OBJECTIVES: Polygenic hazard score (PHS) models can be used to predict the age-associated risk for complex diseases, including Alzheimer's disease (AD). In this study, we present an improved PHS model for AD that incorporates a large number of genetic variants and demonstrates enhanced predictive accuracy for age of onset in European populations compared to alternative models. METHODS: We used the genotyped European Alzheimer & Dementia Biobank (EADB) sample (n=42,120) to develop and evaluate the performance of the PHS model. We developed a PHS model building on 720 genetic variants, including Apolipoprotein E (APOE) ε2 and ε4 alleles. We used Elastic Net-regularized Cox regression approach to develop the PHS model. RESULTS: The new PHS model (EADB720) improved prediction accuracy compared to alternative models in European populations, with the Odds Ratio OR80/20 from the highest quintile of risk (80th risk percentile and above) to the lowest quintile of risk (20th risk percentile and below) varying between 5.10 and 13.15 within the range of age of onset from 65 - 85 years. Our model also improved risk stratification across ε3/3 individuals of European ancestry (OR80/20 ranges from 1.95 to 3.52). It was also successfully validated in independent datasets (HUSK, DemGene and ADNI) by achieving OR80/20 up to 10.00 in each independent dataset. CONCLUSION: Our EADB720 model significantly improves the accuracy of age-associated risk of AD across European populations (pval<0.03). Accurately predicting the age of onset of AD is of large clinical importance to implementing new AD medication and early intervention in clinical settings.

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

Ace Alzheimer Center Barcelona Universitat Internacional de Catalunya Barcelona Spain

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

Alzheimer Research Center and Memory Clinic Instituto Andaluz de Neurociencia Málaga Spain

Alzheimer's Centre Reina Sofia CIEN Foundation ISCIII Madrid Spain

Alzheimer's disease and other cognitive disorders Unit Neurology Department Hospital Clinic Barcelona Spain

Bergen Center for Brain Plasticity Division of Psychiatry Haukeland University Hospital Bergen Norway

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

Biogipuzkoa Health Research Institute Neurosciences Area Group of Neurodegenerative Diseases 20014 San Sebastián Spain

CAEBI Centro Andaluz de Estudios Bioinformáticos Sevilla Spain

Cardiff School of Medicine Cardiff University Cardiff UK

Center for Cognitive Disorders Department of Psychiatry and Psychotherapy TUM University Hospital Technical University of Munich School of Medicine Munich Germany

Center for Multimodal Imaging and Genetics University of California San Diego La Jolla CA USA

Centre for Age Related Medicine Stavanger University Hospital Stavanger Norway

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

Centre for Precision Psychiatry Division of Mental Health and Addiction Oslo University Hospital and Institute of Clinical Medicine University of Oslo Oslo Norway

Centro de Biología Molecular Severo Ochoa Madrid Spain

Chronic Disease Programme Instituto de Salud Carlos 3 Madrid Spain

CHU de Bordeaux Pole santé publique Bordeaux France

CIBERINFEC Network Center for Biomedical Research in Infectious Diseases National Institute of Health Carlos 3 Madrid Spain

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

Clinic of Neurology UH Alexandrovska Medical University Sofia Sofia Bulgaria

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

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

Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna Vienna Austria

Delft Bioinformatics Lab Delft University of technology Delft The Netherlands

Departamento de Bioquímica Médica Biología Molecular e Inmunología Facultad de Medicina Universidad de Sevilla Sevilla Spain

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

Departamento de Medicina Facultad de Medicina Universidad de Sevilla Seville Spain

Departamento de Medicina y Psiquiatría Universidad de Cantabria Santander Spain

Department of Adult Psychiatry University Hospital of Psychiatry Zürich Zürich Switzerland

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 Biomedicine University of Bergen Bergen Norway

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

Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Department of Clinical Biochemistry Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Clinical Sciences and Community Health University of Milan 20122 Milan Italy

Department of Cognitive Science University of California San Diego La Jolla CA USA

Department of Geriatric Medicine Oslo University Hospital Oslo Norway

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

Department of Geriatrics St Olav's Hospital Trondheim University Hospital Trondheim Norway and Department of Neuromedicine and Movement Science Norwegian University of Science and Technology Trondheim Norway

Department of Hematology and Stem Cell Transplant Vito Fazzi Hospital Lecce Italy

Department of Medical Genetics Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Department of Microbiology Immunology and Molecular Genetics University of Texas Health San Antonio TX 78229 3900 USA

Department of Neurology Akershus University Hospital Lørenskog Norway

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

Department of Neurology ErasmusMC Rotterdam The Netherlands

Department of Neurology Hospital Universitario de Navarra Pamplona Spain

Department of Neurology Hospital Universitario Donostia Instituto Biodonostia OSAKIDETZA EHU CIBERNED San Sebastian Spain

Department of Neurology Hospital Universitario Son Espases Palma Spain

Department of Neurology Oslo University Hospital Oslo Norway

Department of Neurology University Hospital of North Norway Tromsø; Department of Psychology Faculty of Health Sciences UiT The Arctic University of Norway Tromsø Norway

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

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 Neuroscience Università Cattolica del Sacro Cuore Rome Italy

Department of Neurosciences Faculty of Medicine and Nursery University of the Basque Country San Sebastián Spain

Department of Old Age Psychiatry and Cognitive Disorders University Hospital Bonn Venusberg Campus 1 53127 Bonn Germany

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

Department of Pharmacy Section for Pharmacology and Pharmaceutical Biosicences University of Oslo Oslo Norway

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

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

Department of Psychiatry and Psychotherapy Medical University of Vienna Vienna Austria

Department of Psychiatry Namsos Hospital Namsos Norway

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

Department of Radiology School of Medicine University of California San Diego La Jolla CA USA

Department of Research and Innovation Helse Fonna Haugesund Norway

Dept of Biomedical Surgical and Dental Sciences University of Milan Milan Italy

Dept of Public Health and Caring Sciences Geriatrics Uppsala University Uppsala Sweden

Division of Clinical Geriatrics Department of Neurobiology Care Sciences and Society Karolinska Institutet Stockholm Sweden

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

Experimental Neuro psychobiology Laboratory IRCCS Fondazione Santa Lucia Rome Italy

Faculty of Medicine University of Lisbon Lisbon Portugal

Faculty of Medicine University of Oslo Oslo Norway

Fundación de Medicina Xenómica Servicio Galego de Saúde Santiago de Compostela Spain

Geriatric Unit Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico 20122 Milan Italy

German Center for Neurodegenerative Diseases Bonn Germany

Grupo de Medicina Xenómica Centro en Red de Investigación en Enfermedades Raras CIMUS Universidade de Santiago de Compostela Santiago de Compostela Spain

Hospital Universitario Ramon y Cajal IRYCIS Madrid Spain

Institut du Cerveau Paris Brain Institute INSERM U1127 UMR CNRS 7225 Paris Sorbonne Université Assistance Publique des Hôpitaux de Paris Paris France

Institute for Regenerative Medicine University of Zürich Zürich Switzerland

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 Epidemiology and Biometrics Julius Maximilians University Würzburg Würzburg Germany

Institute of Clinical Medicine Neurology University of Eastern Finland Kuopio Finland

Institute of Clinical Medicine University of Oslo Oslo Norway

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 Neurology Catholic University of the Sacred Heart Rome Italy

Institute of Social Medicine Occupational Health and Public Health University of Leipzig 04103 Leipzig Germany

Instituto de Investigacion Sanitaria 'Hospital la Paz' Madrid Spain

Instituto de Investigación Sanitaria del Principado de Asturias Oviedo Spain

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

IRCCS Fondazione Don Carlo Gnocchi Florence Italy

Krembil Brain Institute University Health Network Toronto Ontario Canada

Laboratorio de Genética Hospital Universitario Central de Asturias Oviedo Spain

Laboratory of Neuropsychiatry IRCCS Santa Lucia Foundation Rome Italy

Luxembourg Centre for Systems Biomedicine University of Luxembourg Luxembourg

Memory and Aging Center Department of Neurology Weill Institute for Neurosciences University of California San Francisco San Francisco CA USA

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

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

Navarrabiomed Pamplona Spain

Networking Research Center on Neurodegenerative Diseases Instituto de Salud Carlos 3 Madrid Spain

Neurodegenerative Diseases Unit Fondazione IRCCS Ca' Granda Ospedale Policlinico Milan Italy

Neurological Tissue Bank Biobanc Hospital Clinic IDIBAPS Barcelona Spain

Neurology Service Marqués de Valdecilla University Hospital Santander Spain

Neurology Unit IRCCS Fondazione Policlinico Universitario A Gemelli Rome Italy

Neurology Unit IRCCS San Gerardo dei Tintori Monza Italy

Neuroscience Center Zurich University of Zurich and ETH Zurich Zurich Switzerland

Norwegian National Centre for Ageing and Health Vestfold Hospital Trust Tønsberg Norway

Old Age Psychiatry Department of Psychiatry Lausanne University Hospital Lausanne Switzerland

Oslo Delirium Research Group Department of Geriatric Medicine Akershus University Hospital Lørenskog Norway

Research Centre for Age related Functional Decline and Disease Innlandet Hospital Trust Ottestad Norway

Sant Pau Memory Unit IR SANT PAU Hospital de la Santa Creu i Sant Pau Barcelona Spain

School of Medicine and Surgery University of Milano Bicocca Monza Italy

Tanz Centre for Research in Neurodegenerative Diseases Departments of Medicine and Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada

Taub Institute for Research in Alzheimer's Disease and the Aging Brain The Gertrude H Sergievsky Center Department of Neurology Columbia University New York NY USA

Translational Health Sciences Bristol Medical School University of Bristol Bristol UK

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

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

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

Unit of Neurology 8 Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

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

Univ Lille Inserm CHU Lille Institut Pasteur de Lille LabEx DISTALZ U1167 RID AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement Lille France

Univ Rouen Normandie Normandie Univ Inserm U1245 and CHU Rouen Department of Genetics and CNR MAJ F 76000 Rouen France

Universidad Autónoma de Madrid Madrid Spain

University of Bergen Department of Clinical Medicine Bergen Norway

University of Bordeaux Inserm Bordeaux Population Health Research Center U1219 Bordeaux France

Zurich Center for Integrative Human Physiology University of Zurich Zurich Switzerland

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