APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers’s disease
Year: 2026
Type: article
Study design: Observational Study
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.
Source: Nature Genetics
Authors: Jesper Qvist Thomassen, Hampton Leonard, Brittany Ulms, Benjamin Grenier-Boley, Sami Heikkinen, Pablo Garcia-González, Atahualapa Castillo-Morales, Masataka Kikuchi, Jungsoo Gim, Han Cao, Fahri Küçükali, Najaf Amin, Dabin Yoon, Itziar de Rojas, Pilar Alvarez Jerez, Victoria Alvarez, Beatrice Arosio, Céline Bellenguez, Sverre Bergh, Kimberley Billingsley, Cornelis Blauwendraat, Merce Boada, Barbara Borroni, Paola Bossù, María J. Bullido, Antonio Daniele, Ángel Carracedo, Alexandre de Mendonça, Mark Cookson, Jürgen Deckert, Martin Dichgans, Srdjan Djurovic, Oriol Dols-Icardo, Carole Dufouil, Emrah Düzel, Valentina Escott-Price, Tormod Fladby, Laura Fratiglioni, Amy K. Y. Fu, Daniela Galimberti, Jose Maria García-Alberca, Vilmantas Giedraitis, Guillermo Garcia-Ribas, Caroline Graff, Timo Grimmer, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Jakub Hort, Frank Jessen, Kendall Jensen, Caroline Jonson, Yoontae Kim, Nicole Kuznetsov, Ville Leinonen, Anssi Lipponen, Jiao Luo, Mary Makarious, Henna Martiskainen, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Pablo Mir, Akinori Miyashita, Susanne Moebus, Kin Y. Mok, Laura Molina Porcel, Fermin Moreno, Benedetta Nacmias, Lucilla Parnetti, Pau Pastor, Jordi Pérez-Tur, Oliver Peters, Yolande A. L. Pijnenburg, Gerard Piñol-Ripoll, Julius Popp, Innocenzo Rainero, Luis M. Real, Steffi Riedel-Heller, Eloy Rodriguez-Rodriguez, Arvid Rongve, Giacomina Rossi, Jose Luis Royo, Dan Rujescu, Ingvild Saltvedt, María Eugenia Sáez, Raquel Sánchez-Valle, Florentino Sanchez-Garcia, Nicolai Sandau, Nikolaos Scarmeas, Katja Scheffler, Norbert Scherbaum, Anja Schneider, Geir Selbæk, Davide Seripa, Vincenzo Solfrizzi, Marco Spallazzi, Alessio Squassina, Eystein Stordal, Niccoló Tesi, Lucio Tremolizzo, Kumar P. Tripathi, Wiesje M. van der Flier, Julie Williams, Jens Wiltfang, Dag Aarsland, Andrew B. Singleton, Philippe Amouyel, Stéphanie Debette, Magda Tsolaki, Gael Nicolas, Sven van der Lee, Henne Holstege, Maria Victoria Fernandez, Patrick Gavin Kehoe, Kristel Sleegers, Martin Ingelsson, Roberta Ghidoni, Ole A. Andreassen, Peter A. Holmans, Pascual Sánchez-Juan, Rebecca Sims, Nancy Y. Ip, Kun Ho Lee, Takeshi Ikeuchi, Alfredo Ramirez, Agustin Ruiz, Mikko Hiltunen, Jean-Charles Lambert, Cornelia van Duijn, Mike Nalls, Ruth Frikke-Schmidt
Institutions: Copenhagen University Hospital, Rigshospitalet, National Institutes of Health, National Institute on Aging, University of Oxford, Inserm, Université de Lille, Institut Pasteur de Lille, Centre Hospitalier Universitaire de Lille, University of Eastern Finland, Instituto de Salud Carlos III, Universitat Internacional de Catalunya, Biomedical Research Networking Center on Neurodegenerative Diseases, Universitat de Barcelona, UK Dementia Research Institute, Cardiff University, Niigata University, Chosun University, Hong Kong University of Science and Technology, University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, University of Luxembourg, Luxembourg Centre for Systems Biomedicine, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Innlandet Hospital Trust, Sykehuset i Vestfold, Norwegian National Centre for Ageing and Health, Coalition for Aligning Science, Centro San Giovanni di Dio Fatebenefratelli, University of Brescia, Fondazione Santa Lucia, Consejo Superior de Investigaciones Científicas, Hospital La Paz Institute for Health Research, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Università Cattolica del Sacro Cuore, Agostino Gemelli University Polyclinic, Istituti di Ricovero e Cura a Carattere Scientifico, Universidade de Santiago de Compostela, Centre for Biomedical Network Research on Rare Diseases, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago, University of Lisbon, University of Würzburg, Universitätsklinikum Würzburg, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, Oslo University Hospital, University of Oslo, Universitat Autònoma de Barcelona, Hospital de Sant Pau, Institut de Recerca Sant Pau, Université de Bordeaux, Bordeaux Population Health, Otto-von-Guericke-Universität Magdeburg, Akershus University Hospital, Karolinska University Hospital, Karolinska Institutet, HKUST Shenzhen Research Institute, Shenzhen Institutes of Advanced Technology, Uppsala University, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Technical University of Munich, University of Zurich, ETH Zurich, Psychiatrische Universitätsklinik Zürich, Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Hôpital Broca, Maladie d'Alzheimer : marqueurs génétiques et vasculaires, neuropsychologie, Heidelberg University, Central Institute of Mental Health, University of Bonn, University Hospital Bonn, Charles University, University Hospital in Motol, International Clinical Research Center, St. Anne's University Hospital Brno, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospital Cologne, Translational Genomics Research Institute, Kuopio University Hospital, University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Perugia, Alexandrovska Hospital, Medical University of Sofia, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Essen University Hospital, University of Duisburg-Essen, UCL Queen Square Institute of Neurology, University College London, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Biogipuzkoa Health Research Institute, Donostiako Unibertsitate Ospitalea, Don Carlo Gnocchi Foundation, University of Florence, University Hospital Mútua de Terrassa, Mútua Terrassa, Instituto de Biomedicina de Valencia, Humboldt-Universität zu Berlin, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Charité - Universitätsmedizin Berlin, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Hospital Universitari de Santa Maria, Instituto de Investigación Biomédica de Lleida, Centre Hospitalier Universitaire Vaudois, University Hospital Zurich, University of Turin, Hospital Universitario de Valme, Universidad de Málaga, Leipzig University, Universidad de Cantabria, Marqués de Valdecilla University Hospital, Instituto de Investigación Marqués de Valdecilla, Fondazione IRCCS Istituto Neurologico Carlo Besta, Martin Luther University Halle-Wittenberg, Medical University of Vienna, Norwegian University of Science and Technology, St Olav's University Hospital, Hospital Universitario de Gran Canaria Doctor Negrín, National and Kapodistrian University of Athens, Columbia University, Ospedale Vito Fazzi, Azienda Universitaria Ospedaliera Consorziale - Policlinico Bari, University of Bari Aldo Moro, University of Parma, Ospedale di Parma, University of Cagliari, Namsos Hospital, Delft University of Technology, Azienda Ospedaliera San Gerardo, University of Milano-Bicocca, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional Arturo Jauretche, Universitätsmedizin Göttingen, University of Aveiro, King's College London, Stavanger University Hospital, Aristotle University of Thessaloniki, Greek Association of Alzheimer's Disease and Related Disorders, Université de Rouen Normandie, VIB-KU Leuven Center for Brain & Disease Research, KU Leuven, University of Bristol, University Health Network, University of Toronto, Krembil Brain Institute, Fundacion Centro De Investigacion De Enfermedades Neurologicas, Korea Brain Research Institute, The University of Texas at San Antonio Health Science Center, Erasmus MC
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: U.S. Department of Health and Human Services, Hjerteforeningen, Amazon Web Services, Norges Teknisk-Naturvitenskapelige Universitet, Universidad de Málaga, Università degli Studi di Cagliari, Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease, Université de Lille, Korea Brain Research Institute, Amsterdam University Medical Centers, National Institute for Health and Care Research, King's College London, University of Oxford, Cardiff University, University of Bristol, Institut National de la Santé et de la Recherche Médicale, ZonMw, Technische Universiteit Delft, Vrije Universiteit Amsterdam, Consejo Nacional de Investigaciones Científicas y Técnicas, Università degli Studi di Milano-Bicocca, Lundbeckfonden, University of Toronto, KU Leuven, National and Kapodistrian University of Athens, Deutsches Zentrum für Neurodegenerative Erkrankungen, Universita degli Studi di Bari Aldo Moro, Universitetet i Oslo, Universitat de Barcelona, Universidad de Cantabria, Aristotle University of Thessaloniki, Universität zu Köln, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Universität Duisburg-Essen, Faculty of Health and Medical Sciences, University of Western Australia, Alzheimer Nederland, Universitätsklinikum Köln, H. Lundbeck A/S, Sykehuset Innlandet HF, Région Normandie, Instituto de Investigación Marqués de Valdecilla, Medical Research Council Centre for Neurodevelopmental Disorders, National Institutes of Health, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Research Committee, Aristotle University of Thessaloniki, Det Sundhedsvidenskabelige Fakultet, Københavns Universitet, Medisinske fakultet, Universitetet i Oslo, Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Faculty of Medicine and Health, University of Sydney
OpenAlex ID: W7212820066