Translational potential of JAX humanized APOE mice: Hippocampal volume decline in very old mice

Background: Whole brain and hippocampal atrophy are the most prominent structural features of late-onset Alzheimer’s disease (LOAD) and are accepted endpoints in many clinical trials. The APOE ε4 allele is the strongest genetic risk factor for LOAD, with the ε4/ε4 genotype associated with the greatest atrophy rates. To date, there is limited hippocampal volume reporting in preclinical APOE models. To assess the translational potential of a humanized APOE (hAPOE) mouse model, we report age, sex, and genotype effects on total brain and hippocampal volume. Method: High resolution ex-vivo MRIs were obtained from two separate cohorts of male and female hAPOE mice (Cohort 1: n=53, 18.47±0.99 months; Cohort 2: n=33, 24.24±0.58 months). A validated mouse brain atlas was used for volumetric analysis. Cohorts were analyzed separately with genotype by sex analyses of variance for total brain volume (sum of all regions in atlas) as well as left and right hippocampal volume as percent of total brain volume. Result: In Cohort 1, hAPOEε4/ε4 mice had significantly larger brains than hAPOEε3/ε3s or hAPOEε3/ε4s, with female hAPOEε4/ε4s having the largest brains (p<0.001). Regardless of genotype, females had smaller left (p=0.006) and right (p<0.001) hippocampi relative to males. In Cohort 2, there were no genotype or sex differences in total brain volume. However, left (p=0.044) and right (p=0.034) hippocampal volumes were smaller for hAPOEε4/ε4 mice compared to hAPOEε3/ε4 mice without sex effects. Conclusion: Our findings capitalize on a large dataset (n=88) of high-resolution MRIs. At 18-20 months old (∼60 human years), hAPOEε4/ε4 mice had greater total brain volume than comparably aged hAPOEε3/ε3 or hAPOEε3/ε4 mice without hippocampal atrophy. However, hippocampal atrophy was evident when mice were aged to 24-25 months (∼70 human years). These findings of larger brain volume and greater hippocampal atrophy in hAPOEε4/ε4 carriers are consistent with large-scale AD imaging datasets. The timing of evident hippocampal atrophy in these mice also coincides with the global average age of clinical diagnosis. Based on these findings, the translational potential of this model requires utilizing very old mice, limiting the window for therapeutic testing.