Nature genetics · 2026

APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

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Thomassen Jesper Qvist, Leonard Hampton, Ulms Brittany, Grenier-Boley Benjamin, Heikkinen Sami, Garcia-González Pablo, Castillo-Morales Atahualapa, Kikuchi Masataka, Gim Jungsoo, Cao Han, Küçükali Fahri, Amin Najaf, Yoon Dabin, de Rojas Itziar, Alvarez Jerez Pilar, Alvarez Victoria, Arosio Beatrice, Bellenguez Céline, Bergh Sverre, Billingsley Kimberley, Blauwendraat Cornelis, Boada Merce, Borroni Barbara, Bossù Paola, Bullido María J, Daniele Antonio, Carracedo Ángel, de Mendonça Alexandre, Cookson Mark, Deckert Jürgen, Dichgans Martin, Djurovic Srdjan, Dols-Icardo Oriol, Dufouil Carole, Düzel Emrah, Escott-Price Valentina, Fladby Tormod, Fratiglioni Laura, Fu Amy K Y, Galimberti Daniela, García-Alberca Jose Maria, Giedraitis Vilmantas, Garcia-Ribas Guillermo, Graff Caroline, Grimmer Timo, Grünblatt Edna, Hanon Olivier, Hausner Lucrezia, Heilmann-Heimbach Stefanie, Hort Jakub, Jessen Frank, Jensen Kendall, Jonson Caroline, Kim Yoontae, Kuznetsov Nicole, Leinonen Ville, Lipponen Anssi, Luo Jiao, Makarious Mary, Martiskainen Henna, Masullo Carlo, Mecocci Patrizia, Mehrabian Shima, Mir Pablo, Miyashita Akinori, Moebus Susanne, Mok Kin Y, Molina Porcel Laura, Moreno Fermin, Nacmias Benedetta, Parnetti Lucilla, Pastor Pau, Pérez-Tur Jordi, Peters Oliver, Pijnenburg Yolande A L, Piñol-Ripoll Gerard, Popp Julius, Rainero Innocenzo, Real Luis M, Riedel-Heller Steffi, Rodriguez-Rodriguez Eloy, Rongve Arvid, Rossi Giacomina, Royo Jose Luis, Rujescu Dan, Saltvedt Ingvild, Sáez María Eugenia, Sánchez-Valle Raquel, Sanchez-Garcia Florentino, Sandau Nicolai, Scarmeas Nikolaos, Scheffler Katja, Scherbaum Norbert, Schneider Anja, Selbæk Geir, Seripa Davide, Solfrizzi Vincenzo, Spallazzi Marco, Squassina Alessio, Stordal Eystein, Tesi Niccoló, Tremolizzo Lucio, Tripathi Kumar P, van der Flier Wiesje M, Williams Julie, Wiltfang Jens, Aarsland Dag, Singleton Andrew B, Amouyel Philippe, Debette Stéphanie, Tsolaki Magda, Nicolas Gael, van der Lee Sven, Holstege Henne, Fernandez Maria Victoria, Kehoe Patrick Gavin, Sleegers Kristel, Ingelsson Martin, Ghidoni Roberta, Andreassen Ole A, Holmans Peter A, Sánchez-Juan Pascual, Sims Rebecca, Ip Nancy Y, Lee Kun Ho, Ikeuchi Takeshi, Ramirez Alfredo, Ruiz Agustin, Hiltunen Mikko, Lambert Jean-Charles, van Duijn Cornelia, Nalls Mike, Frikke-Schmidt Ruth

Аннотация

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.

APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

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Аннотация