Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E gene (APOE) ε2/ε3/ε4 polymorphism remains the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms for how ε4 increases and for how ε2 decreases dementia risk is not well-understood. Importantly, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in s4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. Such insights may help to understand and overcome side effects, to impact clinical trial enrolment strategies, and to create the scientific basis for targeted mechanism-driven therapies in neurodegenerative diseases.

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

Academic Division C Frugoni and Hospital Division of Internal and Geriatric Medicine Policlinico Hospital Bari Italy

Ace Alzheimer Center Barcelona Universitat Internacional de Catalunya Barcelona Spain

Alzheimer Center Amsterdam Neurology Vrije Universiteit Amsterdam Amsterdam UMC location VUmc Amsterdam The Netherlands

Alzheimer's Centre Reina Sofia CIEN Foundation 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

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

BK FOUR Department of Integrative Biological Sciences Chosun University Gwangju 61452 Republic of Korea

Bristol Medical School University of Bristol Bristol UK

CAEBI Centro Andaluz de Estudios Bioinformáticos Sevilla Spain

Cardiff School of Medicine Cardiff University Cardiff UK

Center for Alzheimer's and Related Dementias National Institute on Aging Bethesda MD USA

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

Center for Noninvasive Diagnostics TGen Phoenix AZ USA

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

Centre for Old Age Psychiatric Research Innlandet Hospital Trust Ottestad Norway

Centre for Precision Psychiatry Institute of Clinical Medicine University of Oslo Oslo Norway

Centro de Biología Molecular Severo Ochoa

Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Institute of Psychiatry and Psychotherapy Hindenburgdamm 30 12203 Berlin Germany

Clinic of Neurology UH Alexandrovska Medical University Sofia Sofia Bulgaria

Coalition for Aligning Science 5425 Wisconsin Ave 600 Chevy Chase MD 20815 USA

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

Delft Bioinformatics Lab Delft University of Technology Delft The Netherlands

Departamento de Medicina Facultad de Medicina Universidad de Sevilla Seville Spain

Department for Cognitive Disorders and Old Age Psychiatry University Hospital Bonn Bonn Germany

Department of Biomedical Science Chosun University Gwangju 61452 Republic of Korea

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 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 Italy

Department of Clinical Biochemistry Copenhagen University Hospital Rigshospitalet Blegdamsvej 9 2100 Copenhagen Denmark

Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Blegdamsvej 3B 2100 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 Germany

Department of Geriatric Psychiatry University Hospital of Psychiatry Zürich Zürich Switzerland

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

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

Department of Medical Genetics Oslo University Hospital Oslo Norway

Department of Medicine and Surgery Unit of Neurology University Hospital of Parma Parma Italy

Department of Molecular Genetics Brain Research Institute Niigata University Japan

Department of Molecular Neuroscience UCL Institute of Neurology London WC1N 3BG U K

Department of Neural Development and Disease Korea Brain Research Institute Daegu 41062 Repuiblic of Korea

Department of Neurology Akershus University Hospital Lørenskog Norway

Department of Neurology and Clinical Neurophysiology Trondheim University Hospital Trondheim Norway

Department of Neurology Hospital Universitario Donostia San Sebastian Spain

Department of Neurology Institut de Recerca Sant Pau Hospital de la Santa Creu i Sant Pau Universitat Autònoma de Barcelona Barcelona Spain

Department of Neuromedicine and Movement Science Faculty of Medicine and Health Sciences Norwegian University of Science and Technology Department of Geriatrics St Olav's Hospital Trondheim University Hospital 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 Leuven Brain Institute KU Leuven Leuven Belgium

Department of Neurosurgery Kuopio University Hospital Puijonlaaksontie 2 FI 70210 Kuopio Finland

Department of Old Age Psychiatry Division of Academic Psychiatry Institute of Psychiatry Psychology and Neuroscience King's College London United Kingdom

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

Department of Psychiatry and Psychotherapy Faculty of Medicine and University Hospital Cologne University of Cologne Cologne Germany

Department of Psychiatry and Psychotherapy LVR Klinikum Essen University of Duisburg Essen Germany

Department of Psychiatry and Psychotherapy Medical University 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 Germany

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

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

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

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

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

Division of Life Science State Key Laboratory of Molecular Neuroscience and Daniel and Mayce Yu Molecular Neuroscience Center The Hong Kong University of Science and Technology Clear Water Bay Hong Kong China

Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

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 UK

Epidemiology and Data Science Vrije Universiteit Amsterdam Amsterdam UMC location VUmc Amsterdam The Netherlands

Estudios en Neurociencias y Sistemas Complejos CONICET HEC UNAJ

Faculty of Medicine University of Lisbon Portugal

Fundació Docència i Recerca MútuaTerrassa Terrassa Barcelona Spain

Fundación Pública Galega de Medicina Xenómica IDIS Santiago de Compostela Spain

Genomics of Neurodegenerative Diseases and Aging Human Genetics Vrije Universiteit Amsterdam Amsterdam UMC location 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

Grupo de Medicina Xenómica CIBERER CIMUS Universidade de Santiago de Compostela Santiago de Compostela Spain

Guangdong Provincial Key Laboratory of Brain Science Disease and Drug Development HKUST Shenzhen Research Institute Shenzhen Guangdong 518057 China

Gwangju Alzheimer's and Related Dementia Cohort Research Center Chosun University Gwangju 61452 Republic of Korea

Haugesund Hospital Department of Research and Innovation Haugesund Norway

Hong Kong Center for Neurodegenerative Diseases InnoHK Hong Kong China

Hospital Universitario Ramon y Cajal IRYCIS Madrid

Institut de Recerca Biomedica de Lleida Lleida Spain

Institute for Regenerative Medicine University of Zürich Switzerland

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 Yliopistoranta 1E 70211 Kuopio Finland

Institute of Clinical Medicine Campus Ahus University of Oslo Oslo Norway

Institute of Clinical Medicine Neurosurgery University of Eastern Finland Kuopio Finland

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

Institute of Health and Society Faculty of Medicine University of Oslo Oslo Norway

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

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

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

IRCCS Fondazione Don Carlo Gnocchi Florence Italy

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

Karolinska University Hospital Theme inflammation and Aging Sweden

KG Jebsen Centre for Neurodevelopmental disorders University of Oslo Oslo Norway

Krembil Brain Institute University Health Network Toronto Ontario Canada

Laboratorio de Genética Hospital Universitario Central de Asturias Oviedo Spain

Laboratory of Experimental Neuropsychobiology Clinical Neuroscience and Neurorehabilitation Department IRCCS Santa Lucia Foundation Rome Italy

Luxembourg Centre for Systems Biomedicine University of Luxembourg Esch sur Alzette Luxembourg

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

Medical Science Department iBiMED Aveiro Portugal

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

Munich Cluster for Systems Neurology Munich Germany

Namsos Hospital Namsos Norway

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 Switzerland

Neurosciences Area Instituto Biodonostia San Sebastian Spain

Norwegian National Advisory Unit on Aging and Health Vestfold Health Trust Tønsberg Norway

Norwegian National Centre for Aging and Health Vestfold Health Trust Tønsberg Norway

Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Science University of Copenhagen Blegdamsvej 3 2200 Copenhagen

Nuffield Department of Population Health University of Oxford Oxford UK

Old Age Psychiatry Department of Psychiatry Lausanne University Hospital Lausanne Switzerland

School of Medicine and Surgery University of Milano Bicocca Monza Italy

SIAT HKUST Joint Laboratory for Brain Science Shenzhen Guangdong 518055 China

Stavanger University Hospital Stavanger Norway

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 Depatment of Neurology Columbia University New York NY

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

UK Dementia Research Institute School of Medicine Cardiff University Wales UK

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 CSIC Universidad de Sevilla Seville Spain

Unit of Neurology 5 Neuropathology Fondazione IRCCS Istituto Neurologico Carlo Besta Milan 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 Rouen Normandie Normandie Univ Inserm U1245 and CHU Rouen Department of Genetics and Reference Center for Developmental Disorders Rouen France

Université de Lille Inserm CHU Lille Institut Pasteur de Lille Lille France

Université Paris Cité EA 4468 APHP Hospital Broca Memory Resource and Research Centre of de Paris Broca Ile de France Paris France

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

VIB Center for Brain and Disease Research ON5 Herestraat 49 box 602 3000 Leuven Belgium

VIB Center for Molecular Neurology VIB Antwerp Belgium

Well aging Medicare Institute and CSU G LAMP Project Group Chosun University Gwangju 61452 Republic of Korea

Wolfson Centre for Age Related Diseases Division of Neuroscience of the Institute of Psychiatry Psychology and Neuroscience King's College London United Kingdom

Zurich Center for Integrative Human Physiology University of Zurich Switzerland

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