期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 62, 期 2, 页码 745-756出版社
IOS PRESS
DOI: 10.3233/JAD-170834
关键词
Alzheimer's disease risk; Clinical Dementia Rating sum of boxes; International Genomics of Alzheimer's Project (IGAP); polygenic risk score; progression
资金
- National Institutes of Health [R01-AG044546, P01-AG003991, RF1AG053303, R01-AG035083, R01-NS085419]
- Alzheimer Association [BAND-14-338165]
- NIH [P50-AG05681, P01-AG03991, P01-AG026276]
- Hope Center for Neurological Disorders
- Departments of Neurology and Psychiatry at Washington University School of Medicine
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant) [U01AG024904]
- 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
- Canadian Institutes of Health Research
- 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
- NATIONAL INSTITUTE ON AGING [P01AG003991, RF1AG044546, P50AG005681, P01AG026276, R01AG044546, RF1AG053303] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R25DA027995] Funding Source: NIH RePORTER
Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (beta = 0.146, p = 0.03). In the case of rare variants, TREM2 (beta = 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.
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