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

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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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NCBI Reference Sequences (RefSeq): current status, new features and genome annotation policy

Kim D. Pruitt, Tatiana Tatusova, Garth R. Brown … (2011)

The National Center for Biotechnology Information (NCBI) Reference Sequence (RefSeq) database is a collection of genomic, transcript and protein sequence records. These records are selected and curated from public sequence archives and represent a significant reduction in redundancy compared to the volume of data archived by the International Nucleotide Sequence Database Collaboration. The database includes over 16 000 organisms, 2.4 × 106 genomic records, 13 × 106 proteins and 2 × 106 RNA records spanning prokaryotes, eukaryotes and viruses (RefSeq release 49, September 2011). The RefSeq database is maintained by a combined approach of automated analyses, collaboration and manual curation to generate an up-to-date representation of the sequence, its features, names and cross-links to related sources of information. We report here on recent growth, the status of curating the human RefSeq data set, more extensive feature annotation and current policy for eukaryotic genome annotation via the NCBI annotation pipeline. More information about the resource is available online (see http://www.ncbi.nlm.nih.gov/RefSeq/).

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ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

Yang Shi, Shane Liddelow, Scott T. Smith … (2017)

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a ‘toxic’ gain of function whereas the absence of ApoE is protective.

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The role of apolipoprotein E in Alzheimer's disease.

Jungsu Kim, Jacob Basak, David Holtzman (2009)

The epsilon4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer's disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, how apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Abeta aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE epsilon4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE.

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Author and article information

Journal

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

Publisher: Springer Science and Business Media LLC

ISSN (Electronic): 1546-1718

ISSN (Print): 1061-4036

Publication date (Electronic): March 2019

Volume: 51

Issue: 3

Affiliations

[1 ] John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. bkunkle@miami.edu.

[2 ] Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France.

[3 ] Institut Pasteur de Lille, Lille, France.

[4 ] Univ. Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France.

[5 ] Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.

[6 ] UK Dementia Research Institute at Cardiff, Cardiff University, Cardiff, UK.

[7 ] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.

[8 ] Department of Biostatistics and Epidemiology/Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

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

[10 ] Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.

[11 ] Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

[12 ] Framingham Heart Study, Framingham, MA, USA.

[13 ] Department of Neurology, Boston University School of Medicine, Boston, MA, USA.

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

[15 ] Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.

[16 ] Laboratory for Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

[17 ] Icelandic Heart Association, Kopavogur, Iceland.

[18 ] Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

[19 ] Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain.

[20 ] Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.

[21 ] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.

[22 ] Department of Neurology, Kuopio University Hospital, Kuopio, Finland.

[23 ] Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY, USA.

[24 ] Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA.

[25 ] Department of Neurology, Columbia University, New York, NY, USA.

[26 ] UMR 894, Center for Psychiatry and Neuroscience, Inserm, Université Paris Descartes, Paris, France.

[27 ] Institute of Human Genetics, University of Bonn, Bonn, Germany.

[28 ] Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.

[29 ] Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.

[30 ] School of Biotechnology, Dublin City University, Dublin, Ireland.

[31 ] Department of Family Medicine, University of Washington, Seattle, WA, USA.

[32 ] Department of Epidemiology, University of Washington, Seattle, WA, USA.

[33 ] Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.

[34 ] Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.

[35 ] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

[36 ] Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX, USA.

[37 ] Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.

[38 ] UK Dementia Research Institute at UCL, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.

[39 ] Neurology Service and CIBERNED, 'Marqués de Valdecilla' University Hospital (University of Cantabria and IDIVAL), Santander, Spain.

[40 ] Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

[41 ] Department of Immunology, Hospital Universitario Doctor Negrín, Las Palmas de Gran Canaria, Spain.

[42 ] Department of Neurology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.

[43 ] Department of Medicine, University of Washington, Seattle, WA, USA.

[44 ] 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.

[45 ] Department of Neurodegenerative Disease, MRC Prion Unit at UCL, Institute of Prion Diseases, London, UK.

[46 ] Centre for Public Health, University of Iceland, Reykjavik, Iceland.

[47 ] Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy.

[48 ] University of Milan, Centro Dino Ferrari, Milan, Italy.

[49 ] Clinical Division of Neurogeriatrics, Department of Neurology, Medical University Graz, Graz, Austria.

[50 ] Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.

[51 ] Institute for Computational Biology, Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.

[52 ] Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany.

[53 ] Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.

[54 ] Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, USA.

[55 ] Laboratory for Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

[56 ] Department of Neurology and Memory Clinic, Hospital Network Antwerp, Antwerp, Belgium.

[57 ] Department of Psychiatry and Psychotherapy, University Hospital, Saarland, Germany.

[58 ] Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.

[59 ] Laboratory for Cognitive Neurology, Department of Neurology, University Hospital and University of Leuven, Leuven, Belgium.

[60 ] Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.

[61 ] National Alzheimer's Coordinating Center, University of Washington, Seattle, WA, USA.

[62 ] Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle, Germany.

[63 ] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.

[64 ] Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

[65 ] Department of Psychiatry, University of Oxford, Oxford, UK.

[66 ] Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA.

[67 ] Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, TX, USA.

[68 ] Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK.

[69 ] Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.

[70 ] Office of Strategy and Measurement, University of North Texas Health Science Center, Fort Worth, TX, USA.

[71 ] C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Charlestown, MA, USA.

[72 ] Theme Aging, Unit for Hereditary Dementias, Karolinska University Hospital-Solna, Stockholm, Sweden.

[73 ] Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Alzheimer Research Center, Division of Neurogeriatrics, Solna, Sweden.

[74 ] German Center for Neurodegenerative Diseases, Bonn, Germany.

[75 ] Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.

[76 ] Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN, USA.

[77 ] Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.

[78 ] Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany.

[79 ] Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.

[80 ] Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.

[81 ] Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

[82 ] Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.

[83 ] Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, PA, USA.

[84 ] Institute of Genetics, Queen's Medical Centre, University of Nottingham, Nottingham, UK.

[85 ] Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.

[86 ] Section of Neuroscience, DIMEC-University of Parma, Parma, Italy.

[87 ] FERB-Alzheimer Center, Gazzaniga (Bergamo), Italy.

[88 ] Department of Pathology, University of Washington, Seattle, WA, USA.

[89 ] Elderly and Psychiatric Disorders Department, Medical University of Lodz, Lodz, Poland.

[90 ] Mercer's Institute for Research on Aging, St. James's Hospital and Trinity College, Dublin, Ireland.

[91 ] St. James's Hospital and Trinity College, Dublin, Ireland.

[92 ] Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.

[93 ] A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.

[94 ] Departments of Medicine, Geriatrics, Gerontology and Neurology, University of Mississippi Medical Center, Jackson, MS, USA.

[95 ] Interdisciplinary Department of Medicine, Geriatric Medicine and Memory Unity, University of Bari, Bari, Italy.

[96 ] Department of Neurology, University of Washington, Seattle, WA, USA.

[97 ] Department of Geriatrics, Center for Aging Brain, University of Bari, Bari, Italy.

[98 ] Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain.

[99 ] Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain.

[100 ] Department of Internal Medicine, Erasmus University Medical Center, Rotterdamt, the Netherlands.

[101 ] Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, the Netherlands.

[102 ] Department of Neurology, Mayo Clinic, Rochester, MN, USA.

[103 ] CHU Lille, Memory Center of Lille (Centre Mémoire de Ressources et de Recherche), Lille, France.

[104 ] Department of Clinical and Behavioral Neurology, Experimental Neuropsychobiology Laboratory, IRCCS Santa Lucia Foundation, Rome, Italy.

[105 ] School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.

[106 ] Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

[107 ] Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.

[108 ] Arizona Alzheimer's Consortium, Phoenix, AZ, USA.

[109 ] Banner Alzheimer's Institute, Phoenix, AZ, USA.

[110 ] Department of Psychiatry, University of Arizona, Phoenix, AZ, USA.

[111 ] 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.

[112 ] Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA.

[113 ] University Paris Descartes, EA 4468, AP-HP, Geriatrics Department, Hôpital Broca, Paris, France.

[114 ] Regional Neurogenetic Centre (CRN), ASP Catanzaro, Lamezia Terme, Italy.

[115 ] 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.

[116 ] University of Bordeaux, Inserm 1219, Bordeaux, France.

[117 ] Department of Neurology, Bordeaux University Hospital / CHU de Bordeaux, Bordeaux, France.

[118 ] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

[119 ] Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06, UMRS 1127, Institut du Cerveau et de la Moelle Épinière, Paris, France.

[120 ] AP-HP, Department of Genetics, Pitié-Salpêtrière Hospital, Paris, France.

[121 ] Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy.

[122 ] Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

[123 ] Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada.

[124 ] Inserm U1061 Neuropsychiatry, La Colombière Hospital, Montpellier, France.

[125 ] Montpellier University, Montpellier, France.

[126 ] Department of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

[127 ] VA Puget Sound Health Care System/>GRECC, Seattle, WA, USA.

[128 ] Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.

[129 ] Institut de la Mémoire et de la Maladie d'Alzheimer and Institut du Cerveau et de la Moelle Épinière, Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France.

[130 ] Institut des Neurosciences Translationnelles de Paris, Institut du Cerveau et de la Moelle Épinière, Paris, France.

[131 ] Inserm, CNRS, UMR-S975, Institut du Cerveau et de la Moelle Epinière, Paris, France.

[132 ] Sorbonne Universités, Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.

[133 ] Ageing Group, Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.

[134 ] Departments of Neurology, Pharmacology & Neuroscience, Texas Tech University Health Science Center, Lubbock, TX, USA.

[135 ] Department of Neurology, University of Michigan, Ann Arbor, MI, USA.

[136 ] Geriatric Research, Education and Clinical Center (GRECC), VA Ann Arbor Healthcare System (VAAAHS), Ann Arbor, MI, USA.

[137 ] Michigan Alzheimer Disease Center, Ann Arbor, MI, USA.

[138 ] Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Stockholm, Sweden.

[139 ] Indiana Alzheimer's Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.

[140 ] Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.

[141 ] Department of Neurology, Indiana University, Indianapolis, IN, USA.

[142 ] Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA.

[143 ] Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

[144 ] Geriatric Research, Education and Clinical Center (GRECC), University of Wisconsin, Madison, WI, USA.

[145 ] Department of Medicine, University of Wisconsin, Madison, WI, USA.

[146 ] Wisconsin Alzheimer's Disease Research Center, Madison, WI, USA.

[147 ] AXA Research Fund & Sorbonne University Chair, Paris, France.

[148 ] Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Paris, France.

[149 ] Brain & Spine Institute, Inserm U 1127, CNRS UMR 7225, Paris, France.

[150 ] Institute of Memory and Alzheimer's Disease, Department of Neurology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

[151 ] Grupo de Medicina Xenomica, Universidade de Santiago de Compostela, Centro Nacional de Genotipado, Centro de Investigación Biomédica en Red de Enfermedades Raras, Santiago de Compostela, Spain.

[152 ] UK Dementia Research Institute, University of Cambridge, Cambridge, UK.

[153 ] Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.

[154 ] Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA.

[155 ] Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

[156 ] Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.

[157 ] Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Phoenix, AZ, USA.

[158 ] Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.

[159 ] Department of Psychology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

[160 ] Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

[161 ] Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

[162 ] Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

[163 ] Swedish Medical Center, Seattle, WA, USA.

[164 ] Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

[165 ] Department of Neurology, Duke University, Durham, NC, USA.

[166 ] Departments of Biology, Brigham Young University, Provo, UT, USA.

[167 ] University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA.

[168 ] Department of Experimental and Clinical Medicine, Neurological Institute, University of Pisa, Pisa, Italy.

[169 ] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

[170 ] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

[171 ] Department of Pathology and Immunology, Washington University, St. Louis, MO, USA.

[172 ] Division of Psychiatry, University College London, London, UK.

[173 ] USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.

[174 ] Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

[175 ] Department of Molecular Neuroscience, UCL, Institute of Neurology, London, UK.

[176 ] Mental Health & Behavioral Science Service, Bruce W. Carter VA Medical Center, Miami, FL, USA.

[177 ] Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.

[178 ] Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

[179 ] Department of Neurology, University of Southern California, Los Angeles, CA, USA.

[180 ] Department of Neurology, Catholic University of Rome, Rome, Italy.

[181 ] Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL, USA.

[182 ] Department of Neurology, University of California, Davis, Sacramento, CA, USA.

[183 ] Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.

[184 ] Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, FL, USA.

[185 ] Rush Institute for Healthy Aging, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.

[186 ] Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

[187 ] Department of Primary Medical Care, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

[188 ] Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.

[189 ] Sanders-Brown Center on Aging, Department of Biostatistics, University of Kentucky, Lexington, KY, USA.

[190 ] Department of Psychiatry, New York University, New York, NY, USA.

[191 ] Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.

[192 ] Department of Psychiatry and Psychotherapy, Charité University Medicine, Berlin, Germany.

[193 ] Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.

[194 ] Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.

[195 ] Emory Alzheimer's Disease Center, Emory University, Atlanta, GA, USA.

[196 ] Department of Psychiatry, University of Freiburg, Freiburg, Germany.

[197 ] Neurogenetics Program, University of California, Los Angeles, Los Angeles, CA, USA.

[198 ] Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.

[199 ] Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, USA.

[200 ] Division of Genetics, Department of Medicine and Partners Center for Personalized Genetic Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

[201 ] Department of Neurology, Washington University, St. Louis, MO, USA.

[202 ] Department of Genetics, Washington University, St. Louis, MO, USA.

[203 ] Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

[204 ] Department of Pathology (Neuropathology), University of Pittsburgh, Pittsburgh, PA, USA.

[205 ] Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.

[206 ] Cologne Center for Genomics, University of Cologne, Cologne, Germany.

[207 ] Department of Pathology, Duke University, Durham, NC, USA.

[208 ] Department of Genome Sciences, University of Washington, Seattle, WA, USA.

[209 ] Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, USA.

[210 ] Sanders-Brown Center on Aging, College of Public Health, Department of Epidemiology, University of Kentucky, Lexington, KY, USA.

[211 ] Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Sevilla, Spain.

[212 ] Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.

[213 ] Functional Genomics Center Zurich, ETH/University of Zurich, Zurich, Switzerland.

[214 ] Department of Neurology, Oregon Health &Science University, Portland, OR, USA.

[215 ] Department of Neurology, Portland Veterans Affairs Medical Center, Portland, OR, USA.

[216 ] Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA.

[217 ] Department of Pathology, Boston University School of Medicine, Boston University, Boston, MA, USA.

[218 ] Inserm U558, University of Toulouse, Toulouse, France.

[219 ] Department of Neuropsychology, University of California San Francisco, San Francisco, CA, USA.

[220 ] Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.

[221 ] Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.

[222 ] Department of Neurology, Emory University, Atlanta, GA, USA.

[223 ] Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany.

[224 ] German Center for Neurodegenerative Diseases, Munich, Germany.

[225 ] Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA.

[226 ] Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

[227 ] Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

[228 ] Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Munich, Germany.

[229 ] Helmholtz Center Munich, Institute of Epidemiology, Neuherberg, Munich, Germany.

[230 ] Ludwig-Maximilians University Chair of Epidemiology, Munich, Germany.

[231 ] Joint Biobank Munich and KORA Biobank, Baltimore, MD, USA.

[232 ] Department of Psychiatry, Johns Hopkins University, Baltimore, MD, USA.

[233 ] Human Genetics, Schools of Life Sciences and Medicine, University of Nottingham, Nottingham, UK.

[234 ] Department of Medicine-Pulmonary, New York University, New York, NY, USA.

[235 ] Department of Neurology, University of Miami, Miami, FL, USA.

[236 ] Department of Pathology, University of California, San Diego, La Jolla, CA, USA.

[237 ] Institute of Neurology, Catholic University of Sacred Hearth, Rome, Italy.

[238 ] School of Nursing Northwest Research Group on Aging, University of Washington, Seattle, WA, USA.

[239 ] Institute of Primary Care and Public Health, Cardiff University, University Hospital of Wales, Cardiff, UK.

[240 ] Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

[241 ] Cambridge Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, UK.

[242 ] Weill Institute for Neurosciences, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.

[243 ] Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.

[244 ] Department of Pathology, University of Southern California, Los Angeles, CA, USA.

[245 ] Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA.

[246 ] Institute of Psychiatry, Psychology and Neuroscienceó, King's College London, London, UK.

[247 ] UK Dementia Research Institute, King's College London, London, UK.

[248 ] Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Goettingen, Germany.

[249 ] German Center for Neurodegenerative Diseases, Goettingen, Germany.

[250 ] IBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal.

[251 ] Molecular Genetics Laboratory-Hospital, University of Central Asturias, Oviedo, Spain.

[252 ] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

[253 ] Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

[254 ] Department of Neurology, University of California, Irvine, Irvine, CA, USA.

[255 ] Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.

[256 ] Centro di Ricerca, Trasferimento e Alta Formazione DENOTHE, University of Florence, Florence, Italy.

[257 ] Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA.

[258 ] IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

[259 ] Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.

[260 ] Division of Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA.

[261 ] Alzheimer's Disease Center, New York University, New York, NY, USA.

[262 ] Oxford Healthy Aging Project, Clinical Trial Service Unit, University of Oxford, Oxford, UK.

[263 ] Department of Epidemiology, Columbia University, New York, NY, USA.

[264 ] Oxford Project to Investigate Memory and Ageing, University of Oxford, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.

[265 ] Department of Neurology, Keck School of Medicine at the University of Southern California, Los Angeles, Los Angeles, CA, USA.

[266 ] Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

[267 ] Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

[268 ] Department of Pathology (Neuropathology), Rush University Medical Center, Chicago, IL, USA.

[269 ] Department of Psychiatry, University of Southern California, Los Angeles, CA, USA.

[270 ] Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

[271 ] Department of Pathology, Johns Hopkins University, Baltimore, MD, USA.

[272 ] Sanders-Brown Center on Aging, Department of Neuroscience, University of Kentucky, Lexington, KY, USA.

[273 ] Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.

[274 ] Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

[275 ] Taub Institute on Alzheimer's Disease and the Aging Brain, Department of Pathology, Columbia University, New York, NY, USA.

[276 ] Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

[277 ] Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.

[278 ] Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

[279 ] Department of Human Genetics, Emory University, Atlanta, GA, USA.

[280 ] Department of Pathology, Oregon Health & Science University, Portland, OR, USA.

[281 ] National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

[282 ] Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.

[283 ] Gerontology and Geriatrics Research Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

[284 ] Department Geriatric Care, Orthogeriatrics and Rehabilitation, Galliera Hospital, Genova, Italy.

[285 ] IdiPAZ, Instituto de Investigación Sanitaria la Paz, Madrid, Spain.

[286 ] Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.

[287 ] German Center for Neurodegenerative Diseases, Berlin, Germany.

[288 ] Instituto di Ricovero e Cura a Carattere Scientifico, Associazione Oasi Maria Santissima Srl, Troina, Italy.

[289 ] Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.

[290 ] Memory Unit, Neurology Department and Sant Pau Biomedical Research Institute, Hospital de la Santa Creu i Sant Pau, Autonomous University Barcelona, Barcelona, Spain.

[291 ] Somerset Partnership NHS Trust, Somerset, UK.

[292 ] The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

[293 ] Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

[294 ] University of Bristol Medical School, Learning & Research level 2, Southmead Hospital, Bristol, UK.

[295 ] Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.

[296 ] Memory Research and Resources Center, CMRR de Bordeaux, Bordeaux, France.

[297 ] Utah State University, Logan, UT, USA.

[298 ] Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

[299 ] Departments of Radiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

[300 ] Department of Research Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France.

[301 ] Department of Neurology, Medical University Graz, Graz, Austria.

[302 ] Center for Applied Genomics, Children's Hospital of Philadelphia, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

[303 ] Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

[304 ] Department of Ophthalmology, Boston University School of Medicine, Boston University, Boston, MA, USA.

[305 ] Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

[306 ] Department of Health Services, University of Washington, Seattle, WA, USA.

[307 ] Kaiser Permanente, Washington Health Research Institute, Seattle, WA, USA.

[308 ] Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA.

[309 ] Centre Hospitalier Universitaire de Lille, Lille, France.

[310 ] Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France. jean-charles.lambert@pasteur-lille.fr.

[311 ] Institut Pasteur de Lille, Lille, France. jean-charles.lambert@pasteur-lille.fr.

[312 ] Univ. Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France. jean-charles.lambert@pasteur-lille.fr.

[313 ] John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. mpericak@miami.edu.

Article

Publisher Item ID: 10.1038/s41588-019-0358-2 Mid ID: NIHMS1021255

DOI: 10.1038/s41588-019-0358-2

PMC ID: 6463297

PubMed ID: 30820047

SO-VID: 96a05776-b06e-4364-879e-ae09b42073c0

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