期刊
ALZHEIMERS & DEMENTIA
卷 15, 期 10, 页码 1333-1347出版社
WILEY
DOI: 10.1016/j.jalz.2019.06.4950
关键词
Alzheimer's disease; Vascular pathology; Cerebral amyloid angiopathy; GWAS; Biological pathway
资金
- Fundacion bancaria La Caixa
- Grifols SA
- Fundacio ACE
- ISCIII (Ministry of Health, Spain)
- European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED project [115975]
- European Union/EFPIA Innovative Medicines Initiative Joint undertaking MOPEAD project [115985]
- ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion
- Fondo Europeo de Desarrollo Regional (FEDER-Una manera de Hacer Europa)
- Consejeria de Salud de la Junta de Andalucia [PI-0001/2017]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd
- Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research AMP
- Development, LLC.
- Johnson AMP
- Johnson Pharmaceutical Research AMP
- Development LLC.
- Lumosity
- Lundbeck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Servier
- Takeda Pharmaceutical Company
- Transition Therapeutics
- Canadian Institutes of Health Research
- SMEs as part of InnoMed (Innovative Medicines in Europe) - European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5
- NIA Division of Neuroscience [U01-AG032984]
- NIA [P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, AG081220]
- NINDS [R01 NS080820]
- CurePSP Foundation
- Mayo Foundation
- Fundacion Alzheimur (Murcia)
- Ministerio de Educacion y Ciencia (Gobierno de Espana)
- Corporacion Tecnologica de Andalucia
- Agencia IDEA (Consejeria de Innovacion, Junta de Andalucia)
- Diabetes Research Laboratory
- Biomedical Research Foundation
- CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM)
- Kronos Life Science Laboratories
- National Institute on Aging (Arizona Alzheimer's Disease Center) [P30 AG19610, RO1 AG023193]
- Mayo Clinic Alzheimer's Disease Center [P50 AG16574]
- National Alzheimer's Coordinating Center [U01 AG016976]
- state of Arizona
- French National Foundation on Alzheimer's disease and related disorders
- LABEX (laboratory of excellence program investment for the future) DISTALZ grant
- Inserm
- Institut Pasteur de Lille
- Universite de Lille 2
- Lille University Hospital
- Medical Research Council [503480]
- Wellcome Trust [082604/2/07/Z]
- German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) [01GI0102, 01GI0711, 01GI0420]
- AGES [N01-AG12100]
- NHLBI [R01 HL105756]
- Icelandic Heart Association
- Erasmus Medical Center and Erasmus University
- NIH/NIA [U01 AG016976, U01 AG032984, U24 AG021886, R01 AG033193]
- Alzheimer's Association [ADGC-10-196728]
- Alzheimer's Research UK [503176]
- Illinois Department of Public Health
- Translational Genomics Research Institute
- Piramal AG
- Laboratorios Echevarne
- Araclon Biotech S.A.
- Trinitat Port-Carbo legacy
- [PI13/02434]
- [PI16/01861]
- [PI17/01474]
Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
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