Abstract
Apolipoprotein E ε4 (APOE ε4) confers the greatest genetic risk for late-onset Alzheimer's disease (AD). The adjacent Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene may increase risk through APOE ε4 independent associations with AD- sensitive brain regions like the hippocampus. ANOVA and multiple linear regression tested TOMM40 rs2075650 ('650) G vs. A genotype on total hippocampal volume using UK Biobank data (n=10,130), across all participants and by APOE haplotype groups. Age and sex interactions with TOMM40 '650 were also tested. Across participants, having both APOE ε4 and TOMM40 '650 G carriage was related to hippocampal atrophy. Among non-APOE ε4 adults, age and sex jointly modulated '650 G carriage effects. Compared to younger middle- aged adults, older women and men respectively showed modest protective and markedly detrimental associations. TOMM40 '650 G carriage may have APOE ε4-independent associations with hippocampal volume based on age and sex.
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