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Humanized APOE mouse brain volume increases over age irrespective of sex and APOE genotype: implications for
Adam C Raikes1, Avnish Bhattrai1, Tian Wang1,2
1Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, United States.
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.
