期刊
ALZHEIMERS & DEMENTIA
卷 14, 期 2, 页码 205-214出版社
WILEY
DOI: 10.1016/j.jalz.2017.08.013
关键词
Polygenic risk score; Sporadic late-onset Alzheimer's disease; Early-onset Alzheimer's disease; Early-onset autosomal dominant; Late-onset Alzheimer's disease; Dominantly inherited Alzheimer network; APOE; APP; PSEN1; PSEN2; Genetic architecture; Area under the curve; Genetic risk factor; Disease modifier; Age at onset; Cerebrospinal fluid; A beta; Tau
资金
- National Institutes of Health [R01-AG044546, P01-AG003991, RF1AG053303, R01-AG035083, R01-NS085419]
- Alzheimer's Association [NIRG-11-200110]
- American Federation for Aging Research
- BrightFocus Foundation Alzheimer's Disease Research grant [A2013359S]
- NIH [P50 AG05681, P01 AG03991, P01 AG026276]
- Dominantly Inherited Alzheimer Network (DIAN) - National Institute on Aging (NIA) [U19AG032438, P50 AG-16570, P50 AG-005142]
- German Center for Neurodegenerative Diseases (DZNE)
- NIHR Queen Square Dementia Biomedical Research Unit
- MRC Dementias Platform UK [MR/L023784/1, MR/009076/1]
- DIAN-TU Pharma Consortium, (DIAN-TU Pharma Consortium)
- 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 & 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
- NCI Cancer Center [P30 CA91842]
- ICTS/CTSA from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1TR000448]
- NIH Roadmap for Medical Research
Objective: To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic earlyonset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). Methods: Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. Results: We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 X 10(-7)) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 X 10(-7)) and sLOAD (OR = 1.40; P = 1.21 X 10(-3)). The PRS was associated with cerebrospinal fluid ptau(181)-A beta(42) on eADAD (P = 4.36 X 10(-2)). Conclusion: Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset. (C) 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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