APOE4 Drives Sex- and Diet-Dependent Effects on AD-Like Pathology, Cognition, and Mitochondrial Function

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), yet it's unclear how this allele promotes disease. While factors like diet and sex may modify AD susceptibility in APOE4 carriers, the interaction between these factors is poorly understood. Here, we sought to determine if APOE4, sex, and diet interact to influence AD related outcomes in mice. Male and female APOE3 and APOE4 targeted replacement (TR) mice were fed a low-fat diet or high-fat diet from 4 to 8 months old. Serum neurodegenerative disease biomarkers, brain amyloid beta (Aβ), APOE, and tau, learning and memory, hippocampal mitochondrial function and proteomics data were collected. Serum GFAP and NfL were unaffected by APOE4, while HFD was associated with greater serum NfL and GFAP. Whole brain Aβ was significantly altered by sex, diet, and genotype. There was a main effect of genotype on levels of brain APOE with levels being lower in APOE4 mice. APOE4 TR mice also exhibited impaired learning before diet. Proteomic analysis revealed that APOE4 exerts diet- and sex-dependent effects on mitochondrial pathways. This included downregulation of pyruvate metabolism in HFD males and oxidative phosphorylation in HFD females. Basal respiration was lower in APOE4 versus APOE3 TR females. We provide novel evidence that APOE4 may drive early sex- and diet-dependent reductions in pathways that support brain mitochondrial energy metabolism.