IMPACT OF APOE GENOTYPE ON THE SEX-DIFFERENTIATED BIOENERGETIC TRAJECTORIES AND AD RISKS IN AGING MOUSE BRAINS

Abstract

Age, APOE4 genotype, and female sex are top risk factors for AD. Our previous studies demonstrated that the bioenergetic shifts occurring in the perimenopausal female brain could contribute to an increased AD risk in women. We also observed substantial sex disparities in brain bioenergetic trajectories in normal aging mice. The goal of this study is to determine the sex differences in the impact of APOE genotype on AD at-risk phenotypes during brain aging. Female and male, APOE3- and APOE4 targeted replacement (TR) mice were assessed for: (a) bioenergetic-, inflammatory-, and AD pathology-related gene expression in hippocampus followed by bioinformatic analysis, and (b) key metabolic parameters in the periphery. Functional assessments are undergoing, including: (a) FDG-microPET for cerebral glucose metabolism, (b) brain mitochondrial function, and (c) glucose tolerance test for peripheral metabolism. Gene expression analyses revealed that female APOE4 mice at pre-menopause age (6-month old) exhibited a significantly different bioenergetic profile relative to APOE3 controls: APOE4 mice showed a higher expression of genes involved in mitochondrial oxidative phosphorylation, mitochondrial membrane transport, and mitochondrial fusion. These changes in female APOE4 brains could represent an adaptive response to deficits in brain glucose availability and a shift in energy fuels from glucose to ketone bodies and glucose. This hypothesis is further supported by: (a) APOE4 mice had lower levels of plasma glucose in both sexes while the higher levels of ketone bodies and triglycerides were only seen in the females; (b) both APOE3 and APOE4 females had lower peripheral glucose levels and higher ketone body levels than their genotype-matched male counterparts, indicating a potential earlier shift in bioenergetic fuel usage in females. These findings suggest that APOE4 genotype interacts with the age-related decline in glucose metabolism and the bioenergetic shift to alternative fuels, particularly in females. Outcomes of this study will provide mechanistic details of the APOE4 genetic burden on the sex-differentiated bioenergetic fluctuation during aging and its contribution to higher AD risks in women. This work was supported by NIA 5P01AG026572 to RDB and Alzheimer's Association SAGA-17–419459 to RDB.