Accelerated hippocampal atrophy in APOE ε4 homozygotes and females: Longitudinal findings from the Tohoku Medical Megabank MRI study

PURPOSE: The apolipoprotein E ε4 allele is a major genetic risk factor for Alzheimer's disease, but its longitudinal effect on hippocampal atrophy is unclear. Selective hippocampal atrophy, defined as greater hippocampal volume (HpV) loss relative to total brain volume (TBV), is an early marker of preclinical Alzheimer's disease. We examined age-related effects of APOE ε4 on longitudinal hippocampal atrophy in a large population-based cohort. METHODS: We analyzed MRI data from 9,453 adults in the Tohoku Medical Megabank MRI Study, including 5,774 participants with follow-up MRI after a mean interval of 4.7 years. Cross-sectional analyses used linear regression to assess HpV and TBV, adjusting for age, sex, APOE genotype, and intracranial volume. Longitudinal analyses assessed HpV-Ratio and TBV-Ratio, defined as the second MRI volume divided by the first volume, using regression models including age, sex, APOE genotype, MRI interval, and interaction terms between age and APOE genotype and between age and sex. Montreal Cognitive Assessment (MoCA) scores obtained at the second MRI were included to assess effects independent of cognition. RESULTS: No significant APOE genotype effects were observed in cross-sectional analyses. Longitudinally, ε4/ε4 carriers showed greater decline in HpV-Ratio than ε3/ε3 and ε3/ε4 carriers, and females showed lower HpV-Ratio than males. No APOE genotype or sex main effects were observed for TBV-Ratio. Interactions between age and APOE genotype and between age and sex demonstrated age-related acceleration of HpV-Ratio decline in ε4/ε4 carriers and females, and these effects persisted after adjustment for MoCA scores. CONCLUSION: APOE ε4 homozygosity and female sex accelerate selective hippocampal atrophy in population-based cohorts.