurovic, Dols-Icardo Dols-Icardo, Dufouil Dufouil, DĂĽzel DĂĽzel, Escott-Price Escott-Price, Fladby Fladby, Fratiglioni Fratiglioni, Fu Fu, Galimberti Galimberti, GarcĂa-Alberca GarcĂa-Alberca, Giedraitis Giedraitis, Garcia-Ribas Garcia-Ribas, Graff Graff, Grimmer Grimmer, GrĂĽnblatt GrĂĽnblatt, Hanon Hanon, Hausner Hausner, Heilmann-Heimbach Heilmann-Heimbach, Hort Hort, Jessen Jessen, Jensen Jensen, Jonson Jonson, Kim Kim, Kuznetsov Kuznetsov, Leinonen Leinonen, Lipponen Lipponen, Luo Luo, Makarious Makarious, Martiskainen Martiskainen, Masullo Masullo, Mecocci Mecocci, Mehrabian Mehrabian, Mir Mir, Miyashita Miyashita, Moebus Moebus, Mok Mok, Molina Porcel Molina Porcel, Moreno Moreno, Nacmias Nacmias, Parnetti Parnetti, Pastor Pastor, PĂ©rez-Tur PĂ©rez-Tur, Peters Peters, Pijnenburg Pijnenburg, Piñol-Ripoll Piñol-Ripoll, Popp Popp, Rainero Rainero, Real Real, Riedel-Heller Riedel-Heller, Rodriguez-Rodriguez Rodriguez-Rodriguez, Rongve Rongve, Rossi Rossi, Royo Royo, Rujescu Rujescu, Saltvedt Saltvedt, Sáez Sáez, Sánchez-Valle Sánchez-Valle, Sanchez-Garcia Sanchez-Garcia, Sandau Sandau, Scarmeas Scarmeas, Scheffler Scheffler, Scherbaum Scherbaum, Schneider Schneider, Selbæk Selbæk, Seripa Seripa, Solfrizzi Solfrizzi, Spallazzi Spallazzi, Squassina Squassina, Stordal Stordal, Tesi Tesi, Tremolizzo Tremolizzo, Tripathi Tripathi, van der Flier van der Flier, Williams Williams, Wiltfang Wiltfang, Aarsland Aarsland, Singleton Singleton, Amouyel Amouyel, Debette Debette, Tsolaki Tsolaki, Nicolas Nicolas, van der Lee van der Lee, Holstege Holstege, Fernandez Fernandez, Kehoe Kehoe, Sleegers Sleegers, Ingelsson Ingelsson, Ghidoni Ghidoni, Andreassen Andreassen, Holmans Holmans, Sánchez-Juan Sánchez-Juan, Sims Sims, Ip Ip, Lee Lee, Ikeuchi Ikeuchi, Ramirez Ramirez, Ruiz Ruiz, Hiltunen Hiltunen, Lambert Lambert, van Duijn van Duijn, Nalls Nalls, Frikke-Schmidt Frikke-Schmidt
View on Pubmed