Sex-specific trajectories of hippocampal aging: structural changes and asymmetry across the lifespan

Background: This study examines the interaction between age and sex on hippocampal volume across the lifespan, focusing on structural changes and asymmetry patterns. Extensive research has demonstrated sex differences in hippocampal structure and function, but the effects of aging on these patterns remain underexplored. Our study aims to elucidate how age-related changes in hippocampal volume differ between men and women, and their implications for cognitive and emotional processes. Methods: We performed correlational analyses of hippocampal subfield volumes, total hippocampal volume, and asymmetry indices in males and females. Age-related trends were assessed using linear mixed models (LMM), focusing on hippocampal subfields such as CA1, CA2-3, and CA4-DG. Sex-specific aging patterns were also examined using principal component analysis (PCA) to account for variance in hippocampal volume. Results: Males showed stronger asymmetry patterns, particularly between CA4-DG and CA2-3 subfields (p < 0.001), whereas females showed a distinct asymmetry pattern between CA4-DG and total hippocampal asymmetry (p < 0.001). Significant age-related hippocampal volume loss was observed in males (p = 0.003) but not in females (slope = 0.0026, p = 0.673). Sex differences were most pronounced in the 40s and 50s groups (p < 0.005). Additionally, males showed significant increase in CA1% volume with age (p = 0.038), while females did not (p = 0.616). Conclusions: These findings reveal distinct sex-specific trajectories of hippocampal aging, with males showing more pronounced age-related atrophy and stronger lateralization than females. The results highlight the need for sex-specific approaches in interventions aimed at mitigating hippocampal atrophy.