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Journal Article Ppublish 23 citations

PubMed: 40533518 DOI: 10.1038/s41588-025-02227-w

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

Nat Genet 57(7):1598-1610

Authors: Aude Nicolas, Richard Sherva, Benjamin Grenier-Boley, Yoontae Kim, Masataka Kikuchi, Jigyasha Timsina, Itziar de Rojas, María Carolina Dalmasso, Xiaopu Zhou, Yann Le Guen, Carlos E Arboleda-Bustos, Maria Aparecida Camargos Bicalho, Maëlenn Guerchet, Sven van der Lee, Monica Goss, Atahualpa Castillo, Céline Bellenguez, Fahri Küçükali, Claudia L Satizabal, Bernard Fongang, Qiong Yang, Oliver Peters, Anja Schneider, Martin Dichgans, Dan Rujescu, Norbert Scherbaum, Jürgen Deckert, Steffi Riedel-Heller, Lucrezia Hausner, Laura Molina-Porcel, Emrah Düzel, Timo Grimmer, Jens Wiltfang, Stefanie Heilmann-Heimbach, Susanne Moebus, Thomas Tegos, Nikolaos Scarmeas, Oriol Dols-Icardo, Fermin Moreno, Jordi Pérez-Tur, María J Bullido, Pau Pastor, Raquel Sánchez-Valle, Victoria Álvarez, Han Cao, Nancy Y Ip, Amy K Y Fu, Fanny C F Ip, Natividad Olivar, Carolina Muchnik … and 152 other authors

Affiliations

  • U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France.
  • Institut du Cerveau - Paris Brain Institute - ICM, Sorbonne Université, CNRS, APHP Hôpital de La Pitié Salpêtrière, Inserm, Paris, France.
  • Behavioral Sciences Division, National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
  • Department of Medicine (Biomedical Genetics), Boston University, Boston, MA, USA.
  • U1167-RID-AGE facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, France.
  • BK FOUR Department of Integrative Biological Sciences, Chosun University, Gwangju, Republic of Korea.
  • Graduate School of Frontier Science, University of Tokyo, Tokyo, Japan.
  • Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
  • NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, USA.
  • ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
  • Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, Division of Neurogenetics and Molecular Psychiatry, University of Cologne, Cologne, Germany.
  • Studies in Neuroscience and Complex Systems Unit (ENyS) CONICET-HEC-UNAJ, Santiago, Chile.
  • Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Kowloon, China.
  • Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
  • Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research InstituteShenzhen-Hong Kong Institute of Brain Science, Shenzhen, China.
  • Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
  • Institut du Cerveau, Paris Brain Institute - ICM, Paris, France.
  • Neuroscience and Cell Death Research Groups, Medical School and Genetic Institute, Universidad Nacional de Colombia, Bogota, Colombia.
  • Department of Clinical Medicine, Federal University of Minas Gerais (UFMG) Belo Horizonte, Minas Geraes, Brazil.
  • National Institute of Science and Technology (INCT) Neurotec R, Federal University of Minas Geraes Belo Horizonte, Minas Geraes, Brazil.
  • Geriatrics Service of the University Hospital, Federal University of Minas Gerais Belo Horizonte, Minas Geraes, Brazil.
  • EpiMaCT - Epidemiology of chronic diseases in tropical zone, Inserm U1094, IRD UMR270, Université Limoges, CHU Limoges, Institute of Epidemiology and Tropical Neurology, OmegaHealth, Limoges, France.
  • Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
  • Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije University, Amsterdam, the Netherlands.
  • Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA.
  • Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
  • Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
  • Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
  • Boston University and the NHLBI's Framingham Heart Study, Boston, MA, USA.
  • Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
  • Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA.
  • Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX, USA.
  • German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
  • Institute of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
  • Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany.
  • Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.
  • German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • Department of Psychiatry and Comprehensive Center of Neuroscience and Mental Health, Medical University of Vienna, Vienna, Austria.
  • Department of Psychiatry and Psychotherapy, LVR-University Hospital Essen, Medical Faculty of the University of Duisburg-Essen, Essen, Germany.
  • Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany.
  • Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.
  • Department of Geriatric Psychiatry, Central Institute for Mental Health Mannheim, Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
  • Neurological Tissue Bank - Biobanc, Hospital Clinic, FRCB, IDIBAPS, Barcelona, Spain.
  • Neurology Department, Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clinic, Barcelona, Spain.
  • German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
  • Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany.
  • Department of Psychiatry and Psychotherapy, Center for Cognitive Disorders, Technical University of Munich, School of Medicine, Munich, Germany.
  • Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Goettingen, Germany.
  • German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany.
  • Medical Science Department, iBiMED, Aveiro, Portugal.
  • Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
  • Institute for Urban Public Health, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
  • First Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
  • First Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.
  • Depatment of Neurology, Columbia University, New York, NY, USA.
  • Genetics of Neurodegenerative Diseases Unit IIB Sant Pau, Barcelona, Spain.
  • Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.
  • Neurosciences Area, Instituto Biogipuzkoa, San Sebastian, Spain.
  • Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC, Valencia, Spain.
  • Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain.
  • Instituto de Investigacion Sanitaria 'Hospital la Paz' (IdIPaz), Madrid, Spain.
  • Universidad Autónoma de Madrid, Madrid, Spain.
  • Department of Neurology, Unit of Neurodegenerative Diseases, University Hospital Germans Trias i Pujol, Badalona, Spain.
  • The Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.
  • Alzheimer's Disease and Other Cognitive Disorders Unit, Service of Neurology, Hospital Clínic of Barcelona. Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
  • Laboratorio de Genética, Hospital Universitario Central de Asturias, Oviedo, Spain.
  • Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
  • Center of Neuropsychiatry and Behavior Neurology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.

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.

MeSH

Alzheimer Disease, Genetic Risk Score

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