{ "abstract": "To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.", "abstract_shown": true, "affiliations": [ "Univ. Lille , Inserm , CHU Lille , Institut Pasteur Lille , LabEx DISTALZ-U1167- RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement , Lille , France", "Univ. Lille, Inserm, CHU Lille, Institut Pasteur Lille, LabEx DISTALZ—U1167-RID-AGE Facteurs de Risque et Déterminants Moléculaires des Maladies Liées au Vieillissement, Lille, France", "UKDRI@ Cardiff, School of Medicine, Cardiff University, Cardiff, UK", "Nuffield Department of Population Health, University of Oxford, Oxford, UK", "Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, The Netherlands", "Amsterdam Neuroscience, Neurodegeneration, Amsterdam, The Netherlands", "Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije University, Amsterdam, The Netherlands", "Department of Cognitive Disorders and Old Age Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany", "Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany", "Complex Genetics of Alzheimer’s Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium", "Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium", "Institute of Biomedicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland", "Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), Barcelona, Spain", "Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain", "Estudios en Neurociencias y Sistemas Complejos (ENyS) CONICET-HEC-UNAJ, Florencio Varela, Argentina", "Department of Neurodegeneration and Geriatric Psychiatry, University of Bonn, Bonn, Germany", "German Center for Neurodegenerative Diseases (DZNE Bonn), Bonn, Germany", "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", "Department of Cognitive Disorders and Old Age Psychiatry, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany", "German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany", "German Center for Neurodegenerative Diseases (DZNE), Munich, Germany", "Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany", "Munich Cluster for Systems Neurology (SyNergy), Munich, Germany", "Martin-Luther-University Halle-Wittenberg, University Clinic and Outpatient Clinic for Psychiatry, Psychotherapy and Psychosomatics, Halle (Saale), Germany", "LVR-University Hospital Essen, Department of Psychiatry and Psychotherapy, Medical Faculty, 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, Mannheim, Germany", "Alzheimer’s Disease and Other Cognitive Disorders Unit, Service of Neurology, Hospital Clínic of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Institute of Neurosciences of the University of Barcelona, Barcelona, Spain", "Neurological Tissue Bank - Biobanc - Hospital Clínic - IDIBAPS, Barcelona, Spain", "German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany", "Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany", "Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, 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 & University Hospital Bonn, Bonn, Germany", "Institute for Urban Public Health, University Hospital of University Duisburg-Essen, Essen, Germany", "German Center for Neurodegenerative Diseases (DZNE, Bonn), Bonn, Germany" ], "article_type": "review", "arxiv": null, "author_total": 100, "authors": [ { "affs": [ 0 ], "name": "EADB (Alzheimer Disease European DNA biobank)" }, { "affs": [ 1 ], "name": "Céline Bellenguez", "orcid": "0000-0002-1240-7874" }, { "affs": [ 2 ], "name": "Atahualpa Castillo-Morales", "orcid": "0000-0001-9733-6923" }, { "affs": [ 3 ], "name": "Najaf Amin", "orcid": "0000-0002-8944-1771" }, { "affs": [ 4, 5, 6 ], "name": "Sven J. van der Lee", "orcid": "0000-0003-1606-8643" }, { "affs": [ 1 ], "name": "Manon Muntaner" }, { "affs": [ 7, 8 ], "name": "Kayenat Parveen" }, { "affs": [ 9, 10 ], "name": "Fahri Küçükali", "orcid": "0000-0002-3835-9639" }, { "affs": [ 1 ], "name": "Benjamin Grenier‐Boley", "orcid": "0009-0004-3412-3997" }, { "affs": [ 11 ], "name": "Sami Heikkinen", "orcid": "0000-0002-6083-2402" }, { "affs": [ 12, 13 ], "name": "Itziar de Rojas", "orcid": "0000-0002-2148-381X" }, { "affs": [ 8, 14 ], "name": "Maria Carolina Dalmasso", "orcid": "0000-0002-4901-9955" }, { "affs": [ 15, 8, 16 ], "name": "Luca Kleineidam", "orcid": "0009-0006-3309-6856" }, { "affs": [ 17, 18 ], "name": "Oliver Peters", "orcid": "0000-0003-0568-2998" }, { "affs": [ 19, 20 ], "name": "Anja Schneider", "orcid": "0000-0001-9540-8700" }, { "affs": [ 21, 22, 23 ], "name": "Martin Dichgans", "orcid": "0000-0002-0654-387X" }, { "affs": [ 24 ], "name": "Dan Rujescu", "orcid": "0000-0002-1432-313X" }, { "affs": [ 25 ], "name": "Norbert Scherbaum", "orcid": "0000-0003-1759-6990" }, { "affs": [ 26 ], "name": "Jürgen Deckert" }, { "affs": [ 27 ], "name": "Steffi Riedel-Heller", "orcid": "0000-0003-4321-6090" }, { "affs": [ 28 ], "name": "Lucrezia Hausner", "orcid": "0000-0001-9009-2356" }, { "affs": [ 29, 30 ], "name": "Laura Molina‐Porcel", "orcid": "0000-0003-4068-8578" }, { "affs": [ 31, 32 ], "name": "Emrah Düzel", "orcid": "0000-0002-0139-5388" }, { "affs": [ 33 ], "name": "Timo Grimmer", "orcid": "0000-0002-6829-6253" }, { "affs": [ 34, 35, 36 ], "name": "Jens Wiltfang", "orcid": "0000-0003-1492-5330" }, { "affs": [ 37 ], "name": "Stefanie Heilmann‐Heimbach", "orcid": "0000-0003-1057-465X" }, { "affs": [ 38 ], "name": "Susanne Moebus", "orcid": "0000-0002-0072-5410" }, { "affs": [ 39 ], "name": "Matthias Schmid" }, { "name": "Thomas Tegos" }, { "name": "Nikolaos Scarmeas", "orcid": "0000-0001-6453-8908" }, { "affs": [ 13 ], "name": "Oriol Dols‐Icardo", "orcid": "0000-0003-2656-8748" }, { "affs": [ 13 ], "name": "Fermín Moreno", "orcid": "0000-0001-5200-3164" }, { "affs": [ 13 ], "name": "Jordi Pérez‐Tur", "orcid": "0000-0002-9111-1712" }, { "affs": [ 13 ], "name": "María José Bullido", "orcid": "0000-0002-6477-1117" }, { "name": "Pau Pástor", "orcid": "0000-0002-7493-8777" }, { "name": "Raquel Sánchez‐Valle", "orcid": "0000-0001-7750-896X" }, { "name": "Victoria Álvarez", "orcid": "0000-0002-1916-2523" }, { "affs": [ 12, 13 ], "name": "Merçé Boada", "orcid": "0000-0003-2617-3009" }, { "affs": [ 12 ], "name": "Pablo García‐González", "orcid": "0000-0003-0125-5403" }, { "affs": [ 12 ], "name": "Raquel Puerta", "orcid": "0000-0002-1191-5893" }, { "affs": [ 13 ], "name": "Pablo Mir", "orcid": "0000-0003-1656-302X" }, { "name": "Luis M. Real", "orcid": "0000-0003-4932-7429" }, { "name": "Gerard Piñol‐Ripoll", "orcid": "0000-0002-4495-2113" }, { "affs": [ 13 ], "name": "José María García‐Alberca", "orcid": "0000-0003-2951-6644" }, { "affs": [ 13 ], "name": "Eloy Rodríguez‐Rodríguez", "orcid": "0000-0001-7742-677X" }, { "name": "Hilkka S. Soininen", "orcid": "0000-0002-2785-9937" }, { "name": "Alexandre de Mendonça", "orcid": "0000-0002-0488-1453" }, { "name": "Shima Mehrabian", "orcid": "0000-0002-3146-6001" }, { "name": "Jakub Hort", "orcid": "0000-0002-1080-3726" }, { "name": "Martin Vyhnálek", "orcid": "0000-0002-5976-4932" }, { "name": "Nicolai Sandau", "orcid": "0000-0002-1941-097X" }, { "name": "Jiao Luo" }, { "name": "Jesper Qvist Thomassen", "orcid": "0000-0003-3484-9531" }, { "affs": [ 4, 5 ], "name": "Yolande A.L. Pijnenburg", "orcid": "0000-0003-2464-1905" }, { "affs": [ 4, 5 ], "name": "Wiesje M. van der Flier", "orcid": "0000-0001-8766-6224" }, { "affs": [ 5 ], "name": "Harro Seelaar", "orcid": "0000-0003-1989-7527" }, { "name": "Inez H.G.B. Ramakers", "orcid": "0000-0002-4747-2879" }, { "affs": [ 5 ], "name": "Janne M. Papma", "orcid": "0000-0002-2790-438X" }, { "affs": [ 4, 5 ], "name": "Marc Hulsman", "orcid": "0000-0002-9889-3606" }, { "affs": [ 5 ], "name": "Gert-Jan Biessels" } ], "bibtex": "https://research.draconitic.com/paper/a944g91kcf0fz.bib", "cited_by": 21, "doi": "10.1038/s41588-026-02583-1", "fulltext_url": null, "id": "a944g91kcf0fz", "issns": [ "1061-4036", "1546-1718" ], "landing_url": "https://doi.org/10.1038/s41588-026-02583-1", "language": "en", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2737|Alzheimer's disease research and treatments" ], [ "openalex", "2804|Alzheimer's disease research and treatments" ] ], "openalex": "W7163386725", "pdf_url": "https://www.nature.com/articles/s41588-026-02583-1.pdf", "pmcid": "PMC13263136", "pmid": "42237039", "published": "2026-06-01", "publisher": "Nature Portfolio", "ris": "https://research.draconitic.com/paper/a944g91kcf0fz.ris", "sources": [ { "first_seen": "2026-10-30T13:26:56Z", "native_id": "W7163386725", "source": "openalex", "url": "https://doi.org/10.1038/s41588-026-02583-1" } ], "subjects": [ { "field": "biology", "origin": "openalex:2804|Alzheimer's disease research and treatments", "subfield": "neuroscience" }, { "field": "medicine", "origin": "openalex:2737|Alzheimer's disease research and treatments", "subfield": "physiology" } ], "title": "Consensus meta-analysis of genome-wide association studies for Alzheimer’s disease and related dementias", "title_text": "Consensus meta-analysis of genome-wide association studies for Alzheimer’s disease and related dementias", "type": "peer-reviewed", "updated_at": "2026-11-07T13:20:55Z", "url": "https://research.draconitic.com/paper/a944g91kcf0fz", "venue": "Nature Genetics", "versions": [] }