期刊
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
卷 77, 期 9, 页码 1734-1742出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/gerona/glac138
关键词
Alzheimer's disease; Epigenetic aging; Mild cognitive impairment; Polygenic risk score; Survival analysis
资金
- National Institute on Aging [R01AG064803, P30AG072958, P30AG028716]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) [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
- National Institute on Aging at National Institute of Health [U01 AG016976]
- NIA [P30 AG019610, P30 AG013846, P30 AG062428-01, P50 AG008702, P50 AG025688, P50 AG047266, P30 AG010133, P50 AG005146, P30 AG06242101, P30 AG062422-01]
- The NIA [P50 AG005138, P30 AG008051, P30 AG013854, P30 AG008017, P30 AG010161, P50 AG047366, P30 AG010129, P50 AG016573, P30 AG062429-01, P50 AG023501, P30 AG035982, P30 AG028383]
- 'NIA' [P30 AG053760, P30 AG010124, P50 AG005133, P50 AG005142, P30 AG012300, P30 AG049638, P50 AG005136, P30 AG062715-01, P50 AG005681, P50 AG047270]
This study investigated the association between genetic variations associated with aging acceleration and the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). The results showed genetic correlations between epigenetic age acceleration (IEAA/EEAA) and AD, and identified multiple SNPs associated with the progression from MCI to AD.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and previous studies have shown its association with accelerated aging. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) that contributed to aging acceleration are also associated with the progression from mild cognitive impairment (MCI) to AD. By applying genetic correlation analysis and single-locus survival analysis, we investigated the associations between intrinsic- and extrinsic-epigenetic-age-acceleration (IEAA and EEAA) related SNPs and the progression time from MCI to AD dementia using the data of 767 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and 1 373 MCI patients from the National Alzheimer's Coordinating Center (NACC) study. Genetic correlations were found between IEAA/EEAA and AD (positive for IEAA-AD and negative for EEAA-AD). We revealed that 70 IEAA and 81 EEAA SNPs had associations with the progression time from MCI to AD with Bayesian false-discovery probability <= 0.8 in the ADNI study, with 22 IEAA SNPs and 16 EEAA SNPs being replicated in the NACC study (p < .05). Polygenic risk score (PRS) analysis showed that EEAA PRS but not IEAA PRS was associated with AD progression and the trend of decreasing fusiform gyrus volume in 2 data sets. Risk models incorporating both EAA PRSs did not show any significant improvement in predictive accuracy. Our results revealed multiple genetic variants with pleiotropic effects on both EAA and AD, which suggested shared genetic architecture between epigenetic age acceleration and AD progression.
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