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

Apolipoprotein E4 (<i>APOE4</i>) 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 <i>APOE4</i> carriers, the interaction between these factors is poorly understood. Here, we sought to determine if <i>APOE4</i>, sex, and diet interact to influence AD related outcomes in mice. Male and female <i>APOE3</i> and <i>APOE4</i> 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 <i>APOE4</i>, 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 <i>APOE4</i> mice. <i>APOE4</i> TR mice also exhibited impaired learning before diet. Proteomic analysis revealed that <i>APOE4</i> 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 <i>APOE4</i> versus <i>APOE3</i> TR females. We provide novel evidence that <i>APOE4</i> may drive early sex- and diet-dependent reductions in pathways that support brain mitochondrial energy metabolism.