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. Genome-wide association analyses of Alzheimer’s disease stratified by APOE carrier status identify variants whose effects are attenuated or augmented by the ε4 risk allele.

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Journal
Nature Genetics
Published
2026-09-14
DOI
https://doi.org/10.1038/s41588-026-02713-9
Primary Topic
Alzheimer's disease research and treatments
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article
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article

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

Laura Molina‐Porcel, Najaf Amin, Kimberley J. Billingsley, Ingvild Saltvedt et al.
Nature Genetics
Alzheimer's disease research and treatments
article

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

Laura Molina‐Porcel, Najaf Amin, Kimberley J. Billingsley, Ingvild Saltvedt, Geir Selbæk, Luís Miguel Real, Olivier Hanon, Caroline Graff, Giacomina Rossi, Caroline Jonson, Laura Fratiglioni, Patrizia Mecocci, Pablo Mir, Oliver Peters, Lucilla Parnetti, Vilmantas Giedraitis, Timo Grimmer, Julius Popp, Jungsoo Gim, Nicolai Sandau, Eloy Rodríguez‐Rodríguez, Norbert Scherbaum, Valentina Escott‐Price, Pau Pástor, Pilar Álvarez Jerez, Henna Martiskainen, Victoria Álvarez, Ville Leinonen, Y T Kim, Dan Rujescu, Lucrezia Hausner, Raquel Sánchez‐Valle, Jürgen Deckert, José María García‐Alberca, Carlo Masullo, Merçé Boada, Anssi Lipponen, Srdjan Djurovic, Davide Seripa, Alessio Squassina, Katja Scheffler, Stefanie Heilmann‐Heimbach, Fahri Küçükali, María J. Bullido, Jesper Qvist Thomassen, Carole Dufouil, Benedetta Nacmias, Sverre Bergh, Amy K.Y. Fu, Martin Dichgans, Steffi G. Riedel‐Heller, Céline Bellenguez, Tormod Fladby, María Eugenia Sáez, Sami Heikkinen, Jordi Pérez‐Tur, Masataka Kikuchi, Cornelis Blauwendraat, Eystein Stordal, Edna Grünblatt, Beatrice Arosio, Anja Schneider, Susanne Moebus, Arvid Rongve, Innocenzo Rainero, Jakub Hort, Daniela Galimberti, Oriol Dols‐Icardo, Pablo García‐González, Han Cao, Fermín Moreno, Akinori Miyashita, Vincenzo Solfrizzi, Dabin Yoon, Nicole Kuznetsov, Benjamin Grenier‐Boley, Brittany Ulms, Mark R Cookson, Mary Makarious, Hampton Leonard, Jiao Luo, Florentino Sanchez-Garcia, Guillermo Garcia-Ribas, Atahualapa Castillo-Morales, Shima Mehrabian, Nikolaos Scarmeas, Ángel Carracedo, Paola Bossù, Gerard Piñol-Ripoll, Alexandre de Mendonça, Marco Spallazzi, Emrah Düzel, Frank Jessen, Yolande A. L. Pijnenburg, Barbara Borroni, Kin Y. Mok, Itziar de Rojas, Jose Luis Royo, Kendall Jensen, Antonio Daniele
article en

Abstract

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. Genome-wide association analyses of Alzheimer’s disease stratified by APOE carrier status identify variants whose effects are attenuated or augmented by the ε4 risk allele.

Nature Genetics
Università Cattolica del Sacro Cuore (IT), Universitat Autònoma de Barcelona (ES), Uppsala University (SE), University of Copenhagen (DK), University of Parma (IT), Oslo University Hospital (NO), Translational Genomics Research Institute (US), Universidad de Cantabria (ES), Karolinska University Hospital (SE), University of Bonn (DE), University of Lisbon (PT), University of Antwerp (BE), Université de Bordeaux (FR), Chosun University (KR), Inserm (FR), University of Cagliari (IT), University of Eastern Finland (FI), University of Cologne (DE), University of Oslo (NO), University of Luxembourg (LU), University of Milan (IT), Universidade de Santiago de Compostela (ES), Hong Kong University of Science and Technology (HK), National and Kapodistrian University of Athens (GR), University of Zurich (CH), Université Paris Cité (FR), Norwegian University of Science and Technology (NO), Charles University (CZ), Heidelberg University (DE), Innlandet Hospital Trust (NO), Université de Lille (FR), University of Perugia (IT), Alexandrovska Hospital (BG), University Hospital Bonn (DE), Akershus University Hospital (NO), Institut Pasteur de Lille (FR), Novo Nordisk Foundation (DK), German Center for Neurodegenerative Diseases (DE), Privatsykehuset Haugesund (NO), Hospital de Sant Pau (ES), Sykehuset i Vestfold (NO), Agostino Gemelli University Polyclinic (IT), Copenhagen University Hospital (DK), Rigshospitalet (DK), Namsos Hospital (NO), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), Medical University of Sofia (BG), Centre Hospitalier Universitaire de Lille (FR), LMU Klinikum (DE), Universitat Internacional de Catalunya (ES), ETH Zurich (CH), Humboldt-Universität zu Berlin (DE), University of Oxford (GB), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Hospital Universitari de Santa Maria (ES), Kuopio University Hospital (FI), Azienda Universitaria Ospedaliera Consorziale - Policlinico Bari (IT), University Hospital Mútua de Terrassa (ES), HKUST Shenzhen Research Institute (CN), Assistance Publique – Hôpitaux de Paris (FR), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Marqués de Valdecilla University Hospital (ES), Biogipuzkoa Health Research Institute (ES), University Hospital of Zurich (CH), University Hospital Brno (CZ), Hospital La Paz Institute for Health Research (ES), St Olav's University Hospital (NO), Central Institute of Mental Health (DE), Bordeaux Population Health (FR), Hôpital Broca (FR), Amsterdam Neuroscience (NL), Centro Andaluz de Biología del Desarrollo (ES), Center for Research in Molecular Medicine and Chronic Diseases (ES), Instituto de Investigación Marqués de Valdecilla (ES), Munich Cluster for Systems Neurology (DE), Centro San Giovanni di Dio Fatebenefratelli (IT), Hospital Clínic de Barcelona (ES), Don Carlo Gnocchi Foundation (IT), Fundación Pública Galega de Medicina Xenómica (ES), Swiss Integrative Center for Human Health (CH), Universitätsklinikum Würzburg (DE), UK Dementia Research Institute (GB), Instituto Ramón y Cajal de Investigación Sanitaria (ES), Mútua Terrassa (ES), VIB-UAntwerp Center for Molecular Neurology (BE), Instituto de Biomedicina de Sevilla (ES), Instituto de Investigación Biomédica de Lleida (ES), Hospital Universitario Central de Asturias (ES), National Institute on Aging (US), St. Anne's University Hospital Brno (CZ), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Eginition Hospital (GR), Centro de Biología Molecular Severo Ochoa (ES), Hospital Universitario de Valme (ES), Instituto de Biomedicina de Valencia (ES), Fondazione Santa Lucia (IT), Ospedale Vito Fazzi (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Hospital Universitario Virgen del Rocío (ES), University Hospital Cologne (DE), Hospital Universitario Ramón y Cajal (ES), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Maladie d'Alzheimer : marqueurs génétiques et vasculaires, neuropsychologie (FR), Institut für Schlaganfall- und Demenzforschung (DE), University of Florence (IT), University College London (GB), University of Turin (IT), University of Bari Aldo Moro (IT), University of Duisburg-Essen (DE), Technical University of Munich (DE), Universidad Autónoma de Madrid (ES), Martin Luther University Halle-Wittenberg (DE), Niigata University (JP), Universitat de Barcelona (ES), Medical University of Vienna (AT), Columbia University (US), Gwangju University (KR), Universidad de Sevilla (ES), Cardiff University (GB), University of Brescia (IT), Ludwig-Maximilians-Universität München (DE), Universidad de Málaga (ES), Vrije Universiteit Amsterdam (NL), University of Hong Kong (HK), Amsterdam UMC Location Vrije Universiteit Amsterdam (NL), Leipzig University (DE), Otto-von-Guericke-Universität Magdeburg (DE), University of Lausanne (CH)
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Alzheimer's disease research and treatments
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