Differential age effects on functional network development link to contextual memory disruption in APOE4 versus APOE3 homozygous mice

Apolipoprotein-ε4 (APOE4) homozygosity is the strongest genetic risk-factor for Alzheimer's Disease (AD). The combined effects of APOE4 with age on the brain are unclear. In the present work, we tested the hypothesis that age alters contextual fear memory, functional network topology, diffusion imaging measures, and RNA expression differentially between APOE4 and APOE3 homozygous mice. Male and female mice, 1.5-5.5 month (young) and 9-13.5 month (adult), homozygous for human APOE4 or APOE3, were scanned using an 11.1 Tesla MRI scanner. Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) were performed, and images were processed and analyzed, followed by a contextual fear conditioning (CFC) protocol to test contextual memory. Functional imaging revealed decreases in various functional network measures and decreased network development for APOE4 adults as well as significant differences between groups in brain activity in motor, sensory, memory, and emotional processing related regions. APOE3 adult mice showed increasing network complexity with aging. DTI-based fractional anisotropy (FA) increased with age independent of genotype. Behaviorally APOE4 adult mice experienced contextual memory dysfunction relative to other groups. No sex differences were observed. The results suggest that in APOE4 adult mice there may be a link of network connectivity changes with increases in fear behavior and a decreased ability to recognize contextual changes. Furthermore, the lack of network development in aging APOE4 mice is indicative of a loss of functional network resilience in the brains of AD-susceptible individuals.