Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.

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

1st Department of Neurology Aristotle University of Thessaloniki Thessaloniki Greece

A 1 Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio Finland

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

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

Alzheimer Research Center and Memory Clinic Andalusian Institute for Neuroscience Málaga 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

Amsterdam UMC Vrije Universiteit Amsterdam Department of Epidemiology and Data Science Amsterdam Public Health Research Institute Amsterdam The Netherlands

Amsterdam UMC Vrije Universiteit Amsterdam Department of Psychiatry Amsterdam Public Health Research Institute Amsterdam The Netherlands

APHP Hôpital Broca Paris France

APHP Hôpital Brousse equipe INSERM 1178 MOODS Villejuif France

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

Azienda Ospedaliero Universitaria Careggi Largo Brambilla Florence Italy

Azienda Ospedaliero Universitaria Parma Italy

Beth K and Stuart C Yudofsky Division of Neuropsychiatry Department of Psychiatry and Behavioral Sciences Baylor College of Medicine Houston TX USA

Bristol Medical School University of Bristol Southmead Hospital Bristol UK

Brown Foundation Institute of Molecular Medicine University of Texas Health Sciences Center at Houston Houston TX USA

BT CIEN Madrid Spain

CAEBI Centro Andaluz de Estudios Bioinformáticos Sevilla Spain

Campus for Ageing anf Vitality Newcastle upon Tyne UK

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

Center for Neurosciences Vrije Universiteit Brussel Brussels Belgium

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

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

CHU CNR MAJ Lille France

CHU de Bordeaux Pole de Santé Publique Bordeaux France

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

Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

Complex Structure of Geriatrics Department of Medical Sciences Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo Italy

Delft Bioinformatics Lab Delft Univeristy of Technology Delft The Netherlands

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

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

Departamento de Medicina Universidad de Oviedo Oviedo Spain

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 Biostatistics Boston University School of Public Health Boston MA USA

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

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

Department of Clinical Biochemistry Herlev Gentofte Hospital Herlev Denmark

Department of Clinical Biochemistry Rigshospitalet Copenhagen Denmark

Department of Clinical Medicine Faculty of Health and Medical Sciences 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 VU University Amsterdam The Netherlands

Department of Epidemiology Erasmus Medical Center Rotterdam The Netherlands

Department of Geriatric Medicine Oslo University Hospital Oslo Norway

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

Department of Geriatric Psychiatry University Hospital of Psychiatry Zürich Zürich Switzerland

Department of Geriatrics Clinic of Medicine St Olavs Hospital University Hospital of Trondheim Trondheim Norway

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

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Genetics Oslo University Hospital Oslo Norway

Department of Neurodegenerative Disease UCL Institute of Neurology London UK

Department of Neurodegenerative diseases and Geriatric Psychiatry University Clinic 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 Boston University School of Medicine Boston MA USA

Department of Neurology CIEN Foundation Queen Sofia Foundation Alzheimer Center Madrid Spain

Department of Neurology Columbia University New York NY USA

Department of Neurology Hospital Universitario Donostia San Sebastian Spain

Department of Neurology La Paz University Hospital Instituto de Investigación Sanitaria del Hospital Universitario La Paz IdiPAZ Madrid Spain

Department of Neurology La Paz University Hospital Madrid Spain

Department of Neurology Medical School University of Cyprus Nicosia Cyprus

Department of Neurology University of Bonn Bonn Germany

Department of Neurology VUB University Hospital Brussels Brussels Belgium

Department of Neuromedicine and Movement Science Faculty of Medicine and Health Sciences Norwegian University of Science and Technology Trondheim Norway

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

Department of Neuroscience and Mental Health AOU Città della Salute e della Scienza di Torino Torino 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 Faculty of Medicine and Nursery University of the Basque Country San Sebastián Spain

Department of Nutrition and Dietetics Harokopio University Athens Greece

Department of Old Age Psychiatry Institute of Psychiatry Psychology and Neuroscience King's College London London UK

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

Department of Population Health Sciences UT Health San Antonio San Antonio TX USA

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

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Department of Psychiatry and Psychotherapy and Experimental and Clinical Research Center Charité Universitätsmedizin Berlin Berlin Germany

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

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

Department of Psychiatry and Psychotherapy University Medical Center Goettingen Goettingen Germany

Department of Psychiatry and Psychotherapy University of Cologne Medical Faculty Cologne Germany

Department of Psychiatry Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases San Antonio TX USA

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 Psychology University of California Riverside Riverside CA USA

Department of Public Health and Caring Sciences Geriatrics Uppsala Sweden

Department of Sociology VU University Amsterdam The Netherlands

Departments of Medicine Neurology Ophthalmology Epidemiology and Biostatistics Boston University Schools of Medicine and Public Health Boston MA USA

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

Division of Clinical Neurosciences School of Medicine University of Southampton Southampton UK

Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

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

Division of Neuropathology and Neurochemistry Department of Neurology Medical University of Vienna Vienna Austria

Division of Psychological Medicine and Clinial Neurosciences MRC Centre for Neuropsychiatric Genetics and Genomics Cardiff University Cardiff UK

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

EA 4468 Sorbonne Paris Cité Université Paris Descartes Paris France

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 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 Terrassa Barcelona Spain

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

Geriatic Unit Fondazione Cà Granda IRCCS Ospedale Maggiore Policlinico Milan 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 San Antonio TX USA

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

Haugesund Hospital Helse Fonna Department of Research and Innovation Haugesund Norway

Hospital de Cabueñes Gijón Spain

Hospital La Paz Institute for Health Research IdiPAZ Madrid Spain

Hospital Universitario Ramon y Cajal IRYCIS Madrid Spain

Human Genome Sequencing Center Baylor College of Medicine Houston TX USA

Inserm Bordeaux Population Health Research Center UMR 1219 Univ Bordeaux ISPED CIC 1401 EC Univ Bordeaux Bordeaux France

Inserm U1172 CHU DISTAlz LiCEND Univ Lille Lille France

Insititute for Regenerative Medicine University of Zürich Zürich Switzerland

Institut de Recerca Biomedica de Lleida Lleida Spain

Institute Born Bunge University of Antwerp Antwerp Belgium

Institute for Gerontology and Aging Research Network Jönköping School of Health and Welfare Jönköping University Jönköping Sweden

Institute for Stroke and Dementia Research Klinikum der Universität München Ludwig Maximilians Universität LMU Munich 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 Finland Kuopio Finland

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 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 Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Institute of Neurology Catholic University of the Sacred Heart School of Medicine Milan Italy

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

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

Instituto de Investigacion Sanitaria 'Hospital la Paz' Madrid Spain

Instituto de Investigación Sanitaria del Principado de Asturias Oviedo Spain

Instituto de Investigación Sanitaria Hospital Clínico San Carlos Madrid Spain

Instituto de Medicina Molecular João lobo Antunes Faculdade de Medicina Universidade de Lisboa Lisboa Portugal

International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

IRCCS Fondazione Don Carlo Gnocchi Florence Italy

John P Hussman Institute for Human Genomics University of Miami Miller School of Medicine Miami FL USA

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

Laboratorio de Genética Hospital Universitario Central de Asturias Oviedo Spain

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

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

Laboratory of Neurogenetics Institute Born Bunge Antwerp Belgium

Laboratory of Neuropsychiatry IRCCS Santa Lucia Foundation Rome Italy

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

Martin Luther University Halle Wittenberg University Clinic and Outpatient Clinic for Psychiatry Psychotherapy and Psychosomatics Halle Germany

Mathematics and Statistics Murdoch University Perth WA Australia

Memory Clinic Department of Neurology 2nd Faculty of Medicine and Motol University Hospital Charles University Prague Czech Republic

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

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

MRC Prion Unit at UCL Institute of Prion Diseases London UK

Munich Cluster for Systems Neurology Munich Germany

Neurocenter neurology Kuopio University Hospital Kuopio Finland

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 University Hospitals Leuven Leuven Belgium

Neurology Service Marqués de Valdecilla University Hospital Santander Spain

Neurology Unit 'San Gerardo' hospital Monza Italy

Neuropsychiatric Epidemiology Unit Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy Centre for Ageing and Health University of Gothenburg Gothenburg Sweden

Neuroscience Center Zurich University of Zurich and ETH Zurich Zurich Switzerland

Neuroscience Research Australia Sydney NSW Australia

Neurosciences and Signaling Group Institute of Biomedicine Department of Medical Sciences University of Aveiro Aveiro Portugal

Neurosciences Area Instituto Biodonostia San Sebastian Spain

Normandie Univ UNIROUEN Inserm U1245 CHU Rouen Department of Genetics and CNR MAJ FHU G4 Génomique F 76000 Rouen France

Normandie Univ UNIROUEN Inserm U1245 CHU Rouen Department of Neurology and CNR MAJ FHU G4 Génomique F 76000 Rouen France

NORMENT Centre Institute of Clinical Medicine University of Oslo Oslo Norway

NORMENT Department of Clinical Science University of Bergen Bergen Norway

Norwegian National Advisory Unit on Ageing and Health Vestfold Hospital Trust Tønsberg Norway

Nuffield Department of Clinical Neurosciences Oxford UK

Nuffield Department of Population Health University of Oxford Oxford UK

Old age Psychiatry University Hospital of Lausanne Lausanne Switzerland

Penn Neurodegeneration Genomics Center Department of Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Population Health Unit Finnish Institute for Health and Welfare Helsinki Finland

Reference Center for Biological Markers of Dementia University of Antwerp Antwerp Belgium

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

School of Medicine and Surgery University of Milano Bicocca and Milan Center for Neuroscience Milan Italy

School of Medicine University of Thessaly Larissa Greece

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

Schools of Life Sciences and Medicine University of Nottingham Nottingham UK

Section Genomics of Neurodegenerative Diseases and Aging Department of Clinical Genetics Vrije Universiteit Amsterdam Amsterdam UMC Amsterdam The Netherlands

Servei de Neurologia Hospital Universitari i Politècnic La Fe Valencia Spain

Servicio de Inmunología Hospital Universitario de Gran Canaria Dr Negrín Las Palmas de Gran Canaria Spain

Servicio de Neurología Hospital Universitario Central de Asturias Oviedo Spain

Servicio de Neurología Hospital Universitario de Gran Canaria Dr Negrín Las Palmas Spain

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

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders Madrid Spain

Stockholms Sjukhem Research and Development Unit Stockholm Sweden

Taub Institute for Research in Alzheimer's Disease and the Aging Brain The Gertrude H Sergievsky Center Depatment of Neurology 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

Translational and Clincial Research Institute Newcastle University Newcastle upon Tyne UK

Translational Neuroscience Laboratory McLean Hospital Harvard Medical School Belmont MA USA

UFIEC Instituto de Salud Carlos 3 Madrid Spain

UK Dementia Research Institute at Cardiff Cardiff University Cardiff UK

UK Dementia Research Institute at UCL London UK

UKDRI Cardiff Cardiff University Cardiff UK

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 Sevilla 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 Sevilla Spain

Unidad Mixta de Neurologia Genètica Instituto de Investigación Sanitaria La Fe Valencia Spain

Unit for Hereditary Dementias Theme Aging Karolinska University Hospital Solna Stockholm Sweden

Unit of Clinical Pharmacology University Hospital of Cagliari Cagliari Italy

Unit of Neuroscience DIMEC University of Parma Parma Italy

Unitat de Genètica Molecular Institut de Biomedicina de València CSIC Valencia Spain

Unitat Trastorns Cognitius Hospital Universitari Santa Maria de Lleida Lleida Spain

Univ Lille Inserm Institut Pasteur de Lille CHU Lille U1167 Labex DISTALZ RID AGE Risk Factors and Molecular Determinants of Aging Related Diseases Lille France

Universidad Autónoma de Madrid Madrid Spain

Université Paris Saclay UVSQ Inserm CESP Team MOODS Le Kremlin Bicêtre Paris France

University of Bergen Institute of Clinical Medicine Bergen Norway

University of Milan Dino Ferrari Center Milan Italy

University of Zürich Zürich Switzerland

VIB Center for Molecular Neurology Antwerp Belgium

Zurich Center for Integrative Human Physiology University of Zurich Zurich Switzerland

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The SORL1 p.Y1816C variant causes impaired endosomal dimerization and autosomal dominant Alzheimer's disease

Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

New insights into the genetic etiology of Alzheimer's disease and related dementias