Sex-specific effects of apolipoprotein E ε4 genotype on longitudinal hippocampal atrophy in amnestic mild cognitive impairment over a 2-year evaluation period

Background Hippocampal atrophy is implicated in the early onset of Alzheimer's disease (AD). It is closely associated with rapid cognitive decline and serves as a critical predictor for conversion from mild cognitive impairment (MCI) to AD. Consequently, with growing interest in utilizing hippocampal volume (HV) as an outcome measure in clinical trials, elucidating the neurobiological mechanisms underlying hippocampal atrophy is essential for early diagnosing AD and predicting its progression. Objective The risk of AD associated with the apolipoprotein E ε4 ( APOE4) allele is higher in females than in males. However, the presence of sex-specific effects of the APOE4 genotype on longitudinal hippocampal atrophy (ΔHV) remains unclear. We aimed to examine the effects of the interaction between the APOE4 genotype and sex on ΔHV in amnestic mild cognitive impairment (aMCI). Methods This hospital-based prospective longitudinal study included 73 patients with aMCI. ΔHV, the major outcome measure, was assessed using magnetic resonance imaging performed at a baseline date and 2 years after the baseline evaluation. A two-way analysis of variance was conducted to examine the effects of the interaction between the APOE4 genotype and sex on ΔHV over the 2-year period. Results A significant interaction was observed between APOE4 and sex concerning ΔHV ( p = 0.036). In females, ΔHV significantly correlated with the APOE4 status. Female APOE4 carriers (ε3/ε4) exhibited 2.3 times higher ΔHV compared with female non-carriers (ε3/ε3) (−0.51 ± 0.28 versus −0.22 ± 0.26, p < 0.001). In contrast, ΔHV was not linked to the APOE4 status in males ( p = 0.599). Conclusions We identified that the APOE4 genotype affected ΔHV in females. Our findings suggest that female APOE4 carriers, unlike males, may be more susceptible than non-carriers to the underlying pathophysiological mechanisms of hippocampal atrophy in aMCI.