Machine learning in Alzheimer's disease genetics.

Journal: Nature communications
Published Date: Jul 22, 2025

Abstract

Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models. ML approaches successfully captured all genome-wide significant genetic variants identified in the training set and 22% of associations from larger meta-analyses. They highlight 6 novel loci which replicate in an external dataset, including variants which map to ARHGAP25, LY6H, COG7, SOD1 and ZNF597. They further identify novel association in AP4E1, refining the genetic landscape of the known SPPL2A locus. Our results demonstrate that machine learning methods can achieve predictive performance comparable to classical approaches in genetic epidemiology and have the potential to uncover novel loci that remain undetected by traditional GWAS. These insights provide a complementary avenue for advancing the understanding of AD genetics.

Authors

  • Matthew Bracher-Smith
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
  • Federico Melograna
    BIO3 - Laboratory for Systems Medicine, Department of Human Genetics, KU Leuven, Leuven, Belgium. federico.melograna@kuleuven.be.
  • Brittany Ulm
    Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
  • Céline Bellenguez
    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.
  • Benjamin Grenier-Boley
    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.
  • Diane Duroux
    BIO3 - Systems Genetics, GIGA-R Molecular and Computational Biology, University of Liege, Liege, Belgium.
  • Alejo J Nevado
    Department of Psychiatry, University of Oxford, Oxford, UK.
  • Peter Holmans
    Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
  • Betty M Tijms
    From the Laboratory of Neuroinformatics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Via Pilastroni 4, Brescia 25125, Italy (D.A., A.R.); Alzheimer Centre Amsterdam, Neurology, Vrije Universiteit, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands (V.V., W.M.v.d.F., B.M.T.); Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands (V.V., W.M.v.d.F., B.M.T.); Brain Imaging Centre, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary (B.W., T.A., Z.V.); Biomatics and Applied Artificial Intelligence Institute, John von Neumann Faculty of Informatics, Óbuda University, Budapest, Hungary (B.W.); The Australian e-Health Research Centre, CSIRO Health and Biosecurity, Brisbane, Australia (P.B.); School of Psychology, University of Surrey, Guildford, United Kingdom (T.A.); Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, CNRS, Inria, Inserm, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France (S.D.); Department of Epidemiology and Data Science, Vrije Universiteit, Amsterdam UMC, location VUmc, Amsterdam, the Netherlands (W.M.v.d.F.); Department of Radiology and Nuclear Medicine, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands (F.B.); Queen Square Institute of Neurology, University College London, United Kingdom (F.B.); and UCL Hawkes Institute, Department of Medical Physics and Biomedical Engineering and Department of Computer Science, University College London, London, United Kingdom (F.B., D.C.A., A.A., N.P.O.).
  • Marc Hulsman
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
  • Itziar de Rojas
    Research Center and Memory Clinic, ACE Alzheimer Center Barcelona. Universitat Internacional de Catalunya, Catalunya, Spain.
  • Rafael Campos-Martin
    Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Sven van der Lee
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
  • Atahualpa Castillo
    Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
  • Fahri Küçükali
    Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
  • Oliver Peters
  • Anja Schneider
    Clinic for Psychiatry and Psychotherapy, University of Goettingen, Germany.
  • Martin Dichgans
    Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany.
  • Dan Rujescu
    Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna, Austria.
  • Norbert Scherbaum
    Head of the Department of Psychiatry and Psychotherapy, LVR-Hospital Essen, Faculty of Medicine, University of Duisburg/Essen and Professor, University of Duisburg/Essen, Essen, Germany.
  • Jürgen Deckert
    Center for Mental Health, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, Germany.
  • Steffi Riedel-Heller
    Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, 04103, Leipzig, Germany.
  • Lucrezia Hausner
    Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • Laura Molina-Porcel
    Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic of Barcelona, Fundació Recerca Clinic Barcelona- Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), and University of Barcelona, Barcelona, Spain.
  • Emrah Düzel
    German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
  • Timo Grimmer
    Clinic and Polyclinic for Psychiatry & Psychotherapy, Technical University Munich, Germany.
  • Jens Wiltfang
    Department of Psychiatry and Psychotherapy (NH, HE, JW), University of Göttingen Medical Center, Göttingen, Germany; German Center for Neurodegenerative Diseases (DZNE) (JW), Göttingen, Germany; Neurosciences and Signaling Group (JW), Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, Aveiro, Portugal.
  • Stefanie Heilmann-Heimbach
    Institute of Human Genetics, University Hospital Bonn and Division of Genomics, Life & Brain Research Centre, University of Bonn School of Medicine, Bonn, Germany.
  • Susanne Moebus
    Institute for Urban Public Health, University Hospital of University Duisburg-Essen, Essen, Germany.
  • Thomas Tegos
    1st Department of Neurology, Medical school, Aristotle University of Thessaloniki, Thessaloniki, Makedonia, Greece.
  • Nikolaos Scarmeas
    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.
  • Oriol Dols-Icardo
    Sant Pau Memory Unit, Institut de Recerca Sant Pau, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • Fermin Moreno
    From the Department of Neuroimaging (A.L.Y., S.C.R.W.), Institute of Psychiatry, Psychology and Neuroscience, King's College London; Departments of Computer Science (A.L.Y., D.C.A.) and Medical Physics and Biomedical Engineering (D.M.C.), Centre for Medical Image Computing, University College London; Dementia Research Centre (M.B., L.L.R., R.S.C., G.P., E.T., D.M.C., C.V.G., L.J., J.D.R.), Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (J.v.S., L.J., H.S.), Erasmus Medical Centre, Rotterdam, the Netherlands; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia University Hospital; Neuroscience Area (F.M.), Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Spain; Neurology Unit (B.B.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine (R.L.), Université Laval, Québec; Sunnybrook Health Sciences Centre, Sunnybrook Research Institute (M.M.), and Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Fondazione Ca'Granda (D.G.), IRCCS Ospedale Policlinico; University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust (J.B.R.), University of Cambridge, UK; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Laboratory for Cognitive Neurology, Department of Neurosciences (R.V.), and Leuven Brain Institute (R.V.), KU Leuven; Neurology Service (R.V.), University Hospitals Leuven, Belgium; Faculty of Medicine (A.d.M.), University of Lisbon, Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University Hospital of Coimbra (HUC), Neurology Service (I.S.), and Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, University of Coimbra, Portugal; Department of Psychiatry, McGill University Health Centre (S.D.), and McConnell Brain Imaging Centre, Montreal Neurological Institute (S.D.), McGill University, Montreal, Canada; Nuffield Department of Clinical Neurosciences (C.B.), Medical Sciences Division, University of Oxford; Division of Neuroscience and Experimental Psychology (A.G.), Wolfson Molecular Imaging Centre, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), University of Duisburg-Essen; Department of Neurology (J.L., A.D.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) (J.L.); Munich Cluster of Systems Neurology (SyNergy) (J.L.), Munich; Department of Neurology (M.O.), University of Ulm, Germany; Departments of Neuroscience, Psychology, Drug Research, and Child Health (S.S.), University of Florence; and IRCCS Don Gnocchi (S.S.), Florence, Italy.
  • Jordi Pérez-Tur
    CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
  • María J Bullido
    CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
  • Pau Pastor
    Fundació Docència i Recerca MútuaTerrassa, Terrassa, Barcelona, Spain.
  • Raquel Sánchez-Valle
    Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • Victoria Alvarez
    Complejo Hospitalario de Pontevedra, Department of Gastroenterology, Pontevedra, Spain.
  • Mercè Boada
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Pablo García-González
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Raquel Puerta
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Pablo Mir
    CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
  • Luis M Real
    Unidad Clínica de Enfermedades Infecciosas y Microbiología. Hospital Universitario de Valme, Sevilla, Spain.
  • Gerard Piñol-Ripoll
    Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, Lleida, Spain.
  • Jose María García-Alberca
    CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
  • Eloy Rodriguez-Rodriguez
    CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
  • Hilkka Soininen
    Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.
  • Sami Heikkinen
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
  • Alexandre de Mendonça
    Laboratório de Neurociências, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
  • Shima Mehrabian
    Clinic of Neurology, UH "Alexandrovska", Medical University - Sofia, Sofia, Bulgaria.
  • Latchezar Traykov
    Department of Neurology, Medical University - Sofia, Sofia, Bulgaria.
  • Jakub Hort
    Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.
  • Martin Vyhnalek
    Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Praha, Czech Republic.
  • Nicolai Sandau
    Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
  • Jesper Qvist Thomassen
    Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark.
  • Yolande A L Pijnenburg
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
  • Henne Holstege
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
  • John van Swieten
    From the Department of Neuroimaging (A.L.Y., S.C.R.W.), Institute of Psychiatry, Psychology and Neuroscience, King's College London; Departments of Computer Science (A.L.Y., D.C.A.) and Medical Physics and Biomedical Engineering (D.M.C.), Centre for Medical Image Computing, University College London; Dementia Research Centre (M.B., L.L.R., R.S.C., G.P., E.T., D.M.C., C.V.G., L.J., J.D.R.), Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (J.v.S., L.J., H.S.), Erasmus Medical Centre, Rotterdam, the Netherlands; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia University Hospital; Neuroscience Area (F.M.), Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Spain; Neurology Unit (B.B.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine (R.L.), Université Laval, Québec; Sunnybrook Health Sciences Centre, Sunnybrook Research Institute (M.M.), and Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Fondazione Ca'Granda (D.G.), IRCCS Ospedale Policlinico; University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust (J.B.R.), University of Cambridge, UK; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Laboratory for Cognitive Neurology, Department of Neurosciences (R.V.), and Leuven Brain Institute (R.V.), KU Leuven; Neurology Service (R.V.), University Hospitals Leuven, Belgium; Faculty of Medicine (A.d.M.), University of Lisbon, Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University Hospital of Coimbra (HUC), Neurology Service (I.S.), and Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, University of Coimbra, Portugal; Department of Psychiatry, McGill University Health Centre (S.D.), and McConnell Brain Imaging Centre, Montreal Neurological Institute (S.D.), McGill University, Montreal, Canada; Nuffield Department of Clinical Neurosciences (C.B.), Medical Sciences Division, University of Oxford; Division of Neuroscience and Experimental Psychology (A.G.), Wolfson Molecular Imaging Centre, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), University of Duisburg-Essen; Department of Neurology (J.L., A.D.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) (J.L.); Munich Cluster of Systems Neurology (SyNergy) (J.L.), Munich; Department of Neurology (M.O.), University of Ulm, Germany; Departments of Neuroscience, Psychology, Drug Research, and Child Health (S.S.), University of Florence; and IRCCS Don Gnocchi (S.S.), Florence, Italy.
  • Inez Ramakers
    Maastricht University, Department of Psychiatry & Neuropsychologie, Alzheimer Center Limburg, Maastricht, the Netherlands.
  • Frans Verhey
    Maastricht University, Department of Psychiatry & Neuropsychologie, Alzheimer Center Limburg, Maastricht, the Netherlands.
  • Philip Scheltens
    Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
  • Caroline Graff
    From the Department of Neuroimaging (A.L.Y., S.C.R.W.), Institute of Psychiatry, Psychology and Neuroscience, King's College London; Departments of Computer Science (A.L.Y., D.C.A.) and Medical Physics and Biomedical Engineering (D.M.C.), Centre for Medical Image Computing, University College London; Dementia Research Centre (M.B., L.L.R., R.S.C., G.P., E.T., D.M.C., C.V.G., L.J., J.D.R.), Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (J.v.S., L.J., H.S.), Erasmus Medical Centre, Rotterdam, the Netherlands; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia University Hospital; Neuroscience Area (F.M.), Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Spain; Neurology Unit (B.B.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine (R.L.), Université Laval, Québec; Sunnybrook Health Sciences Centre, Sunnybrook Research Institute (M.M.), and Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Fondazione Ca'Granda (D.G.), IRCCS Ospedale Policlinico; University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust (J.B.R.), University of Cambridge, UK; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Laboratory for Cognitive Neurology, Department of Neurosciences (R.V.), and Leuven Brain Institute (R.V.), KU Leuven; Neurology Service (R.V.), University Hospitals Leuven, Belgium; Faculty of Medicine (A.d.M.), University of Lisbon, Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University Hospital of Coimbra (HUC), Neurology Service (I.S.), and Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, University of Coimbra, Portugal; Department of Psychiatry, McGill University Health Centre (S.D.), and McConnell Brain Imaging Centre, Montreal Neurological Institute (S.D.), McGill University, Montreal, Canada; Nuffield Department of Clinical Neurosciences (C.B.), Medical Sciences Division, University of Oxford; Division of Neuroscience and Experimental Psychology (A.G.), Wolfson Molecular Imaging Centre, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), University of Duisburg-Essen; Department of Neurology (J.L., A.D.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) (J.L.); Munich Cluster of Systems Neurology (SyNergy) (J.L.), Munich; Department of Neurology (M.O.), University of Ulm, Germany; Departments of Neuroscience, Psychology, Drug Research, and Child Health (S.S.), University of Florence; and IRCCS Don Gnocchi (S.S.), Florence, Italy.
  • Goran Papenberg
    Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
  • Vilmantas Giedraitis
    Dept.of Public Health and Carins Sciences / Geriatrics, Uppsala University, Uppsala, Sweden.
  • Julie Williams
    School of Medicine, Cardiff University, Cardiff, UK.
  • Philippe Amouyel
    From the Department of Neuroradiology (B.L.G., A.L., C.B., J.P.P., G.K.), Department of Public Health (B.L.G., P.A., A.H.), and INclude Health Data Warehouse (C.G., L.S.), CHU Lille-Université Lille, Rue Emile Laine, 59000 Lille, France; Department of Radiology, UC Davis Health, Sacramento, Calif (L.H.B.); Université Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France (P.A., A.H.); INSERM, U1172-LilNCog-Lille Neuroscience & Cognition, Université Lille, Lille, France (J.P.P., G.K.); and UAR 2014-US 41-PLBS-Plateformes Lilloises en Biologie & Santé, Université Lille, Lille, France (J.P.P., G.K.).
  • Anne Boland
    Laboratory of Excellence GENMED (Medical Genomics), Strasbourg, France.
  • Jean-François Deleuze
    Centre National de Recherche en Génomique Humaine (CNRGH), Direction de la Recherche Fondamentale, CEA, Institut de Biologie François Jacob, Evry, France; LaBex GenMed, Fondation Jean Dausset, Paris, France; Centre d'Etudes du Polymorphisme Humain (CEPH), Fondation Jean Dausset, Paris, France.
  • Gael Nicolas
    Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department of Genetics and CNRMAJ, F-, 76000, Rouen, France.
  • Carole Dufouil
    Inserm, Bordeaux Population Health Research Center, UMR 1219, Univ. Bordeaux, ISPED, CIC 1401-EC, Univ Bordeaux, Bordeaux, France.
  • Florence Pasquier
    INSERM, U1172-LilNCog-Lille Neuroscience & Cognition, University of Lille, Lille, France; Memory Center, DISTALZ, Lille, France; Neurology Department, Lille University Medical Center, Lille, France.
  • Olivier Hanon
    Université Paris-Descartes, EA 4468, Hôpital Broca, APHP, Gérontopôle d'Ile-de-France Paris, France.
  • Stéphanie Debette
    BPH-U1219, INSERM, Université de Bordeaux, Bordeaux, France.
  • Edna Grünblatt
    Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.
  • Julius Popp
    CHUV, Old Age Psychiatry, Department of Psychiatry, Lausanne, Switzerland.
  • Roberta Ghidoni
    Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
  • Daniela Galimberti
    From the Department of Neuroimaging (A.L.Y., S.C.R.W.), Institute of Psychiatry, Psychology and Neuroscience, King's College London; Departments of Computer Science (A.L.Y., D.C.A.) and Medical Physics and Biomedical Engineering (D.M.C.), Centre for Medical Image Computing, University College London; Dementia Research Centre (M.B., L.L.R., R.S.C., G.P., E.T., D.M.C., C.V.G., L.J., J.D.R.), Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (J.v.S., L.J., H.S.), Erasmus Medical Centre, Rotterdam, the Netherlands; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia University Hospital; Neuroscience Area (F.M.), Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Spain; Neurology Unit (B.B.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine (R.L.), Université Laval, Québec; Sunnybrook Health Sciences Centre, Sunnybrook Research Institute (M.M.), and Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Fondazione Ca'Granda (D.G.), IRCCS Ospedale Policlinico; University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust (J.B.R.), University of Cambridge, UK; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Laboratory for Cognitive Neurology, Department of Neurosciences (R.V.), and Leuven Brain Institute (R.V.), KU Leuven; Neurology Service (R.V.), University Hospitals Leuven, Belgium; Faculty of Medicine (A.d.M.), University of Lisbon, Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University Hospital of Coimbra (HUC), Neurology Service (I.S.), and Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, University of Coimbra, Portugal; Department of Psychiatry, McGill University Health Centre (S.D.), and McConnell Brain Imaging Centre, Montreal Neurological Institute (S.D.), McGill University, Montreal, Canada; Nuffield Department of Clinical Neurosciences (C.B.), Medical Sciences Division, University of Oxford; Division of Neuroscience and Experimental Psychology (A.G.), Wolfson Molecular Imaging Centre, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), University of Duisburg-Essen; Department of Neurology (J.L., A.D.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) (J.L.); Munich Cluster of Systems Neurology (SyNergy) (J.L.), Munich; Department of Neurology (M.O.), University of Ulm, Germany; Departments of Neuroscience, Psychology, Drug Research, and Child Health (S.S.), University of Florence; and IRCCS Don Gnocchi (S.S.), Florence, Italy.
  • Beatrice Arosio
    Geriatric Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Patrizia Mecocci
    Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.
  • Vincenzo Solfrizzi
    Interdisciplinary Department of Medicine, Geriatric Medicine and Memory Unit, University of Bari "A. Moro", Bari, Italy.
  • Lucilla Parnetti
    Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06100 Perugia, Italy.
  • Alessio Squassina
    Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
  • Lucio Tremolizzo
    Neurology Unit, "San Gerardo" hospital, Monza and University of Milano-Bicocca, Milan, Italy.
  • Barbara Borroni
    From the Department of Neuroimaging (A.L.Y., S.C.R.W.), Institute of Psychiatry, Psychology and Neuroscience, King's College London; Departments of Computer Science (A.L.Y., D.C.A.) and Medical Physics and Biomedical Engineering (D.M.C.), Centre for Medical Image Computing, University College London; Dementia Research Centre (M.B., L.L.R., R.S.C., G.P., E.T., D.M.C., C.V.G., L.J., J.D.R.), Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (J.v.S., L.J., H.S.), Erasmus Medical Centre, Rotterdam, the Netherlands; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia University Hospital; Neuroscience Area (F.M.), Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Spain; Neurology Unit (B.B.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Clinique Interdisciplinaire de Mémoire, Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine (R.L.), Université Laval, Québec; Sunnybrook Health Sciences Centre, Sunnybrook Research Institute (M.M.), and Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Fondazione Ca'Granda (D.G.), IRCCS Ospedale Policlinico; University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust (J.B.R.), University of Cambridge, UK; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Laboratory for Cognitive Neurology, Department of Neurosciences (R.V.), and Leuven Brain Institute (R.V.), KU Leuven; Neurology Service (R.V.), University Hospitals Leuven, Belgium; Faculty of Medicine (A.d.M.), University of Lisbon, Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University Hospital of Coimbra (HUC), Neurology Service (I.S.), and Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, University of Coimbra, Portugal; Department of Psychiatry, McGill University Health Centre (S.D.), and McConnell Brain Imaging Centre, Montreal Neurological Institute (S.D.), McGill University, Montreal, Canada; Nuffield Department of Clinical Neurosciences (C.B.), Medical Sciences Division, University of Oxford; Division of Neuroscience and Experimental Psychology (A.G.), Wolfson Molecular Imaging Centre, University of Manchester, UK; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), University of Duisburg-Essen; Department of Neurology (J.L., A.D.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) (J.L.); Munich Cluster of Systems Neurology (SyNergy) (J.L.), Munich; Department of Neurology (M.O.), University of Ulm, Germany; Departments of Neuroscience, Psychology, Drug Research, and Child Health (S.S.), University of Florence; and IRCCS Don Gnocchi (S.S.), Florence, Italy.
  • Michael Wagner
  • Benedetta Nacmias
    Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence Florence Italy.
  • Marco Spallazzi
    Department of Medicine and Surgery, Unit of Neurology, University-Hospital of Parma, Parma, Italy.
  • Davide Seripa
    Department of Hematology and Stem Cell Transplant, Vito Fazzi Hospital, Lecce, Italy.
  • Innocenzo Rainero
    Department of Neuroscience "Rita Levi Montalcini", University of Torino, Torino, Italy.
  • Antonio Daniele
    Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.
  • Fabrizio Piras
    Laboratory of Neuropsychiatry, Santa Lucia Foundation IRCCS, Rome, Italy.
  • Carlo Masullo
    Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy.
  • Giacomina Rossi
    Unit of Neurology V - Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • Frank Jessen
    Clinic and Polyclinic for Psychiatry and Psychotherapy, University of Bonn, Germany.
  • Patrick Kehoe
    Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Tsolaki Magda
    1st Department of Neurology, Medical school, Aristotle University of Thessaloniki, Thessaloniki, Makedonia, Greece.
  • Pascual Sánchez-Juan
    CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
  • Kristel Sleegers
    Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
  • Martin Ingelsson
    Dept. of Public Health and Caring Sciences / Geriatrics, Uppsala University, Uppsala, Sweden.
  • Mikko Hiltunen
    Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
  • Rebecca Sims
    Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
  • Wiesje van der Flier
    Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
  • Ole A Andreassen
    NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: o.a.andreassen@medisin.uio.no.
  • Agustín Ruiz
    Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
  • Alfredo Ramirez
  • Ruth Frikke-Schmidt
    Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
  • Najaf Amin
    Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
  • Gennady Roshchupkin
    Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands. g.roshchupkin@erasmusmc.nl.
  • Jean-Charles Lambert
    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.
  • Kristel Van Steen
  • Cornelia van Duijn
    King Abdulaziz University and the University of Oxford Centre for Artificial Intelligence in Precision Medicine (KO-CAIPM), Jeddah, Saudi Arabia.
  • Valentina Escott-Price
    MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. escottpricev@cardiff.ac.uk.

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