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Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Nature Geneticsvolume 51pages414430 (2019) | Download Citation

Abstract

Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

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Data availability

Genome-wide summary statistics for the Stage 1 discovery have been deposited in The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS)—a NIA/NIH-sanctioned qualified-access data repository, under accession NG00075. Stage 1 data (individual level) for the GERAD cohort can be accessed by applying directly to Cardiff University. Stage 1 ADGC data are deposited in NIAGADS. Stage 1 CHARGE data are accessible by applying to dbGaP for all US cohorts and to Erasmus University for Rotterdam data. AGES primary data are not available owing to Icelandic laws. Stage 2 and Stage 3 primary data are available upon request.

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

We thank all the participants of this study for their contributions. Additional acknowledgements and detailed acknowledgments of funding sources for the study are provided in the Supplementary Note.

Author information

Author notes

  1. These authors contributed equally: Brian W. Kunkle, Benjamin Grenier-Boley, Jean Charles-Lambert, Margaret A. Pericak-Vance.

  2. These authors jointly supervised this work: Agustin Ruiz, Cornelia M. van Duijn, Peter A. Holmans, Sudha Seshadri, Julie Williams, Phillippe Amouyel, Gerard D. Schellenberg, Jean-Charles Lambert, Margaret A. Pericak-Vance.

  3. A list of members and affiliations appears in the Supplementary Note.

Affiliations

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

    • Brian W. Kunkle
    • , Eden R. Martin
    • , Kara L. Hamilton-Nelson
    • , Gary W. Beecham
    • , Patrice Whitehead
    • , John R. Gilbert
    • , William R. Perry
    • , Michael L. Cuccaro
    • , Jeffery M. Vance
    • , Susan Slifer
    •  & Margaret A. Pericak-Vance
  2. Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France

    • Benjamin Grenier-Boley
    • , Vincent Damotte
    • , Céline Bellenguez
    • , Vincent Chouraki
    • , Nathalie Fievet
    • , Phillippe Amouyel
    •  & Jean-Charles Lambert
  3. Institut Pasteur de Lille, Lille, France

    • Benjamin Grenier-Boley
    • , Vincent Damotte
    • , Céline Bellenguez
    • , Vincent Chouraki
    • , Nathalie Fievet
    • , Phillippe Amouyel
    •  & Jean-Charles Lambert
  4. Univ. Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France

    • Benjamin Grenier-Boley
    • , Vincent Damotte
    • , Céline Bellenguez
    • , Vincent Chouraki
    • , Nathalie Fievet
    • , Phillippe Amouyel
    •  & Jean-Charles Lambert
  5. Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK

    • Rebecca Sims
    • , Maria Vronskaya
    • , Aura Frizatti
    • , Nandini Badarinarayan
    • , Rachel Raybould
    • , Taniesha Morgan
    • , Nicola Denning
    • , Thomas D. Cushion
    • , Paul Hollingworth
    • , Rachel Marshall
    • , Alun Meggy
    • , Georgina E. Menzies
    • , Ganna Leonenko
    • , Detelina Grozeva
    • , Michael C. O’Donovan
    • , Lesley Jones
    • , Michael J. Owen
    • , Valentina Escott-Price
    • , Peter A. Holmans
    •  & Julie Williams
  6. UK Dementia Research Institute at Cardiff, Cardiff University, Cardiff, UK

    • Rebecca Sims
    • , Rachel Raybould
    • , Nicola Denning
    • , Thomas D. Cushion
    • , Georgina E. Menzies
    • , Lesley Jones
    • , Valentina Escott-Price
    •  & Julie Williams
  7. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA

    • Joshua C. Bis
    • , Jennifer A. Brody
    •  & Bruce M. Psaty
  8. Department of Biostatistics and Epidemiology/Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    • Adam C. Naj
  9. Centre National de Recherche en Génomique Humaine, Institut de Biologie François Jacob, CEA, Université Paris-Saclay, and LabEx GENMED, Evry, France

    • Anne Boland
    • , Robert Olaso
    • , Jean-Guillaume Garnier
    • , Marie-Laure Moutet
    • , Delphine Bacq
    • , Fabienne Garzia
    • , Bertrand Fin
    • , Stéphane Meslage
    •  & Jean-Francois Deleuze
  10. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands

    • Sven J. van der Lee
    • , Shahzad Ahmad
    • , Hieab H. Adams
    • , Dina Voijnovic
    • , Hata Karamujić-Čomić
    • , Gena Roschupkin
    • , Fernando Rivadeneira
    • , A. G. Andre Uitterlinden
    • , Najaf Amin
    • , M. Arfan Ikram
    •  & Cornelia M. van Duijn
  11. Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    • Alexandre Amlie-Wolf
    • , Amanda B. Kuzma
    • , Otto Valladares
    • , Liming Qu
    • , Yi Zhao
    • , John Malamon
    • , Beth A. Dombroski
    • , Laura B. Cantwell
    • , Mitchell Tang
    • , Li-San Wang
    •  & Gerard D. Schellenberg
  12. Framingham Heart Study, Framingham, MA, USA

    • Vincent Chouraki
    • , L. Adrienne Cupples
    • , Jayanadra J. Himali
    • , Alexa S. Beiser
    •  & Sudha Seshadri
  13. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    • Vincent Chouraki
    • , Jayanadra J. Himali
    • , Alexa S. Beiser
    • , Neil W. Kowall
    • , Ann C. McKee
    • , Robert A. Stern
    • , Lindsay A. Farrer
    • , Anita L. DeStefano
    •  & Sudha Seshadri
  14. Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium

    • Kristel Sleegers
    •  & Christine Van Broeckhoven
  15. Laboratory for Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

    • Kristel Sleegers
    •  & Christine Van Broeckhoven
  16. Icelandic Heart Association, Kopavogur, Iceland

    • Johanna Jakobsdottir
    • , Gudny Eiriksdottir
    • , Thor Aspelund
    •  & Vilmundur Gudnason
  17. Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain

    • Sonia Moreno-Grau
    • , Merce Boada
    • , Seung-Hoan Choi
    • , Adelina Orellana
    • , Isabel Hernández
    • , Lluís Tarraga
    • , Itziar de Rojas
    •  & Agustin Ruiz
  18. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain

    • Sonia Moreno-Grau
    • , Merce Boada
    • , Isabel Hernández
    • , Lluís Tarraga
    • , Itziar de Rojas
    • , Maria J. Bullido
    • , Alberto Lleo
    • , Jordi Clarimon
    •  & Agustin Ruiz
  19. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    • Yuning Chen
    • , Chloe Sarnowski
    • , L. Adrienne Cupples
    • , Jayanadra J. Himali
    • , Shuo Li
    • , Qiong Yang
    • , Alexa S. Beiser
    • , Kathryn L. Lunetta
    • , Lindsay A. Farrer
    •  & Anita L. DeStefano
  20. Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

    • Mikko Hiltunen
    • , Seppo Helisalmi
    • , Anne Maria Koivisto
    •  & Hilkka Soininen
  21. Department of Neurology, Kuopio University Hospital, Kuopio, Finland

    • Mikko Hiltunen
    • , Seppo Helisalmi
    • , Anne Maria Koivisto
    •  & Hilkka Soininen
  22. Taub Institute on Alzheimer’s Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA

    • Badri N. Vardarajan
    • , Sandra Barral
    • , Lawrence S. Honig
    • , Christiane Reitz
    • , Jennifer Williamson
    •  & Richard Mayeux
  23. Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA

    • Badri N. Vardarajan
    • , Sandra Barral
    • , Christiane Reitz
    •  & Richard Mayeux
  24. Department of Neurology, Columbia University, New York, NY, USA

    • Badri N. Vardarajan
    • , Sandra Barral
    •  & Richard Mayeux
  25. UMR 894, Center for Psychiatry and Neuroscience, Inserm, Université Paris Descartes, Paris, France

    • Jacques Epelbaum
  26. Institute of Human Genetics, University of Bonn, Bonn, Germany

    • Per Hoffmann
    •  & Markus M. Nöthen
  27. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    • Per Hoffmann
    •  & Markus M. Nöthen
  28. Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland

    • Per Hoffmann
  29. School of Biotechnology, Dublin City University, Dublin, Ireland

    • Denise Harold
  30. Department of Family Medicine, University of Washington, Seattle, WA, USA

    • Annette L. Fitzpatrick
  31. Department of Epidemiology, University of Washington, Seattle, WA, USA

    • Annette L. Fitzpatrick
    • , Walter A. Kukull
    • , W. T. Longstreth Jr
    •  & Bruce M. Psaty
  32. Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    • Amy Gerrish
    • , Nick C. Fox
    • , Jonathan M. Schott
    • , Jason D. Warren
    •  & Martin Rossor
  33. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    • Albert V. Smith
  34. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    • Albert V. Smith
    •  & Vilmundur Gudnason
  35. Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX, USA

    • Xueqiu Jian
    •  & Myriam Fornage
  36. Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy

    • Maria Del Zompo
    •  & Alessio Squassina
  37. UK Dementia Research Institute at UCL, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    • Nick C. Fox
    • , Jose Bras
    •  & Rita Guerreiro
  38. Neurology Service and CIBERNED, ‘Marqués de Valdecilla’ University Hospital (University of Cantabria and IDIVAL), Santander, Spain

    • Ignacio Mateo
    • , Eloy Rodriguez-Rodriguez
    •  & Pascual Sanchez-Juan
  39. Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    • Joseph T. Hughes
    • , Yogen Patel
    • , Didier Hannequin
    • , Michelle K. Lupton
    • , Petra Proitsi
    •  & John F. Powell
  40. Department of Immunology, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain

    • Florentino Sanchez-Garcia
    • , Maria Candida Deniz Naranjo
    • , Carmen Munoz-Fernadez
    •  & Yolanda A. Benito
  41. Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

    • Makrina Daniilidou
    • , Magda Tsolaki
    • , Despoina Avramidou
    • , Antonia Germanou
    • , Maria Koutroumani
    •  & Olymbia Gkatzima
  42. Department of Medicine, University of Washington, Seattle, WA, USA

    • Shubhabrata Mukherjee
    • , Wayne C. McCormick
    • , Chang-En Yu
    •  & Paul K. Crane
  43. Normandie University, UNIROUEN, Inserm U1245, and Rouen University Hospital, Department of Neurology, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France

    • David Wallon
    • , Gael Nicolas
    •  & Dominique Campion
  44. Department of Neurodegenerative Disease, MRC Prion Unit at UCL, Institute of Prion Diseases, London, UK

    • James Uphill
    • , John Collinge
    • , Simon Mead
    •  & Natalie S. Ryan
  45. Centre for Public Health, University of Iceland, Reykjavik, Iceland

    • Thor Aspelund
  46. Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy

    • Daniela Galimberti
    •  & Elio Scarpini
  47. University of Milan, Centro Dino Ferrari, Milan, Italy

    • Daniela Galimberti
    •  & Elio Scarpini
  48. Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, Graz, Austria

    • Edith Hofer
    •  & Reinhold Schmidt
  49. Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria

    • Edith Hofer
  50. Institute for Computational Biology, Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA

    • Mariusz Butkiewicz
    • , Will S. Bush
    • , Yuenjoo Song
    •  & Jonathan L. Haines
  51. Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany

    • Johannes Kornhuber
  52. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    • Charles C. White
  53. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA

    • Robert C. Barber
    •  & Sid O’Bryant
  54. Laboratory for Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium

    • Sebastiaan Engelborghs
    •  & Peter P. De Deyn
  55. Department of Neurology and Memory Clinic, Hospital Network Antwerp, Antwerp, Belgium

    • Sebastiaan Engelborghs
    •  & Peter P. De Deyn
  56. Department of Psychiatry and Psychotherapy, University Hospital, Saarland, Germany

    • Sabrina Sordon
    • , Manuel Mayhaus
    • , Wei Gu
    • , Matthias Riemenschneider
    •  & Thomas Feulner
  57. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Perrie M. Adams
  58. Laboratory for Cognitive Neurology, Department of Neurology, University Hospital and University of Leuven, Leuven, Belgium

    • Rik Vandenberghe
  59. Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

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  60. National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, USA

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  61. Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle, Germany

    • Annette M. Hartmann
    •  & Ina Giegling
  62. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA

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  63. Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA

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  64. Department of Psychiatry, University of Oxford, Oxford, UK

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  65. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA

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    • M. Ilyas Kamboh
    • , Paolo Caffarra
    •  & Oscar L. Lopez
  83. Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, UK

    • James Turton
    • , Jenny Lord
    • , Paolo Caffarra
    • , Kristelle Brown
    •  & Christopher Medway
  84. Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA

    • Mindy J. Katz
    •  & Richard B. Lipton
  85. Section of Neuroscience, DIMEC-University of Parma, Parma, Italy

    • Letizia Concari
  86. FERB-Alzheimer Center, Gazzaniga (Bergamo), Italy

    • Letizia Concari
  87. Department of Pathology, University of Washington, Seattle, WA, USA

    • C. Dirk Keene
    • , Thomas J. Montine
    •  & Joshua A. Sonnen
  88. Elderly and Psychiatric Disorders Department, Medical University of Lodz, Lodz, Poland

    • Iwona Kloszewska
  89. Mercer’s Institute for Research on Aging, St. James’s Hospital and Trinity College, Dublin, Ireland

    • Aoibhinn Lynch
    • , Brian Lawlor
    •  & Michael Gill
  90. St. James’s Hospital and Trinity College, Dublin, Ireland

    • Aoibhinn Lynch
    • , Brian Lawlor
    •  & Michael Gill
  91. Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA

    • Eric B. Larson
  92. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

    • Annakaisa Haapasalo
  93. Departments of Medicine, Geriatrics, Gerontology and Neurology, University of Mississippi Medical Center, Jackson, MS, USA

    • Thomas H. Mosley
  94. Interdisciplinary Department of Medicine, Geriatric Medicine and Memory Unity, University of Bari, Bari, Italy

    • Vincenzo Solfrizzi
  95. Department of Neurology, University of Washington, Seattle, WA, USA

    • W. T. Longstreth Jr
    •  & Thomas D. Bird
  96. Department of Geriatrics, Center for Aging Brain, University of Bari, Bari, Italy

    • Vincenza Frisardi
    •  & Francesco Panza
  97. Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain

    • Monica Diez-Fairen
    • , Ignacio Alvarez
    •  & Pau Pastor
  98. Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain

    • Monica Diez-Fairen
    • , Ignacio Alvarez
    •  & Pau Pastor
  99. Department of Internal Medicine, Erasmus University Medical Center, Rotterdamt, the Netherlands

    • Fernando Rivadeneira
    •  & A. G. Andre Uitterlinden
  100. Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, the Netherlands

    • Fernando Rivadeneira
    •  & A. G. Andre Uitterlinden
  101. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    • Ronald C. Petersen
    •  & Bradley F. Boeve
  102. CHU Lille, Memory Center of Lille (Centre Mémoire de Ressources et de Recherche), Lille, France

    • Vincent Deramecourt
    •  & Florence Pasquier
  103. Department of Clinical and Behavioral Neurology, Experimental Neuropsychobiology Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy

    • Francesca Salani
    • , Antonio Ciaramella
    • , Eleonora Sacchinelli
    •  & Paola Bossù
  104. School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA

    • Eric Boerwinkle
  105. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    • Eric Boerwinkle
  106. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA

    • Eric M. Reiman
    •  & Matthew J. Huentelman
  107. Arizona Alzheimer’s Consortium, Phoenix, AZ, USA

    • Eric M. Reiman
  108. Banner Alzheimer’s Institute, Phoenix, AZ, USA

    • Eric M. Reiman
  109. Department of Psychiatry, University of Arizona, Phoenix, AZ, USA

    • Eric M. Reiman
  110. Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA

    • Jerome I. Rotter
  111. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • Joan S. Reisch
  112. University Paris Descartes, EA 4468, AP-HP, Geriatrics Department, Hôpital Broca, Paris, France

    • Olivier Hanon
  113. Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy

    • Chiara Cupidi
    • , Raffaele Giovanni Maletta
    • , Amalia Cecilia Bruni
    •  & Maura Gallo
  114. Departments of Psychiatry, Medicine, Family & Community Medicine, South Texas Veterans Health Administration Geriatric Research Education & Clinical Center (GRECC), UT Health Science Center at San Antonio, San Antonio, TX, USA

    • Donald R. Royall
  115. University of Bordeaux, Inserm 1219, Bordeaux, France

    • Carole Dufouil
  116. Department of Neurology, Bordeaux University Hospital / CHU de Bordeaux, Bordeaux, France

    • Carole Dufouil
  117. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Mary Sano
    •  & Joseph D. Buxbaum
  118. Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Institut du Cerveau et de la Moelle Épinière, Paris, France

    • Alexis Brice
    •  & Stéphanie Debette
  119. AP-HP, Department of Genetics, Pitié-Salpêtrière Hospital, Paris, France

    • Alexis Brice
    •  & Stéphanie Debette
  120. Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy

    • Roberta Cecchetti
    • , Patrizia Mecocci
    •  & Virginia Boccardi
  121. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

    • Peter St George-Hyslop
    •  & David C. Rubinsztein
  122. Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada

    • Peter St George-Hyslop
    •  & Ekaterina Rogaeva
  123. Inserm U1061 Neuropsychiatry, La Colombière Hospital, Montpellier, France

    • Karen Ritchie
    •  & Claudine Berr
  124. Montpellier University, Montpellier, France

    • Karen Ritchie
    •  & Claudine Berr
  125. Department of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

    • Karen Ritchie
  126. VA Puget Sound Health Care Syst