IMPORTANCE: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES: Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). CONCLUSIONS AND RELEVANCE: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.

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

Alzheimer Center Amsterdam Neurology Vrije Universiteit Amsterdam Amsterdam UMC locatie VUmc 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

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 Neuroscience Neurodegeneration Amsterdam the Netherlands

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

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

Centro de Biología Molecular Severo Ochoa UAM CSIC Madrid Spain

CHU de Bordeaux Pole santé publique Bordeaux France

Clinic of Neurology UH Alexandrovska Medical University Sofia Sofia Bulgaria

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

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

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

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

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 Surgical and Dental Sciences University of Milan Milan Italy

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

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 Milan Italy

Department of Epidemiology ErasmusMC Rotterdam the Netherlands

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

Department of Geriatric Psychiatry University Hospital of Psychiatry Zürich Zürich Switzerland

Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases University of Toronto Toronto Canada

Department of Neurodegenerative diseases and Geriatric Psychiatry University Hospital Bonn Medical Faculty 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 Bordeaux University Hospital Bordeaux France

Department of Neurology Hospital Universitario Donostia San Sebastian Spain

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 Psychiatry and Behavioral Sciences Baylor College of Medicine Houston Texas

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

Department of Psychiatry and Psychotherapy Medical University of Vienna Vienna Austria

Department of Psychiatry and Psychotherapy University Medical Center Goettingen Goettingen Germany

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

Department of Psychiatry Psychotherapy and Psychosomatics University of Zürich Zurich Switzerland

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

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

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

Division of Psychological Medicine and Clinical Neuroscience School of Medicine Cardiff University Wales United Kingdom

Faculty of Medicine University of Lisbon Portugal

Genomics of Neurodegenerative Diseases and Aging Human Genetics Vrije Universiteit Amsterdam Amsterdam UMC locatie VUmc Amsterdam the Netherlands

Geriatric Unit Fondazione IRCCS Ca' Granda 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

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

Institut de Recerca Biomedica de Lleida Lleida Spain

Institute for Stroke and Dementia Research University Hospital LMU Munich 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 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 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 Università Cattolica del Sacro Cuore Rome Italy

Institute of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Institute of Psychiatry and Psychotherapy Berlin Germany

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

Instituto de Investigación Sanitaria del Principado de Asturias Asturias Spain

Instituto de Investigacion Sanitaria Hospital la Paz Madrid Spain

Interdisciplinary Department of Medicine Geriatric Medicine and Memory Unit University of Bari Aldo Moro Bari Italy

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 Canada

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 of Neuropsychiatry IRCCS Santa Lucia Foundation Rome Italy

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

Medical Science Department Instituto de Biomedicina Aveiro Portugal

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

Munich Cluster for Systems Neurology Munich Germany

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

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

Neurological Tissue Bank Biobanc Hospital Clinic Instituto de Investigaciones Biomédicas August Pi i Sunyer Barcelona Spain

Neurology Service Marqués de Valdecilla University Hospital University of Cantabria and IDIVAL Santander Spain

Neurology Unit Hospital San Gerardo Monza and University of Milano Bicocca Milan Italy

Neurology Unit IRCCS Fondazione Policlinico Universitario A Gemelli Rome Italy

Neuroscience Center Zurich University of Zurich and ETH Zurich Zurich Switzerland

Neurosciences Area Instituto Biodonostia San Sebastian Spain

Normandie Univ Université de Rouen Normandie Inserm U1245 and CHU Rouen Department of Genetics and Centre national de référence pour les malades Alzheimer jeunes Rouen France

NORMENT Centre Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Nuffield Department of Population Health Oxford University Oxford United Kingdom

Old Age Psychiatry Department of Psychiatry Lausanne University Hospital Lausanne Switzerland

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

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

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

Translational Health Sciences Bristol Medical School University of Bristol Bristol United Kingdom

UK Dementia Research Institute at Cardiff School of Medicine Cardiff University Cardiff United Kingdom

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

Unidad de Trastornos del Movimiento Servicio de Neurología y Neurofisiología Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío Consejo Superior de Investigaciones Científicas Universidad de Sevilla Seville 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 Neurodegenerative Diseases Department of Neurology University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute Badalona Barcelona Spain

Unit of Neurology 5 Neuropathology Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Unit of Neurology University of Parma Parma Italy

Unitat de Genètica Molecular Institut de Biomedicina de València Consejo Superior de Investigaciones Científicas Valencia Spain

Unitat Trastorns Cognitius Hospital Universitari Santa Maria de Lleida Lleida Spain

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

Université de Paris EA 4468 Assistance Publique Hôpitaux de Paris Hôpital Broca Paris France

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

University Bordeaux Inserm Bordeaux Population Health Research Center France

University of Lille Inserm CHU Lille UMR1172 Resources and Research Memory Center of Distalz Licend Lille France

Zurich Center for Integrative Human Physiology University of Zurich Zurich Switzerland

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A genome-wide association meta-analysis of all-cause and vascular dementia