期刊
CEREBRAL CORTEX
卷 22, 期 11, 页码 2653-2661出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhr348
关键词
Alzheimer's disease; imaging genetics; polygenic score
资金
- ADNI
- National Institutes of Health (NIH) [U01 AG024904, P01AG036694, P50AG005134, P41RR14074, R01AG021910, R01AG027435, NIBIB 1K25EB013649-01]
- National Institute on Aging (NIA) [AG022381]
- National Institute of Biomedical Imaging and Bioengineering
- National Center for Research Resources [P41-RR14075]
- NCRR BIRN Morphometric Project [BIRN002, U24 RR021382]
- National Institute for Biomedical Imaging and Bioengineering [R01EB006758]
- National Center for Alternative Medicine [RC1 AT005728-01]
- National Institute for Neurological Disorders and Stroke [R01 NS052585-01, 1R21NS072652-01]
- Shared Instrumentation Grants [1S10RR023401, 1S10RR019, 1S10RR023043]
- Autism & Dyslexia Project
- Ellison Medical Foundation
- Harvard Catalyst, The Harvard Clinical, and Translational Science Center (NIH) [1KL2RR025757-01]
- Harvard University
- NIH Blueprint for Neuroscience Research [U01-MH093765]
Late-onset Alzheimer's disease (AD) is 50-70% heritable with complex genetic underpinnings. In addition to Apoliprotein E (APOE) epsilon 4, the major genetic risk factor, recent genome-wide association studies (GWAS) have identified a growing list of sequence variations associated with the disease. Building on a prior large-scale AD GWAS, we used a recently developed analytic method to compute a polygenic score that involves up to 26 independent common sequence variants and is associated with AD dementia, above and beyond APOE. We then examined the associations between the polygenic score and the magnetic resonance imaging-derived thickness measurements across AD-vulnerable cortex in clinically normal (CN) human subjects (N = 104). AD-specific cortical thickness was correlated with the polygenic risk score, even after controlling for APOE genotype and cerebrospinal fluid (CSF) levels of beta-amyloid (A beta(1-42)). Furthermore, the association remained significant in CN subjects with levels of CSF A beta(1-42) in the normal range and in APOE epsilon 3 homozygotes. The observation that genetic risk variants are associated with thickness across AD-vulnerable regions of interest in CN older individuals, suggests that the combination of polygenic risk profile, neuroimaging, and CSF biomarkers may hold synergistic potential to aid in the prediction of future cognitive decline.
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