期刊
NEUROBIOLOGY OF AGING
卷 93, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2020.03.012
关键词
Alzheimer's disease (AD); Cerebrospinal fluid (CSF); Polygenic risk scores (PGRS); Complement cascades; Cell adhesion molecules; Cytokines
资金
- Stichting Alzheimer Nederland
- Stichting VUmc fonds
- EU-PRISM Project (Psychiatric Ratings using Intermediate Stratified Markers) from the Innovative Medicines Initiative 2 Joint Undertaking [115916]
- European Union's Horizon 2020 research and innovation program
- European Federation of Pharmaceutical Industries and Associations (EFPIA)
- Alzheimer's Disease Neuroimaging Initiative (ADNI)
- National Institutes of Health [U01 AG024904]
- DOD ADNI (Department of Defense award) [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
- company Genentech, Inc
- Fujirebio
- GE Healthcare
- IXICO Ltd
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Johnson & Johnson Pharmaceutical Research & 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
- 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]
- Alzheimer's Research UK [503176]
- Wellcome Trust [082604/2/07/Z]
- German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, BMBF): Competence Network Dementia (CND) grant [01GI0102, 01GI0711, 01GI0420]
- NIH/NIA grant [R01 AG033193]
- NIA [AG081220]
- AGES contract [N01-AG-12100]
- NHLBI [R01 HL105756]
- Icelandic Heart Association
- Erasmus Medical Center
- Erasmus University
- Alzheimer's Association grant [ADGC-10-196728]
- NIH/NIA grants [U01 AG032984, U24 AG021886, U01 AG016976]
- European Commission
- Dutch Research Council (ZonMW)
- Association of Frontotemporal Dementia/Alzheimer's Drug Discovery Foundation
- Alzheimer Netherlands
- Probiodrug
- Janssen prevention center
- Boehringer
- Brains online
- Axon Neurosciences
- EIP pharma
- Roche
- Piramal
- Dutch brain foundation
- EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant) [115372]
- ZonMW Memorabel grant program [73305056, 733050824]
Genetic factors play a major role in Alzheimer's disease (AD) pathology, but biological mechanisms through which these factors contribute to AD remain elusive. Using a cerebrospinal fluid (CSF) proteomic approach, we examined associations between polygenic risk scores for AD (PGRS) and CSF proteomic profiles in 250 individuals with normal cognition, mild cognitive impairment, and AD-type dementia from the Alzheimer's Disease Neuroimaging Initiative. Out of 412 proteins, 201 were associated with PGRS. Hierarchical clustering analysis on proteins associated with PGRS at different single-nucleotide polymorphism p-value inclusion thresholds identified 3 clusters: (1) a protein cluster correlated with highly significant single-nucleotide polymorphisms, associated with amyloid-beta pathology and complement cascades; (2) a protein cluster associated with PGRS additionally including variants contributing to modest risk, involved in neural injury; (3) a protein cluster that also included less strongly associated variants, enriched with cytokine-cytokine interactions and cell adhesion molecules. These findings suggest that CSF protein levels reflect varying degrees of genetic liability for AD and may serve as a tool to investigate biological mechanisms in AD. (C) 2020 Elsevier Inc. All rights reserved.
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