Sex and APOE Genotype Differentially Modify the Association Between Hippocampal Volume and Memory Performance

Abstract

Background: The hippocampus, vital for memory processing, is one of the first regions affected by Alzheimer's disease (AD). APOE‐ε4 (risk) and APOE‐ε2 (protective) alleles are key genetic drivers of AD risk and cognitive decline. This study aimed to assess the modifying effect of the APOE genotype on the association between hippocampal volume and memory performance. Furthermore, we considered the modifying effects of sex, self‐reported race, and clinical diagnosis. Methods: Data were obtained from 6,895 participants (mean age at baseline=75.2 years; 21% AD, 43% male, 81% non‐Hispanic white (NHW), 12% APOE‐ε2 carriers, and 40% APOE‐ε4 carriers) from four cohorts of aging and AD: ADNI, NACC, ROS/MAP/MARS, and WRAP. MRI data, processed with deep learning MUSE, included left and right hippocampal volumes, harmonized for batch differences using Longitudinal Combat. Memory composite scores were harmonized across cohorts using latent variable modeling. Linear regression on baseline memory assessed two‐way interactions between total hippocampal volume×sex, total hippocampal volume×APOE (modeled dominantly), and three‐way interactions that included sex, race, or diagnosis. Mixed effects regression models assessed these interactions on memory trajectories and included fixed and random effects for intercept and the slope (years from baseline). Results: The association between hippocampal volume and memory performance is stronger in females than in males, whereby females with larger hippocampi outperform males with larger hippocampi (p = 7.47×10‐13; R2=0.007; Figure 1). APOE haplotype also interacted with hippocampal volume on baseline memory, whereby the association is stronger in ε4(p = 6.07×10−13; R2=0.004) carriers and attenuated in ε2 carriers (p = 3.22×10−5; R2=0.001), particularly among individuals with mild cognitive impairment (p = 0.048; b=5.41×10‐5). Notably, APOE interactions with hippocampal volume were consistent across NHW and non‐Hispanic black (NHB) participants. In longitudinal analyses, we found a significant three‐way interaction between APOE‐ε2, AD diagnosis, and hippocampal volume on memory (p = 0.0001; R2c=0.8; R2m=0.5), driven by a stronger interaction among participants with AD (p = 0.036; R2c=0.5; R2m=0.04). Conclusion: While hippocampal volume is a potent predictor of memory performance, sex, and APOE modify this association with the most pronounced effects observed among APOE‐ε4 carriers, women, and participants with AD. These results emphasize the importance of considering genetic, clinical, and demographic factors in AD research.