Age and sex, not APOE, drive brain volume changes in humanized APOE mice: A model of aging and risk, not disease

Our findings leverage a large dataset (n = 159) of high-resolution MRIs in mice spanning 6-24 months (human age range: ∼34-70). Age-related changes indicate cortical contraction and midbrain/white matter expansion. Observed sex differences align with prior mouse studies: females exhibit greater cortical volume, while males show greater subcortical volume. Notably, there were identifiable areas of the hippocampi where volume was smaller in females than males, consistent with human studies. No genotypic effects survived multiple comparison correction, suggesting that age and sex drive volumetric changes rather than APOE and that the ε4 allele in this model does not result in the phenotypic atrophy observed in LOAD. This model reflects aging and neurodegenerative risk rather than disease, providing insights into brain structural dynamics over the lifespan.