Alzheimer’s disease; Cognitive decline; Mild cognitive impairment; PLCG2; Phospholipase C gamma 2; Amyloid beta-Peptides; Biomarkers; tau Proteins; PLCG2 protein, human; Phospholipase C gamma; Aged; Aged, 80 and over; Alzheimer Disease/genetics; Alzheimer Disease/pathology; Amyloid beta-Peptides/genetics; Biomarkers/analysis; Cognition/physiology; Cognitive Dysfunction/genetics; Cognitive Dysfunction/pathology; Disease Progression; Female; Humans; Male; Middle Aged; Phospholipase C gamma/metabolism; tau Proteins/cerebrospinal fluid; tau Proteins/metabolism; Cognition; Cognitive Dysfunction; Pathology and Forensic Medicine; Neurology (clinical); Cellular and Molecular Neuroscience
Abstract :
[en] A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.
Disciplines :
Neurology
Author, co-author :
Kleineidam, Luca; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany ; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Chouraki, Vincent; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Facteurs de risque Et déterminants moléculaires des maladies liées au vieillissement, Lille, France ; Epidemiology and Public Health Department, Centre Hospitalier Universitaire de Lille, Lille, France
Próchnicki, Tomasz; Institute of Innate Immunity, University Hospitals Bonn, Bonn, Germany
van der Lee, Sven J; Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands ; Department of Clinical Genetics, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Madrid-Márquez, Laura; Andalusian Bioinformatics Research Centre (CAEBi), Seville, Spain
Wagner-Thelen, Holger; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany ; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany
Karaca, Ilker; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
Weinhold, Leonie; Institute of Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany
Wolfsgruber, Steffen; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Boland, Anne; Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Évry, France
Martino Adami, Pamela V; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany
Lewczuk, Piotr; Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany ; Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, Poland ; Department of Biochemical Diagnostics, University Hospital of Białystok, Białystok, Poland
Popp, Julius; Department of Psychiatry, Lausanne University Hospital, Prilly, Switzerland ; Department of Geriatric Psychiatry, University Hospital of Psychiatry Zurich, Zurich, Switzerland
Brosseron, Frederic; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Jansen, Iris E; Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands ; Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Hulsman, Marc; Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands ; Department of Clinical Genetics, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Kornhuber, Johannes; Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
Peters, Oliver; Department of Psychiatry, Charité - Universitätsmedizin Berlin, Berlin, Germany ; DZNE, German Center for Neurodegenerative Diseases, Berlin, Germany
Berr, Claudine; INSERM, University Montpellier, Neuropsychiatry: Epidemiological and Clinical Research, Montpellier, France
Heun, Reinhard; Department of Psychiatry and Psychotherapy, University Hospital Bonn, 53127, Bonn, Germany
Frölich, Lutz; Department of Geriatric Psychiatry, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
Tzourio, Christophe; Inserm, Bordeaux Population Health Research Center, UMR1219, University of Bordeaux, Bordeaux, France
Dartigues, Jean-François; Inserm, Bordeaux Population Health Research Center, UMR1219, University of Bordeaux, Bordeaux, France
Hüll, Michael; Department of Psychiatry and Psychotherapy, Center for Psychiatry, Clinic for Geriatric Psychiatry and Psychotherapy Emmendingen, University of Freiburg, Freiburg, Germany
Espinosa, Ana; Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Hernández, Isabel; Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
de Rojas, Itziar; Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Orellana, Adelina; Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain
Valero, Sergi; Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Stringa, Najada; Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC-Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
van Schoor, Natasja M; Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC-Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Huisman, Martijn; Department of Epidemiology and Biostatistics, Amsterdam Public Health Research Institute, Amsterdam UMC-Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Scheltens, Philip; Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Rüther, Eckart; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany
Deleuze, Jean-Francois; Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Évry, France
Wiltfang, Jens; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany ; iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal
Tarraga, Lluis; Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Schmid, Matthias; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Institute of Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany
Scherer, Martin; Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Riedel-Heller, Steffi; Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany
HENEKA, Michael ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
Amouyel, Philippe; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Facteurs de risque Et déterminants moléculaires des maladies liées au vieillissement, Lille, France
Jessen, Frank; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany
Boada, Merce; Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Maier, Wolfgang; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Schneider, Anja; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
González-Pérez, Antonio; Andalusian Bioinformatics Research Centre (CAEBi), Seville, Spain
van der Flier, Wiesje M; Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Wagner, Michael; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Lambert, Jean-Charles; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Facteurs de risque Et déterminants moléculaires des maladies liées au vieillissement, Lille, France
Holstege, Henne; Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands ; Department of Clinical Genetics, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
Sáez, Mª Eugenia; Andalusian Bioinformatics Research Centre (CAEBi), Seville, Spain
Latz, Eicke; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Institute of Innate Immunity, University Hospitals Bonn, Bonn, Germany ; Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA ; Centre for Molecular Inflammation Research (CEMIR), Norwegian University of Science and Technology, Trondheim, Norway
Ruiz, Agustin ✱; Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya-Barcelona, Barcelona, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
Ramirez, Alfredo ✱; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany. alfredo.ramirez@uk-koeln.de ; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany. alfredo.ramirez@uk-koeln.de
Bundesministerium für Bildung und Forschung Bundesministerium für Bildung und Forschung Bundesministerium für Bildung und Forschung Deutsche Forschungsgemeinschaft ZonMw Innovative Medicines Initiative Instituto de Salud Carlos III Instituto de Salud Carlos III Netherlands Organization for Scientific Research Swiss National Science Foundation
Funding text :
All authors report no conflict of interest. Piotr Lewczuk received a consultation and/or lecture honoraria from IBL International, Fujirebio Europe, AJ Roboscreen, and Roche. Jens Wiltfang received honoraria for consulting activities, lectures or advisory board participation from Pfizer, Eli Lilly, Hoffmann-La-Roche, MSD Sharp + Dome, Janssen-Cilag GmbH, Immungenetics AG, Boehringer Ingelheim. Lutz Frölich received honoraria for consulting activities, lectures, or advisory board participation from Allergan, Eli Lilly, Avraham Pharmaceuticals, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, Lundbeck, MerckSharpe and Dohme, Novartis, Pfizer, Pharnext, Roche, Schwabe Pharma; he served on Data and Safety Monitoring boards or endpoint committees with Avraham Pharmaceuticals, Axon Neuroscience, Forschungszentrum Jülich, Novartis, Pharmatropix. Julius Popp received honoraria for consulting activities, lectures or advisory board participation from Fujirebio Europe, Ono Pharma, Eli Lilly, and Nestlé Institute of Health Sciences. Agustin Ruiz reports consulting Fees: Landsteiner Genmed, Grifols, Araclon biotech. And Lecture Fees: Araclon Biotech.PA reports personal fees from Servier, Total, Genoscreen, Takeda, and Foundation Alzheimer. Oliver Peters received research funding, consultancy fees, or speech honoraria from Axovant, Biogen, Genentech, Lilly, Lundbeck, Novartis, Pharmatrophix, Piramal, Probiodrug, Roche, Takeda, and TauRx Pharmaceuticals. Merce Boada receives fees or has received for consulting from Lab. Servier, Roche, Lilly, Avid, Bayer, Elan, Janssen, Neuroptix, and Sanofi. She receives or has received fees for lectures from Lilly, Nutricia, Roche, Schwabe, Araclon, Esteve, Grifols, Janssen, Novartis, Piramal, Pfizer-Wyett, and Servier. She receives fees for being part of the Advisory Board of Lilly and Schwabe. She reports grants/research funding from Abbvie, Araclon, Biogen Research Limited, Bioiberica, Grifols, Lilly, S.A, Merck Sharp and Dohme, Kyowa Hakko Kirin, Laboratorios Servier, Nutricia SRL, Oryzon Genomics, Piramal Imaging Limited, Roche Pharma SA, and Schwabe Farma iberica SLU, all outside the submitted work. She has not received personal compensations from these organizations.Open Access funding provided by Projekt DEAL. This publication was funded in part by the German Federal Ministry of Education and Research (BMBF) (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project “Diet-Body-Brain: from epidemiology to evidence-based communication”. Part of the work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Part of the analysis was funded by the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case–control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; ElanPharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research and Development, LLC.; Johnson and Johnson Pharmaceutical Research and Development LLC.; Lumosity; Lundbeck; Merck and Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and transition Therapeutics.Open Access funding provided by Projekt DEAL. This publication was funded in part by the German Federal Ministry of Education and Research (BMBF) (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, 01ET1006B). Analyses were also funded by the German Federal Ministry of Education and Research (BMBF 01EA1410A) within the project “Diet-Body-Brain: from epidemiology to evidence-based communication”. Part of the work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Part of the analysis was funded by the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Research of the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case–control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; ElanPharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research and Development, LLC.; Johnson and Johnson Pharmaceutical Research and Development LLC.; Lumosity; Lundbeck; Merck and Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. The Three-City Study genotyping and analysis was funded by the GENMED Labex, the Joint Programming Initiative on Neurodegenerative Diseases Research (JPND; PERADES project), the Institute Pasteur de Lille, the University of Lille, and the Nord-Pas de Calais Regional Council. This work also benefited from the Lille Métropole Communauté Urbaine Council, the French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to Alzheimer’s disease). In addition, the Three-City Study was performed as part of a collaboration between the Institut National de la Santé et de la Recherche Médicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. Additional funding for the 3C Study was also obtained from the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, MGEN, Institut de la Longévité, Agence Française de Sécurité Sanitaire des Produits de Santé, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM “Cohortes et collections de données biologiques” programme. Lille Génopôle received an unconditional grant from Eisai. Fundacio ACE cohort receives support from the Innovative Medicines Initiative 2 Joint Undertaking which receives support from the European Union’s Horizon 2020 research and innovation programme (ADAPTED Grant No. 115975). A. Ruiz’s research is also supported by Instituto de Salud Carlos III (ISCIII) grants PI13/02434, PI16/01861, and PI19/01301. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-“Una manera de Hacer Europa”), by Fundación bancaria “La Caixa” and Grifols SA (GR@ACE project). For the Longitudinal Aging Study Amsterdam (LASA) supports was largely obtained from a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The data collection in 2012–2013 was financially supported by the Netherlands Organization for Scientific Research (NWO) in the framework of the project “New Cohorts of young old in the twenty-first century” (File Number 480-10-014). Genotyping using Axiom-NL array was financially supported by EMGO+ Research Institute. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies in kind contribution. JW is supported by an Ilídio Pinho professorship and iBiMED (UID/BIM/04501/2013), at the University of Aveiro, Portugal. JP was supported by a grant from the Swiss National Science Foundation (320030L_141179).
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