Greater effect of polygenic risk score for Alzheimer's disease among younger cases who are apolipoprotein E-ε4 carriers

NEUROBIOLOGY OF AGING

卷:99

Article

Fulton-Howard, Brian¹  Goate, Alison M.¹  Adelson, Robert P.²  Koppel, Jeremy^2,3,4  Gordon, Marc L.^2,4,5  Consortium, Alzheimer's Disease Genetics⁵  Barzilai, Nir⁶  Atzmon, Gil^6,7  Davies, Peter^2,4  Freudenberg-Hua, Yun^2,3,4 

[1] Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, Dept Neurosci, New York, NY 10029 USA

[2] Feinstein Inst Med Res, Litwin Zucker Ctr Alzheimers Dis, 350 Community Dr, Manhasset, NY 11030 USA

[3] Zucker Hillside Hosp, Div Geriatr Psychiat, Glen Oaks, NY USA

[4] Donald & Barbara Zucker Sch Med Hofstra Northwell, Hempstead, NY USA

[5] Univ Penn, Sch Med, Philadelphia, PA 19104 USA

[6] Albert Einstein Coll Med, Inst Aging Res, Bronx, NY 10467 USA

[7] Univ Haifa, Fac Nat Sci, Abba Hushi Blvd, Haifa, Israel

关键词: Alzheimer's disease;    Polygenic risk score;    Superager;    Genetic risks;    Risk interactions;    APOE;   

DOI  :  10.1016/j.neurobiolaging.2020.09.014

来源: Elsevier

【 摘 要 】

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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