TY - JOUR
T1 - Greater effect of polygenic risk score for Alzheimer's disease among younger cases who are apolipoprotein E-ε4 carriers
AU - Alzheimer's Disease Genetics Consortium
AU - Fulton-Howard, Brian
AU - Goate, Alison M.
AU - Adelson, Robert P.
AU - Koppel, Jeremy
AU - Gordon, Marc L.
AU - Barzilai, Nir
AU - Atzmon, Gil
AU - Davies, Peter
AU - Freudenberg-Hua, Yun
N1 - Funding Information:
Funding: This work was supported by the National Institutes of Health , National Institute on Aging (NIH-NIA). The Alzheimer's Disease Genetics Consortium (ADGC) is funded by grant numbers U01 AG032984 and RC2 AG036528 . Samples from the National Cell Repository for Alzheimer's Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement awarded by the NIH-NIA (grant number U24 AG21886 ), were used in this study. The National Alzheimer's Coordinating Center (NACC) database is funded by the NIH-NIA (grant number U01 AG016976 ). Data for this study were prepared, archived, and distributed by the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (grant number U24-AG041689-01 ). In addition, this work was funded by the NIH (grant numbers U01AG052411, U01AG058635, K08AG054727, R01 AG618381, and R01 AG046949) and the Einstein Nathan Shock Center (grant number P30 AG038072). Additional support was provided by the Mildred and Frank Feinberg Family Foundation, the Advancing Women in Science and Medicine Foundation, and the JPB Foundation.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/3
Y1 - 2021/3
N2 - To evaluate how age and apolipoprotein E-ε4 (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 × 10−6), which is twice the OR as using 89− controls (OR = 2.38, p = 4.6 × 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 noncarriers. 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 × 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 (β = −0.02, p = 4.8 × 10−3) as a predictor of PRSnon-APOE. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.
AB - To evaluate how age and apolipoprotein E-ε4 (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 × 10−6), which is twice the OR as using 89− controls (OR = 2.38, p = 4.6 × 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 noncarriers. 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 × 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 (β = −0.02, p = 4.8 × 10−3) as a predictor of PRSnon-APOE. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.
KW - APOE
KW - Alzheimer's disease
KW - Genetic risks
KW - Polygenic risk score
KW - Risk interactions
KW - Superager
UR - http://www.scopus.com/inward/record.url?scp=85094147759&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2020.09.014
DO - 10.1016/j.neurobiolaging.2020.09.014
M3 - Article
C2 - 33164815
AN - SCOPUS:85094147759
SN - 0197-4580
VL - 99
SP - 101.e1-101.e9
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -