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16 páginas, 5 figuras ; Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease. ; The present work has been performed as part of the doctoral program of I. de Rojas at the Universitat de Barcelona (Barcelona, Spain) supported by national grant from the Instituto de Salud Carlos III FI20/00215. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria "La Caixa", Fundació ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER—"Una manera de hacer Europa"). Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. Amsterdam dementia Cohort (ADC): 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). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW project number 733050814, 733050512) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND) and also funded by Inserm, Institut Pasteur de Lille, the Lille Métropole Communauté Urbaine, the French government's LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Genotyping of the German case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND (German Federal Ministry of Education and Research, BMBF: 01ED1619A). Full acknowledgments for the studies that contributed data can be found in the Supplementary Note. We thank the numerous participants, researchers, and staff from many studies who collected and contributed to the data. We thank the International Genomics of Alzheimer's Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips was funded by the French National Foundation on AD and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant n° 503480), Alzheimer's Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant n° 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIA/NHLBI grants AG049505, AG058589, HL105756 and AGES contract N01–AG–12100, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC–10–196728. This research has been conducted using the UK Biobank public resource obtained through the University of Edinburg Data Share (https://datashare.is.ed.ac.uk/handle/10283/3364). ; Peer reviewed

Austrian Federal Ministry of Science, Research and Economy ; Austrian Science Fund ; Belgian Fonds de la Recherche Scientifique ; Fonds voor Wetenschappelijk Onderzoek ; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) ; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) ; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) ; Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) ; Bulgarian Ministry of Education and Science ; CERN ; Chinese Academy of Sciences ; Ministry of Science and Technology ; National Natural Science Foundation of China ; COLCIENCIAS ; Croatian Ministry of Science, Education and Sport ; Croatian Science Foundation ; Research Promotion Foundation, Cyprus ; Secretariat for Higher Education, Science, Technology and Innovation, Ecuador ; Ministry of Education and Research ; Estonian Research Council ; European Regional Development Fund, Estonia ; Academy of Finland ; Finnish Ministry of Education and Culture ; Helsinki Institute of Physics ; Institut National de Physique Nucleaire et de Physique des Particules / CNRS ; Commissariat a l'Energie Atomique et aux Energies Alternatives / CEA, France ; Bundesministerium fur Bildung and Forschung ; Deutsche Forschungsgemeinschaft ; Helmholtz-Gemeinschaft Deutscher Forschungszentren, Germany ; General Secretariat for Research and Technology, Greece ; National Scientific Research Foundation ; National Innovation Office, Hungary ; Department of Atomic Energy ; Department of Science and Technology, India ; Institute for Studies in Theoretical Physics and Mathematics, Iran ; Science Foundation, Ireland ; Istituto Nazionale di Fisica Nucleare, Italy ; Ministry of Science, ICT and Future Planning ; National Research Foundation (NRF), Republic of Korea ; Lithuanian Academy of Sciences ; Ministry of Education ; University of Malaya (Malaysia) ; BUAP ; CINVESTAV ; CONACYT ; LNS ; SEP ; UASLP-FAI ; Ministry of Business, Innovation and Employment, New Zealand ; Pakistan Atomic Energy Commission ; Ministry of Science and Higher Education ; National Science Centre, Poland ; Fundacao para a Ciencia e a Tecnologia, Portugal ; JINR, Dubna ; Ministry of Education and Science of the Russian Federation ; Federal Agency of Atomic Energy of the Russian Federation ; Russian Academy of Sciences ; Russian Foundation for Basic Research ; Ministry of Education, Science and Technological Development of Serbia ; Secretaria de Estado de Investigacion, Desarrollo e Innovacion ; Programa Consolider-Ingenio, Spain ; ETH Board ; ETH Zurich ; PSI ; SNF ; UniZH ; Canton Zurich ; SER ; Ministry of Science and Technology, Taipei ; Thailand Center of Excellence in Physics ; Institute for the Promotion of Teaching Science and Technology of Thailand ; Special Task Force for Activating Research ; National Science and Technology Development Agency of Thailand ; Scientific and Technical Research Council of Turkey ; Turkish Atomic Energy Authority ; National Academy of Sciences of Ukraine ; State Fund for Fundamental Researches, Ukraine ; Science and Technology Facilities Council, UK ; US Department of Energy ; US National Science Foundation ; Marie-Curie programme ; European Research Council ; EPLANET (European Union) ; Leventis Foundation ; A. P. Sloan Foundation ; Alexander von Humboldt Foundation ; Belgian Federal Science Policy Office ; Fonds pour la Formation a la Recherche dans l'Industrie et dans l'Agriculture (FRIA-Belgium) ; Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium) ; Ministry of Education, Youth and Sports (MEYS) of the Czech Republic ; Council of Science and Industrial Research, India ; Foundation for Polish Science - European Union, Regional Development Fund ; National Science Center (Poland) ; Thalis programme - EU-ESP ; Aristeia programme - EU-ESP ; Greek NSRF ; National Priorities Research Program by Qatar National Research Fund ; Programa Clarin-COFUND del Principado de Asturias ; Rachadapisek Sompot Fund for Postdoctoral Fellowship, Chulalongkorn University ; Chulalongkorn Academic into Its 2nd Century Project Advancement Project (Thailand) ; Welch Foundation ; Estonian Research Council: IUT23-4 ; Estonian Research Council: IUT23-6 ; National Science Center (Poland): Harmonia 2014/14/M/ST2/00428 ; National Science Center (Poland): Opus 2013/11/B/ST2/04202 ; National Science Center (Poland): 2014/13/B/ST2/02543 ; National Science Center (Poland): 2014/15/B/ST2/03998 ; National Science Center (Poland): Sonata-bis 2012/07/E/ST2/01406 ; Welch Foundation: C-1845 ; The nuclear modification factor R-AA and the azimuthal anisotropy coefficient v(2) ofprompt and nonprompt (i.e. those from decays of b hadrons) J/psi mesons, measured from PbPb and pp collisions at root S-NN = 2.76 rfeV at itheLHC, are reported. The results are presented in several event centrality intervals and several kinematic regions, for transverse momenta p(T) > 6.5 GeV/c and rapidity vertical bar y vertical bar < 2.4, extending down to p(T) = 3 GeV/c in the 1.6 < vertical bar y vertical bar < 2.4 range. The v(2) of prompt J/psi is found to be nonzero, but with no strong dependence on centrality, rapidity, or p(T) over the full kinematic range studied. The measured v(2) of nonprompt J/psi is consistent with zero. The R-AA of prompt J/psi exhibits a suppression that increases from peripheral to central collisions but does not vary strongly as a function of either y or pT in the fiducial range. The nonprompt J/psi RAA shows a suppression which becomes stronger as rapidity or p(T) increases. The v(2) and R-AA of open and hidden charm, and of open charm and beauty, are compared.