Sex differences in gene expression patterns associated with the APOE4 allele

Abstract

<b>Background:</b> The <i>APOE</i> gene encodes apolipoprotein ε (ApoE), a protein that associates with lipids to form lipoproteins that package and traffic cholesterol and lipids through the bloodstream. There are at least three different alleles of the <i>APOE</i> gene: <i>APOE2</i>, <i>APOE3</i>, and <i>APOE4</i>. The <i>APOE4</i> allele increases an individual's risk for developing late-onset Alzheimer disease (AD) in a dose-dependent manner. Sex differences have been reported for AD susceptibility, age of onset, and symptom progression, with females being more affected than males. <b>Methods:</b> In this study, we use a systems biology approach to examine gene expression patterns in the brains of aged female and male individuals who are positive for the <i>APOE4</i> allele in order to identify possible sex-related differences that may be relevant to AD. <b>Results:</b> Based on correlation analysis, we identified a large number of genes with an expression pattern similar to that of <i>APOE</i> in <i>APOE4</i>-positive individuals. The number of these genes was much higher in <i>APOE4</i>-positive females than in <i>APOE4</i>-positive males, who in turn had more of such genes than <i>APOE4</i>-negative control groups. Our findings also indicate a significant sex* genotype interaction for the CNTNAP2 gene, a member of the neurexin family and a significant interaction for brain area*sex* genotype for PSEN2, a risk factor gene for AD. <b>Conclusions:</b> Profiling of these genes using Gene Ontology (GO) term classification, pathway enrichment, and differential expression analysis supports the idea of a transcriptional role of <i>APOE</i> with respect to sex differences and AD.