In this study, we aimed to explore the age-related effect of APOE gene on brain volume. We hypothesized that APOE might have differential effects on brain volume in different age stages. 

Inhabitants in Shunyi District in Beijing aged 35 years and above and living independently were invited to join this study from 2013 to 2016. The baseline assessments, APOE genotyping and brain magnetic resonance imaging were performed. The detailed neuroimaging characteristics and brain volumes (global measures, cerebral lobes, subcortical nuclei and brainstem) were acquired. The general linear model was used to analyze the interaction of APOE genotypes by age on brain volumes, and the age of 60 years was chosen as a cut-off value for stratification analysis.

A total of 1,105 subjects were enrolled in the final analysis with a mean age of 56.18 (9.30) years, and 37.7% were men. APOE ε3/ε3 carriers accounted for 71.8%, ε2 allele 14.0%, and ε4 allele 14.2%. Compared with APOE ε3/ε3, a significant protective effect for APOE ε4 (+) on brain parenchyma fraction (β = 0.450, p = 0.048) was observed in subjects aged ≤60 years; in participants aged >60 years, a negative effect for APOE ε4 (+) on hippocampus (β = 1.087, p = 0.021) was found.

Our study reveals that APOE ε4 has differential effects on cerebral structures in different stages of lifespan, suggesting its complicated biological function and underlying antagonistic pleiotropy.