Journal
NEUROBIOLOGY OF AGING
Volume 99, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2020.09.014
Keywords
Alzheimer's disease; Polygenic risk score; Superager; Genetic risks; Risk interactions; APOE
Categories
Funding
- National Institutes of Health, National Institute on Aging (NIH-NIA)
- NIH-NIA [U24 AG21886, U01 AG016976]
- National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania [U24-AG041689-01]
- NIH [U01AG052411, U01AG058635, K08AG054727, R01 AG618381, R01 AG046949]
- Einstein Nathan Shock Center [P30 AG038072]
- Mildred and Frank Feinberg Family Foundation
- Advancing Women in Science and Medicine Foundation
- JPB Foundation
- [U01 AG032984]
- [RC2 AG036528]
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The study shows a significant correlation between age-related polygenic risk score and the risk of Alzheimer's disease, particularly in APOE4 carriers. Furthermore, there is a significant difference of 5 years in age at onset between the highest and lowest risk scores among APOE4 carriers.
To evaluate how age and apolipoprotein E-epsilon 4 (APOE4) status interact with APOE-independent polygenic risk score (PRSnon-APOE), we estimated PRSnon-APOE in superagers (age >= 90 years, N = 346), 89- controls (age 60-89, N = 2930), and Alzheimer's disease (AD) cases (N =1760). Using superagers, we see a nearly 5 times greater odds ratio (OR) for AD comparing the top PRSnon-APOE decile to the lowest decile (OR = 4.82, p = 2.5 x 10(-6)), which is twice the OR as using 89- controls (OR = 2.38, p = 4.6 x 10(-9)). Thus PRSnon-APOE is correlated with age, which in turn is associated with APOE. Further exploring these relationships, we find that PRSnon-APOE modifies age at onset among APOE4 carriers, but not among non carriers. More specifically, PRSnon-APOE in the top decile predicts an age at onset 5 years earlier compared with the lowest decile (70.1 vs. 75.0 years; t-test p = 2.4 x 10(-5)) among APOE4 carriers. This disproportionally large PRSnon-APOE among younger APOE4-positive cases is reflected in a significant statistical interaction between APOE4 status and age at onset (beta =-0.02, p = 4.8 x 10(-3)) as a predictor of PRSnon-APOE. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers. (C) 2020 Elsevier Inc. All rights reserved.
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