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The ε4 allele of apolipoprotein E ( APOE ) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD). However, the reason for the association between  APOE4  and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of Aβ, there is also an abundance of data showing that  APOE4  negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of  APOE4 ′s role in AD pathogenesis, we performed a transcriptomics analysis of  APOE4  vs.  APOE3  expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged  APOE  mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of  APOE4  vs.  APOE3  mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by  APOE4  expression in the EC of aged  APOE  mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as  APOE4  may point to a causative factor in the pathogenesis of AD.

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice