Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

1st Department of Neurology Aiginition Hospital National and Kapodistrian University of Athens Medical School Athens Greece

1st Department of Neurology Medical School Aristotle University of Thessaloniki Thessaloniki Greece

Aging Research Center Department of Neurobiology Care Sciences and Society Karolinska Institutet and Stockholm University Stockholm Sweden

AI Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio Finland

Alzheimer Center Amsterdam Department of Neurology Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands

Alzheimer Hellas Thessaloniki Greece

Alzheimer Research Center and Memory Clinic Andalusian Institute for Neuroscience Málaga Spain

Alzheimer's Disease and Other Cognitive Disorders Unit Neurology Department Hospital Clinic Barcelona Spain

Athens Association of Alzheimer's Disease and Related Disorders Athens Greece

Azienda Ospedaliero Universitaria Careggi Florence Italy

Bioinformatics College of Life Sciences Brigham Young University Provo UT USA

Biosciences School of Science and Technology Nottingham Trent University Nottingham UK

Biostatistics University of Kentucky College of Public Health Lexington KY USA

Bordeaux Population Health Research Center University Bordeaux INSERM Bordeaux France

Boston University and the NHLBI's Framingham Heart Study Boston MA USA

Brain Institute Federal University of Rio Grande do Norte Natal Brazil

CAEBI Centro Andaluz de Estudios Bioinformáticos Sevilla Spain

Cardiff School of Medicine Cardiff University Cardiff UK

Cardiovascular Health Research Unit Department of Medicine University of Washington Seattle WA USA

CEA Centre National de Recherche en Génomique Humaine Université Paris Saclay Evry France

Center for Alzheimer Research Department NVS Division of Neurogeriatrics Karolinska Institutet Stockholm Sweden

Center for Neurosciences Vrije Universiteit Brussel Brussels Belgium

Center of Mental Health Clinic and Policlinic of Psychiatry Psychosomatics and Psychotherapy University Hospital of Würzburg Wuerzburg Germany

Centre for Healthy Brain Ageing School of Psychiatry Faculty of Medicine University of New South Wales Sydney New South Wales Australia

Centre for Memory Disturbances Lab of Clinical Neurochemistry Section of Neurology University of Perugia Perugia Italy

Centre for Neurodegenerative Disorders Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Centre of Age Related Medicine Stavanger University Hospital Stavanger Norway

Centro de Biología Molecular Severo Ochoa Madrid Spain

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas CIBERDEM Hospital Clínico San Carlos Madrid Spain

Centro de Neuropsiquiatría y Neurología de la Conducta C A B A Buenos Aires Argentina

CHUV Old Age Psychiatry Department of Psychiatry Lausanne Switzerland

CIBERNED Network Center for Biomedical Research in Neurodegenerative Diseases National Institute of Health Carlos 3 Madrid Spain

CIEN Foundation Queen Sofia Foundation Alzheimer Center Madrid Spain

Cleveland Institute for Computational Biology Case Western Reserve University Cleveland OH USA

Clinic of Neurology UH 'Alexandrovska' Medical University Sofia Sofia Bulgaria

Clinical and Experimental Science Faculty of Medicine University of Southampton Southampton UK

Complex Genetics of Alzheimer's Disease Group VIB Center for Molecular Neurology VIB Antwerp Belgium

Delft Bioinformatics Lab Delft University of Technology Delft the Netherlands

Dementia Centre for Research Collaboration School of Psychiatry University of New South Wales Sydney New South Wales Australia

Dementia Research Centre UCL Queen Square Institute of Neurology London UK

Departamento Ciencias Fisiológicas UAII Facultad de Medicina UBA C A B A Buenos Aires Argentina

Departamento de Especialidades Quirúrgicas Bioquímicas e Inmunología School of Medicine University of Málaga Málaga Spain

Department of Biology Brigham Young University Provo UT USA

Department of Biomedical Sciences Section of Neuroscience and Clinical Pharmacology University of Cagliari Cagliari Italy

Department of Biomedical Sciences University of Antwerp Antwerp Belgium

Department of Biomedical Sciences University of Cagliari Cagliari Italy

Department of Biostatistics Boston University School of Public Health Boston MA USA

Department of Biostatistics Epidemiology and Informatics Penn Neurodegeneration Genomics Center University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Department of Biostatistics Epidemiology and Informatics Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

Department of Child and Adolescent Psychiatry and Psychotherapy University Hospital of Psychiatry Zurich University of Zurich Zurich Switzerland

Department of Clinical Biochemistry Herlev and Gentofte Hospital Herlev Denmark

Department of Clinical Biochemistry Rigshospitalet Copenhagen Denmark

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Clinical Sciences and Community Health University of Milan Milan Italy

Department of Complex Trait Genetics Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience Vrije University Amsterdam the Netherlands

Department of Epidemiology Erasmus MC Rotterdam the Netherlands

Department of Epidemiology University of Washington Seattle WA USA

Department of Genetics and CNR MAJ Normandie University UNIROUEN INSERM U1245 CHU Rouen Rouen France

Department of Genetics and Genomic Sciences and Icahn Institute for Data Science and Genomic Technology Icahn School of Medicine at Mount Sinai New York NY USA

Department of Genetics and Genomic Sciences Ronald M Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai New York NY USA

Department of Geriatric Medicine Oslo University Hospital Oslo Norway

Department of Geriatric Psychiatry Central Institute for Mental Health Mannheim University of Heidelberg Heidelberg Germany

Department of Geriatric Psychiatry University Hospital of Psychiatry Zürich Zürich Switzerland

Department of Geriatrics St Olav's Hospital Trondheim University Hospital Trondheim Norway

Department of Health Service University of Washington Seattle WA USA

Department of Immunology Hospital Universitario Doctor Negrín Las Palmas de Gran Canaria Las Palmas Spain

Department of Internal Medicine and Biostatistics Erasmus MC Rotterdam the Netherlands

Department of Laboratory Diagnostics 3 Laboratory of Analysis Brescia Hospital Brescia Italy

Department of Medical and Molecular Genetics Indiana University Indianapolis IN USA

Department of Medicine Boston University School of Medicine Boston MA USA

Department of Medicine University of Washington Seattle WA USA

Department of Neurodegenerative Diseases and Geriatric Psychiatry University Hospital Bonn Bonn Germany

Department of Neurology 2 B Sant Pau Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona Spain

Department of Neurology and Clinical Neurophysiology University Hospital of Trondheim Trondheim Norway

Department of Neurology and CNR MAJ F 76000 Normandy Center for Genomic and Personalized Medicine Normandie University UNIROUEN INSERM U1245 CHU Rouen Rouen France

Department of Neurology Boston University School of Medicine Boston MA USA

Department of Neurology Columbia University New York NY USA

Department of Neurology Erasmus MC Rotterdam the Netherlands

Department of Neurology ErasmusMC Rotterdam the Netherlands

Department of Neurology Hospital Universitario Donostia OSAKIDETZA Servicio Vasco de Salud San Sebastian Spain

Department of Neurology Kuopio University Hospital Kuopio Finland

Department of Neurology Medical School University of Cyprus Nicosia Cyprus

Department of Neurology UMC Utrecht Brain Center Utrecht the Netherlands

Department of Neurology University Medical Center Groningen Groningen the Netherlands

Department of Neurology University of Bonn Bonn Germany

Department of Neurology UZ Brussel Brussels Belgium

Department of Neuromedicine and Movement Science Norwegian University of Science and Technology Trondheim Norway

Department of Neuropsychiatry and Laboratory of Molecular Psychiatry Charité Charitéplatz 1 Berlin Germany

Department of Neuroscience and Mental Health AOU Città della Salute e della Scienza di Torino Torino Italy

Department of Neuroscience Catholic University of Sacred Heart Fondazione Policlinico Universitario A Gemelli IRCCS Rome Italy

Department of Neuroscience Psychology Drug Research and Child Health University of Florence Florence Italy

Department of Neuroscience Rita Levi Montalcini University of Torino Torino Italy

Department of Neurosciences University of Helsinki and Department of Geriatrics Helsinki University Hospital Helsinki Finland

Department of Nutrition and Diatetics Harokopio University Athens Greece

Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Department of Pathology and Laboratory Medicine University of Pennsylvania Philadelphia PA USA

Department of Population and Quantitative Health Sciences Case Western Reserve University Cleveland OH USA

Department of Primary Medical Care University Medical Centre Hamburg Eppendorf Hamburg Germany

Department of Psychiatry and Neuropsychologie Maastricht University Alzheimer Center Limburg Maastricht the Netherlands

Department of Psychiatry and Psychotherapy Medical University of Vienna Vienna Austria

Department of Psychiatry and Psychotherapy Universitätsklinikum Erlangen and Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Department of Psychiatry and Psychotherapy University Medical Center Goettingen Goettingen Germany

Department of Psychiatry Harvard Medical School McLean Hospital Belmont MA USA

Department of Psychiatry Icahn School of Medicine at Mount Sinai New York NY USA

Department of Psychiatry Namsos Hospital Namsos Norway

Department of Psychiatry Psychosomatics and Psychotherapy Center of Mental Health University Hospital Wuerzburg Germany

Department of Psychiatry Social Medicine Center East Donauspital Vienna Austria

Department of Public Health and Carins Sciences Geriatrics Uppsala University Uppsala Sweden

Department of Research and Innovation Helse Fonna Haugesund Hospital Haugesund Norway

Department of Surgery Biochemistry and Molecular Biology School of Medicine University of Málaga Málaga Spain

Departments of Neurology and Epidemiology University of Washington Seattle WA USA

Depatamento de Especialidades Quirúrgicas Bioquímica e Inmunología Facultad de Medicina Universidad de Málaga Málaga Spain

DIMEC University of Parma Parma Italy

Division of Clinical Geriatrics Center for Alzheimer Research Care Sciences and Society Karolinska Institutet Stockholm Sweden

Division of Genetic Medicine Vanderbilt University Nashville TN USA

Division of Neurogenetics and Molecular Psychiatry Department of Psychiatry and Psychotherapy University of Cologne Medical Faculty Cologne Germany

Dr John T Macdonald Foundation Department of Human Genetics University of Miami Miami FL USA

EA 4468 Université de Paris APHP Hôpital Broca Paris France

Estelle and Daniel Maggin Department of Neurology Icahn School of Medicine at Mount Sinai New York NY USA

Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases University of Cologne Cologne Germany

Experimental Neuro psychobiology Laboratory Department of Clinical and Behavioral Neurology IRCCS Santa Lucia Foundation Rome Italy

Faculty of Medical and Health Sciences University of Auckland Auckland New Zealand

Faculty of Medicine University of Lisbon Lisbon Portugal

Fondazione IRCCS Ca'Granda Ospedale Policlinico Milan Italy

Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Framingham Heart Study Framingham MA USA

Fundació Docència i Recerca MútuaTerrassa and Movement Disorders Unit Department of Neurology University Hospital MútuaTerrassa Terrassa Spain

Fundación Pública Galega de Medicina Xenómica CIBERER IDIS University of Santiago de Compostela Santiago de Compostela Spain

Geriatic Unit Fondazione Cà Granda IRCCS Ospedale Maggiore Policlinico Milan Italy

Geriatrics Unit Fondazione Policlinico A Gemelli IRCCS Rome Italy

German Center for Neurodegenerative Diseases Berlin Germany

German Center for Neurodegenerative Diseases Bonn Germany

German Center for Neurodegenerative Diseases Goettingen Germany

German Center for Neurodegenerative Diseases Magdeburg Germany

German Center for Neurodegenerative Diseases Munich Germany

Gertrude H Sergievsky Center Columbia University New York NY USA

Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases University of Texas Health Sciences Center San Antonio TX USA

GRC 21 Alzheimer Precision Medicine Initiative Sorbonne University AP HP Pitié Salpêtrière Hospital Paris France

Grupo de Medicina Xenómica Centro Nacional de Genotipado Universidade de Santiago de Compostela Santiago de Compostela Spain

Hospital Interzonal General de Agudos Eva Perón San Martín Buenos Aires Argentina

Hospital Universitario la Paz Madrid Spain

Hospital Universitario Ramon y Cajal IRYCIS Madrid Spain

Human Genetics Center School of Public Health University of Texas Health Science Center at Houston Houston TX USA

Human Genetics School of Life Sciences Life Sciences Building University Park University of Nottingham Nottingham UK

Human Genetics School of Life Sciences University of Nottingham Nottingham UK

Human Genome Sequencing Center Baylor College of Medicine Houston TX USA

Icelandic Heart Association Faculty of Medicine University of Iceland Reykjavik Iceland

Icelandic Heart Association Kopovagur Iceland

INSERM Bordeaux Population Health Research Center UMR 1219 ISPED CIC 1401 EC Université de Bordeaux Bordeaux France

Institut de Biomedicina de València CSIC CIBERNED València Spain

Institut de Recerca Biomedica de Lleida Lleida Spain

Institute Born Bunge University of Antwerp Antwerp Belgium

Institute for Regenerative Medicine University of Zürich Schlieren Switzerland

Institute for Stroke and Dementia Research Klinikum der Universität München Ludwig Maximilians Universität Munich Germany

Institute for Urban Public Health University Hospital of University Duisburg Essen Essen Germany

Institute of Biomedicine University of Eastern Finland Kuopio Finland

Institute of Clinical Medicine Internal Medicine University of Eastern Finland Kuopio Finland

Institute of Clinical Medicine Neurology University of Eastern Kuopio Finland

Institute of Clinical Medicine The University of Bergen Bergen Norway

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Cognitive Neurology and Dementia Research Otto Von Guericke University Magdeburg Germany

Institute of Gerontology and Geriatrics Department of Medicine and Surgery University of Perugia Perugia Italy

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Medical Biometry Informatics and Epidemiology University Hospital of Bonn Bonn Germany

Institute of Neurology Catholic University of the Sacred Heart Rome Italy

Institute of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Freie Universität Berlin Humboldt Universität Zu Berlin and Berlin Institute of Health Berlin Germany

Institute of Psychiatry Psychology and Neuroscience London UK

Institute of Public Health and Clinical Nutrition University of Eastern Finland Kuopio Finland

Institute of Public Health University of Cambridge Cambridge UK

Institute of Social Medicine Occupational Health and Public Health University of Leipzig Leipzig Germany

Instituto de Investigacion Sanitaria 'Hospital la Paz' Madrid Spain

International Clinical Research Center St Anne's University Hospital Brno Brno Czechia

Intramural Research Program National Institute on Aging National Institutes of Health Bethesda MD USA

IRCCS Fondazione Don Carlo Gnocchi Florence Italy

Klinikum rechts der Isar Department of Psychiatry and Psychotherapy Technical University of Munich School of Medicine Munich Germany

Laboratorio de Bioquímica Molecular Facultad de Medicina Instituto de Investigaciones Médicas A Lanari UBA C A B A Buenos Aires Argentina

Laboratorio de Genética Hospital Universitario Central de Asturias Oviedo Spain

Laboratory for Advanced Hematological Diagnostics Department of Hematology and Stem Cell Transplant Vito Fazzi Hospital Lecce Italy

Laboratory for Cognitive Neurology Department of Neurosciences University of Leuven Leuven Belgium

Laboratory of Brain Aging and Neurodegeneration FIL CONICET Buenos Aires Argentina

Laboratory of Cognitive Neuroscience School of Psychology Aristotle University of Thessaloniki Thessaloniki Greece

Laboratory of Epidemiology Demography and Biometry National Institute of Aging The National Institutes of Health Bethesda MD USA

Laboratory of Neurogenetics Department of Internal Medicine Texas Tech University Health Science Center Lubbock TX USA

Laboratory of Neurogenetics Institute Born Bunge Antwerp Belgium

Laboratory of Neuropsychiatry Department of Clinical and Behavioral Neurology IRCCS Santa Lucia Foundation Rome Italy

LACDR Leiden the Netherlands

LVR Hospital Essen Department of Psychiatry and Psychotherapy Medical Faculty University of Duisburg Essen Essen Germany

MAC Memory Clinic IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia Italy

Medical Science Department iBiMED Aveiro Portugal

Medicine Biomedical Genetics Boston University School of Medicine Boston MA USA

Memory Clinic Department of Neurology Charles University 2nd Faculty of Medicine and Motol University Hospital Praha Czechia

Memory Disorders Unit Department of Neurology Hospital Universitari Mutua de Terrassa Terrassa Spain

Memory Impairment and Neurodegenerative Dementia Center University of Mississippi Medical Center Jackson MS USA

Molecular Markers Laboratory IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia Italy

MRC Centre for Neuropsychiatric Genetics and Genomics Division of Psychological Medicine and Clinical Neuroscience School of Medicine Cardiff University Cardiff UK

MRC Prion Unit at UCL UCL Institute of Prion Diseases London UK

Munich Cluster for Systems Neurology Munich Germany

Nash Family Department of Neuroscience and Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York NY USA

Neurodegenerative Brain Diseases Group VIB Center for Molecular Neurology VIB Antwerp Belgium

Neuroepidemiology and Ageing Research Unit School of Public Health Imperial College London London UK

Neurological Tissue Bank of the Biobanc Hospital Clinic IDIBAPS Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Neurology Department Hospital Clínic IDIBAPS Universitat de Barcelona Barcelona Spain

Neurology Department University Hospitals Leuven Leuven Belgium

Neurology Service Marqués de Valdecilla University Hospital Santander Spain

Neurology Unit San Gerardo Hospital Monza Italy

Neuropsychiatry Epidemiological and Clinical Research PSNREC Université de Montpellier INSERM U1061 Montpellier France

Neuroscience Center Zurich University of Zurich and ETH Zurich Zurich Switzerland

Neurosciences Area Instituto Biodonostia San Sebastian Spain

NORMENT Centre University of Oslo Oslo Norway

Nuffield Department of Population Health Oxford University Oxford UK

Old Age Psychiatry Department of Psychiatry Lausanne University Hospital Lausanne Switzerland

Pole Santé Publique CHU de Bordeaux Bordeaux France

Public Health Promotion Unit Finnish Institute for Health and Welfare Helsinki Finland

Radboudumc Alzheimer Center Department of Geriatrics Radboud University Medical Center Nijmegen the Netherlands

Reference Center for Biological Markers of Dementia Institute Born Bunge University of Antwerp Antwerp Belgium

Research and Development UnitStockholms Sjukhem Stockholm Sweden

Research Center and Memory Clinic Fundació ACE Institut Català de Neurociències Aplicades Universitat Internacional de Catalunya Barcelona Spain

Resources and Research Memory Center of Distalz LicendUniversity of Lille INSERM CHU Lille UMR1172 Lille France

Reta Lila Weston Research Laboratories Department of Molecular Neuroscience UCL Institute of Neurology London UK

Ronald M Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai New York NY USA

Sanders Brown Center on Aging Department of Biostatistics University of Kentucky Lexington KY USA

School of Health Sciences Bangor University Bangor UK

School of Medicine and Surgery University of Milano Bicocca Milano Italy

School of Medicine University of Thessaly Larissa Greece

School of Public Health University of Texas Health Science Center at Houston Houston TX USA

Section Genomics of Neurodegenerative Diseases and Aging Department of Human Genetics Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam the Netherlands

Servei de Neurologia Hospital Universitari i Politècnic La Fe Valencia Spain

Servicio de Neurología Hospital Universitario Central de Asturias Oviedo and Instituto de Investigación Biosanitaria del Principado de Asturias Oviedo Spain

Stockholm Gerontology Research Center Stockholm Sweden

Taub Institute Columbia University New York NY USA

Taub Institute on Alzheimer's Disease and the Aging Brain Department of Neurology Columbia University New York NY USA

The John P Hussman Institute for Human Genomics University of Miami Miami FL USA

Translational Health Sciences Bristol Medical School University of Bristol Bristol UK

UFIEC Instituto de Salud Carlos 3 Madrid Spain

Unidad Clínica de Enfermedades Infecciosas y Microbiología Hospital Universitario de Valme Sevilla Spain

Unidad de Demencias Hospital Clínico Universitario Virgen de la Arrixaca Murcia Spain

Unidad de Demencias Servicio de Neurología y Neurofisiología Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío CSIC Universidad de Sevilla Seville Spain

Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío CSIC Universidad de Sevilla Seville Spain

Unit for Hereditary Dementias Karolinska University Hospital Solna Stockholm Sweden

Unit of Clinical Pharmacology University Hospital of Cagliari Cagliari Italy

Unit of Neurology University of Parma and AOU Parma Italy

Unitat Mixta de de Neurología y Genética Institut d'Investigació Sanitària La Fe València Spain

Unitat Trastorns Cognitius Hospital Universitari Santa Maria de Lleida Lleida Spain

Université de Lille INSERM CHU Lille Institut Pasteur Lille U1167 RID AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement Lille France

University of Bari A Moro Bary Italy

University of Milan Milan Italy

US 41 UMS 2014 PLBS bilille Université de Lille CNRS INSERM CHU Lille Institut Pasteur de Lille Lille France

Vanderbilt Brain Institute Vanderbilt University Nashville TN USA

Wales Centre for Ageing and Dementia Research Swansea University Wales New Zealand

Zurich Center for Integrative Human Physiology University of Zurich Zurich Switzerland

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