Transferability of European-derived Alzheimer’s disease polygenic risk scores across multiancestry populations

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

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Journal
Nature Genetics
Published
2025-06-18
DOI
https://doi.org/10.1038/s41588-025-02227-w
Citations
11
Primary Topic
Genetic Associations and Epidemiology
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article
Field-Weighted Citation Impact
19.99

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article

Transferability of European-derived Alzheimer’s disease polygenic risk scores across multiancestry populations

Emrah Düzel, Yann Le Guen, Gonzálo Arboleda, Victoria C. Merritt et al.
11 citations
Nature Genetics
Genetic Associations and Epidemiology
19.99
article

Transferability of European-derived Alzheimer’s disease polygenic risk scores across multiancestry populations

Emrah Düzel, Yann Le Guen, Gonzálo Arboleda, Victoria C. Merritt, Norikazu Hara, Paolo Caffarra, Anita L. DeStefano, Ellen M. Wijsman, Laura Molina‐Porcel, Jean‐Charles Lambert, Martin Ingelsson, John Cornelis Van Swieten, Aad van der Lugt, Maëlenn Guerchet, Katrine Laura Rasmussen, Geir Selbæk, Jens Wiltfang, Clifton L. Dalgard, Luís Miguel Real, Lorenzo Campanelli, Bernardo de Mattos Viana, Olivier Hanon, Sudha S. Seshadri, Caroline Graff, Jurgen A.H.R. Claassen, Giacomina Rossi, María F. Mahecha, Patricia Solís, Agustı́n Ruiz, Bébène Bandzouzi, Monica Goss, Kristel Sleegers, Rafael Aránguiz, Cornelia M. van Duijn, Patrizia Mecocci, Pablo Mir, Silvia Kochen, Oliver Peters, Lucilla Parnetti, Paulina Orellana, Ole A. Andreassen, Vilmantas Giedraitis, Jonathan L. Haines, Xiaopu Zhou, Shahram Bahrami, Julius Popp, Takeshi Ikeuchi, Mark W. Logue, Eloy Rodríguez‐Rodríguez, Philip Scheltens, Laura Morelli, Andrew J. Saykin, David Wallon, Norbert Scherbaum, Itziar de Rojas, Kun Ho Lee, Patrick G. Kehoe, Valentina Escott‐Price, Pau Pástor, Jenny Ortega-Rojas, Karen A. Mather, Natividad Olivar, Daniel Gustavo Politis, Bárbara Ángel, Alfredo Ramı́rez, Wiesje M. van der Flier, Teresa Juárez‐Cedillo, Hampton L. Leonard, Philippe Amouyel, Luis Ignacio Brusco, Yuk Yee Leung, Fanny C.F. Ip, José Luís Royo, Vera Fominykh, Nancy Y. Ip, Patricio Fuentes, Lindsay A. Farrer, Cecilia Albala, Alexandre de Mendonça, Humberto Arboleda, María Victoria Chacón, Victoria Álvarez, Carlos C Cruchaga, Rebecca Sims, Perminder Singh Sachdev, Mike A. Nalls, Y T Kim, Dan Rujescu, Gerard Piñol‐Ripoll, Lucrezia Hausner, Christian González‐Billault, Edgar Nunes de Moraes, Raquel Sánchez‐Valle, Henne Holstege, Pierre‐Marie Preux, Harro Seelaar, Jean‐François Deleuze, Maria Aparecida Camargos Bicalho, Marco Túlio Gualberto Cintra, José María García‐Alberca, Carlo Masullo, Julie Williams, Lotfi Cherni, Merçé Boada, Richard L. Hauger, Kouichi Ozaki, Davide Seripa, Alessio Squassina, Frans R.J. Verhey, Stefanie Heilmann‐Heimbach, Bernard Fongang, Inez H.G.B. Ramakers, Fahri Küçükali, Sven J. van der Lee, María J. Bullido, Pascal M'Belesso, Jesper Qvist Thomassen, Carole Dufouil, Benedetta Nacmias, Amy K.Y. Fu, Martin Dichgans, Jennifer S. Yokoyama, Sergio Gloger, Carolina Muchnik, Magda Tsolaki, Pascual Sánchez‐Juan, Jürgen Deckert, Martin Vyhnálek, Lucio Tremolizzo, Frank Jessen, Andrea Slachevsky, Anne Boland, Goran Papenberg, Steffi Gerlinde Riedel-Heller, Céline Bellenguez, Roberta Ghidoni, Margaret A. Pericak‐Vance, Sami Heikkinen, Jordi Pérez‐Tur, Atahualpa Castillo-Morales, Mikko Hiltunen, Masataka Kikuchi, Edna Grünblatt, Michael D. Greicius, Matthew S. Panizzon, Beatrice Arosio, Anja Schneider, Carolina Dalmasso, Stéphanie Debette, Richard P Mayeux, Richard Sherva, Nikolaos Scarmeas, Susanne Moebus, Hilkka Soininen, Raquel Puerta, Willemijn J. Jansen, Innocenzo Rainero, Jakub Hort, Ruth Frikke‐Schmidt, Tenielle Porter, Daniela Galimberti, Nesrine Ben Salem, Shumpei Niida, Marco Aurélio Romano‐Silva, Shima Mehrabian, Oriol Dols‐Icardo, Brian W. Kunkle, Pablo García‐González, Simon M. Laws, Han Cao, Gaël Nicolas, Fermín Moreno, Anthony J. Griswold, Alison Goate, Akinori Miyashita, Barbara Borroni, Thomas Tegos, Vincenzo Solfrizzi, Badri Narayan Vardarajan, Tatiana Forund, Rui Zhang, Rodrigo Pardo, Qiong Yang, Carlos Bustos, Yolande A.L. Pijnenburg, Luiz Armando De Marco, Aude Nicolas, Claudia Liliana Satizábal, Timo Grimmer, Gerard D. Schellenberg, Li-San Wang, Jigyasha Timsina, J. Michael Gaziano, Antonio Daniele, Carolina De La Cuesta, Ana Gabriela Concha Mera, Jean‐François Dartigues, Latchezar Traykov, Fabrizio Piras, Florence Pasquier, Benjamin Grenier‐Boley
article en
11 citations

Abstract

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.

Nature GeneticsVol. 57(7)
Università Cattolica del Sacro Cuore (IT), Tunis University (TN), Universidade Federal de Minas Gerais (BR), Boston University (US), Edith Cowan University (AU), Universitat Autònoma de Barcelona (ES), Uppsala University (SE), University of Copenhagen (DK), University of Parma (IT), Alzheimer's Association (US), Oslo University Hospital (NO), Brigham and Women's Hospital (US), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), Universidad de Cantabria (ES), University Health Network (CA), University Medical Center Groningen (NL), Karolinska University Hospital (SE), University of Helsinki (FI), Vrije Universiteit Brussel (BE), University of Bonn (DE), Harvard University (US), Instituto Federal de Educação, Ciência e Tecnologia de Minas Gerais (BR), University of Lisbon (PT), University of Nottingham (GB), University of Miami (US), University of Thessaly (GR), Radboud University Nijmegen (NL), Uniformed Services University of the Health Sciences (US), University of Antwerp (BE), Université de Bordeaux (FR), Consejo Nacional de Investigaciones Científicas y Técnicas (AR), Chosun University (KR), University of Leicester (GB), University of Auckland (NZ), Inserm (FR), Universität Hamburg (DE), Tokyo University of Science (JP), Bangor University (GB), Stockholm University (SE), Mexican Social Security Institute (MX), The University of Texas at San Antonio Health Science Center (US), University of Monastir (TN), University of Cagliari (IT), University of Eastern Finland (FI), University of California, San Francisco (US), University of Cologne (DE), University of Oslo (NO), University of Milan (IT), Université de Montpellier (FR), Universidade de Santiago de Compostela (ES), Hong Kong University of Science and Technology (HK), National and Kapodistrian University of Athens (GR), University of Washington (US), University of Zurich (CH), Washington University in St. Louis (US), Norwegian University of Science and Technology (NO), Curtin University (AU), Adolfo Ibáñez University (CL), Charles University (CZ), Aristotle University of Thessaloniki (GR), Heidelberg University (DE), Université de Lille (FR), University of Cambridge (GB), Universidad de Buenos Aires (AR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), University of Perugia (IT), Université Paris-Saclay (FR), Alexandrovska Hospital (BG), University Hospital Bonn (DE), Stavanger University Hospital (NO), Helsinki University Hospital (FI), Hospital Universitario La Paz (ES), Institut Pasteur de Lille (FR), McLean Hospital (US), Instituto de Salud Carlos III (ES), German Center for Neurodegenerative Diseases (DE), Privatsykehuset Haugesund (NO), VA Boston Healthcare System (US), Fundación Instituto Leloir (AR), Hospital de Sant Pau (ES), Clínica Alemana (CL), University of Washington Medical Center (US), Erasmus MC (NL), Sykehuset i Vestfold (NO), Agostino Gemelli University Polyclinic (IT), Copenhagen University Hospital (DK), Gentofte Hospital (DK), TUM Klinikum (DE), Rigshospitalet (DK), Radboud University Medical Center (NL), Namsos Hospital (NO), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Karolinska Institutet (SE), El Hospital General de Agudos Carlos G. Durand (AR), Medical University of Sofia (BG), Centre Hospitalier Universitaire de Bordeaux (FR), University Medical Center Utrecht (NL), Centre Hospitalier Universitaire de Lille (FR), LMU Klinikum (DE), Hospital Universitari i Politècnic La Fe (ES), Donauspital (AT), Universitat Internacional de Catalunya (ES), UNSW Sydney (AU), Harokopio University of Athens (GR), Maastricht University (NL), University of Cyprus (CY), ETH Zurich (CH), University of Bristol (GB), Universidad Nacional de Colombia (CO), University of California San Diego (US), Humboldt-Universität zu Berlin (DE), Swansea University (GB), Finnish Institute for Health and Welfare (FI), Sorbonne Université (FR), University of Oxford (GB), Centre National de Recherche en Génomique Humaine (FR), Data Tecnica International (United States) (US), Neuropsychiatrie : Recherche Epidemiologique et Clinique (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Universitätsklinikum Erlangen (DE), Instituto de Salud Pública de Chile (CL), Hospital Universitari de Santa Maria (ES), Kuopio University Hospital (FI), Stockholm South General Hospital (SE), University Hospital Mútua de Terrassa (ES), HKUST Shenzhen Research Institute (CN), Assistance Publique – Hôpitaux de Paris (FR), University Hospital in Motol (CZ), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Hospital del Salvador (CL), Zimmer Biomet (Germany) (DE), VA San Diego Healthcare System (US), Marqués de Valdecilla University Hospital (ES), Biogipuzkoa Health Research Institute (ES), University Hospital of Zurich (CH), University Hospital Brno (CZ), Dementia Collaborative Research Centres (AU), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Hospital La Paz Institute for Health Research (ES), National Center for PTSD (US), St Olav's University Hospital (NO), Central Institute of Mental Health (DE), Alzheimer’s Disease Neuroimaging Initiative (US), Normandie Université (FR), Bordeaux Population Health (FR), Hôpital Broca (FR), Amsterdam Neuroscience (NL), University Medical Center Hamburg-Eppendorf (DE), Ministry of Health (CL), Radboud Institute for Molecular Life Sciences (NL), Azienda Ospedaliera San Gerardo (IT), Occupational Cancer Research Centre (CA), Centro Andaluz de Biología del Desarrollo (ES), Institute for Neurodegenerative Disorders (US), University of Bangui (CF), Instituto de Investigación Marqués de Valdecilla (ES), Munich Cluster for Systems Neurology (DE), Centro San Giovanni di Dio Fatebenefratelli (IT), Centre Hospitalier et Universitaire de Brazzaville (CG), Hospital Clínic de Barcelona (ES), Azienda Ospedaliero-Universitaria Careggi (IT), Don Carlo Gnocchi Foundation (IT), Essen University Hospital (DE), Centro Medico Nacional Siglo XXI (MX), Pitié-Salpêtrière Hospital (FR), Framingham Heart Study (US), Fundación Pública Galega de Medicina Xenómica (ES), Swiss Integrative Center for Human Health (CH), Fundació ACE (ES), Universitätsklinikum Würzburg (DE), UK Dementia Research Institute (GB), Universitair Ziekenhuis Brussel (BE), Instituto Ramón y Cajal de Investigación Sanitaria (ES), CEA Paris-Saclay (FR), Mútua Terrassa (ES), Hospital Clínico de la Universidad de Chile (CL), Dr. John T. Macdonald Foundation (US), 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), Hospital das Clínicas da Universidade Federal de Minas Gerais (BR), MRC Prion Unit (GB), St. Anne's University Hospital Brno (CZ), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Eginition Hospital (GR), Onkologikoa (ES), Centro de Biología Molecular Severo Ochoa (ES), Hospital Universitario de Valme (ES), Complex Engineering System Institute (CL), Stockholm Gerontology Research Center Foundation (SE), Instituto de Biomedicina de Valencia (ES), Center for Climate and Resilience Research (CL), Fondazione Santa Lucia (IT), Unidad Funcional de Investigación de Enfermedades Crónicas (ES), National Hospital for Neurology and Neurosurgery (GB), Eisai (United States) (US), Amsterdam University Medical Centers (NL), Institut d’Epidémiologie Neurologique et de Neurologie Tropicale (FR), Ospedale Vito Fazzi (IT), Institut du Cerveau (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Hospital Universitario Virgen del Rocío (ES), Hospital Universitari Germans Trias i Pujol (ES), University Hospital Cologne (DE), Fundacion Centro De Investigacion De Enfermedades Neurologicas (ES), Greek Association of Alzheimer's Disease and Related Disorders (GR), Ontario Brain Institute (CA), National Center for Geriatrics and Gerontology (JP), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Hospital Universitario Ramón y Cajal (ES), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), VSL National Metrology Institute (NL), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Institut de Recherche pour le Développement (FR), University of Southampton (GB), Alzheimer Precision Medicine (FR), University of Bergen (NO), University of Florence (IT), University College London (GB), Imperial College London (GB), Nottingham Trent University (GB), University of Turin (IT), University of Bari Aldo Moro (IT), Indiana University – Purdue University Indianapolis (US), Case Western Reserve University (US), University of Duisburg-Essen (DE), Université de Rouen Normandie (FR), Technical University of Munich (DE), Tunis El Manar University (TN), Universidad Autónoma de Madrid (ES), Université de Limoges (FR), University of Milano-Bicocca (IT), University of Chile (CL), Niigata University (JP), The University of Tokyo (JP), Medical University of Vienna (AT), Columbia University (US), Charité - Universitätsmedizin Berlin (DE), Gwangju University (KR), Universidad de Sevilla (ES), Cardiff University (GB), University of Pennsylvania (US), University of Brescia (IT), Ludwig-Maximilians-Universität München (DE), Universidad de Málaga (ES), Vrije Universiteit Amsterdam (NL), University of Hong Kong (HK), Centro de Estudios Científicos (CL), Amsterdam UMC Location Vrije Universiteit Amsterdam (NL), Erasmus University Rotterdam (NL), Leipzig University (DE), Otto-von-Guericke-Universität Magdeburg (DE), Stanford University (US), University of Lausanne (CH), Delft University of Technology (NL), Icahn School of Medicine at Mount Sinai (US), KU Leuven (BE)
EU Joint Programme – Neurodegenerative Disease Research, Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease, Université de Lille, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Fondation pour la Recherche sur Alzheimer
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Genetic Associations and Epidemiology
19.99
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