Humanized APOE mouse brain volume increases over age irrespective of sex and APOE genotype: implications for translational validity to the human.

BACKGROUND

Humanized APOE mouse models are widely used to study late-onset Alzheimer's disease (LOAD) risk, yet it remains unclear whether they reproduce the macrostructural brain changes observed in human aging and disease.

METHODS

We performed ex vivo magnetic resonance imaging to quantify total and voxelwise brain volumes in male and female mice across APOE genotypes (ε3/ε3, ε3/ε4, ε4/ε4) and ages spanning 6-25 months.

RESULTS

Total brain volume increased with age (cross-sectional estimate: 2.12 mm3/month) and was greater in APOE-ε4 carriers, with no effect of sex. Voxelwise analyses revealed regionally specific changes independent of total volume, characterized by cortical volume decreases and subcortical preservation or increases, as well as sex-dependent spatial patterns. No localized volumetric effects of APOE genotype were detected.

CONCLUSION

These findings indicate that, despite incorporating a major genetic risk factor for LOAD, this model does not reproduce the atrophy phenotype characteristic of human aging and Alzheimer's disease. Instead, the observed pattern is more consistent with non-pathological or vulnerable aging, suggesting that humanized APOE alone is insufficient to induce MRI-detectable macrostructural atrophy within this cross-sectional comparison, though this finding does not preclude other APOE-dependent pathological mechanisms.