TOMM40 and APOC1 variants differentiate the impacts of the APOE ε4 allele on Alzheimer's disease risk across sexes, ages, and ancestries

Abstract

Abstract INTRODUCTION The variability in apolipoprotein E (APOE) ε4‐attributed susceptibility to Alzheimer's disease (AD) across ancestries, sexes, and ages may stem from the modulating effects of other genetic variants. METHODS We examined associations of compound genotypes (CompGs) comprising the ε4‐encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with AD in White (7181/16,356 AD‐affected/unaffected), Hispanic/Latino (2305/2921), and Black American (547/1753) participants across sexes and ages. RESULTS The absence and presence of the rs2075650 and/or rs12721046 minor alleles in the ε4‐bearing CompGs define lower‐ and higher‐AD‐risk profiles, respectively, in White participants. They differentially impact AD risks in men and women of different ancestries, exhibiting an increasing, decreasing, flat, and nonlinear—with lower risks at ages younger than 65/70 years and older than 85 years compared to the ages in between—patterns across ages. DISCUSSION The ε4‐bearing CompGs have a potential to differentiate biological mechanisms of sex‐, age‐, and ancestry‐specific AD risks and serve as AD biomarkers. Highlights Younger White women carrying the lower‐risk (LR) CompG are at small risk of AD. Black carriers of the LR CompG are at negligible risk of AD at 85 years and older. The higher‐risk (HR) CompGs confer high AD risk in Whites and Blacks at 70 to 85 years. AD risk decreases with age for Hispanic/Lation women carrying the HR CompGs. Hispanic/Lation carriers of the LR CompG but not HR CompGs have higher AD risk than Blacks.

Keywords

• Alzheimer's disease risk
• APOE gene cluster
• APOE polymorphism
• haplotypes
• race/ethnic disparities
• sex disparities in Alzheimer's disease