Differences in white matter integrity and hippocampal volumetrics across APOE genotype mice: A blinded preliminary study

Abstract

AbstractBackgroundGenome‐wide association studies have identified Apolipoprotein (APOE) as one of the strongest risk factors associated with Late‐Onset Alzheimer’s disease (LOAD) with females exhibiting a two‐fold higher incidence as compared to males. MRI studies of patients with LOAD link APOE‐e4 gene load with increased hippocampal volume loss as well as reduction in white matter integrity (WMI) in the limbic and medial temporal regions (Bagepally, 2012). However, there are few translational LOAD mouse model studies utilizing imaging. We hypothesized that hippocampal volume and WMI would be reduced in females and APOE e4 carriers in our humanized APOE (hAPOE) LOAD mouse model.MethodSix cohorts of APOE e3 and e4 genotype (M/F; N=53; mean age = 17.95 month) skull‐extracted ex‐vivo mouse brains were imaged (7T Bruker Biospec MRI scanner). Imaging included structural and diffusion weighted imaging. Bilateral hippocampal volumes, as well as total brain volume (TBV), were extracted using a well‐validated mouse brain atlas (Dorr, 2008). Fractional anisotropy (FA) was used to quantify WMI and between‐group comparisons were made using a groupwise connectometry approach (Yeh, 2013; Yeh, 2016).ResultMRI image analysis indicated genotypic differences in white matter FA where APOE‐e4 carriers exhibited lower FA values (mean tractography FA = 0.263 ± 0.043) compared to APOE‐e3/3 (mean tractography FA = 0.311 ± 0.067) in a total of 10657 tracts (FDR corrected p < 0.003; Figure 1). No statistically significant differences were identified across genotypes for left or right hippocampal volumes. However, right hippocampal volume was significantly greater in males as compared to females (p = 0.007) whereas no effect was observed between sexes for left hippocampus.ConclusionOutcomes of MRI analyses indicate a significant reduction in FA values and reduced white matter integrity across the brain in APOE e4 carriers, irrespective of sex. Contrary to human literature, no significant volumetric differences between genotypes were found in this mouse sample. Consistent with sex‐dependent literature, males exhibited greater total brain volume and additionally greater right hippocampal volume compared to females, irrespective of genotype. These findings may provide evidence of deficits in cholesterol or lipid transport manifest in decreased white matter integrity in this hAPOE mouse model.