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