| Summary: | Western diets high in sugars and saturated fats have been reported to induce metabolic and inflammatory impairments that are associated with several age-related disorders, including Alzheimer’s disease (AD) and type 2 diabetes (T2D). The apolipoprotein E (<i>APOE</i>) genotype is associated with metabolic and inflammatory outcomes that contribute to risks for AD and T2D, with the <i>APOE4</i> genotype increasing risks relative to the more common <i>APOE3</i> allele. In this study, we investigated the impacts of the <i>APOE</i> genotype on systemic and neural effects of the Western diet. Female mice with knock-in of human <i>APOE3</i> or <i>APOE4</i> were exposed to control or Western diet for 13 weeks. In the control diet, we observed that <i>APOE4</i> mice presented with impaired metabolic phenotypes, exhibiting greater adiposity, higher plasma leptin and insulin levels, and poorer glucose clearance than <i>APOE3</i> mice. Behaviorally, <i>APOE4</i> mice exhibited worse performance in a hippocampal-dependent learning task. In visceral adipose tissue, <i>APOE4</i> mice exhibited generally higher expression levels of macrophage- and inflammation-related genes. The cerebral cortex showed a similar pattern, with higher expression of macrophage- and inflammation-related genes in <i>APOE4</i> than <i>APOE3</i> mice. Exposure to the Western diet yielded modest, statistically non-significant effects on most metabolic, behavioral, and gene expression measures in both <i>APOE</i> genotypes. Interestingly, the Western diet resulted in reduced gene expression of a few macrophage markers, specifically in <i>APOE4</i> mice. The observed relative resistance to the Western diet suggests protective roles of both female sex and young adult age. Further, the data demonstrate that <i>APOE4</i> is associated with deleterious systemic and neural phenotypes and an altered response to a metabolic stressor, findings relevant to the understanding of interactions between the <i>APOE</i> genotype and risks for metabolic disorders.
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