Utilizing Systems Biology Approaches to Elucidate the Effects of APOE4 Expression in an AD-vulnerable Brain Region Tal Nuriel1,*, Archana Ashok1, Qiuying Chen2, Robin Chan1, Allissa Dillman3, Helen Figueroa1, Mark Cookson3, Gilbert Di Paolo1, Steven S. Gross2, and Karen E. Duff1,* 1Columbia University Medical Center; 2Weill Cornell Medical College; 3National Institute on Aging *Corresponding Author
The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, why the APOE4 variant is associated with increased risk of AD remains a source of debate. In order to obtain an unbiased view of APOE4's effects on neurobiology, we performed a multi-omic analysis on aged APOE targeted replacement mice that were devoid of overt AD pathology. RNA, lipids and small-molecule metabolites were extracted from the entorhinal cortex (EC) and primary visual cortex (PVC) of 14-15 month old APOE4 vs. APOE3 mice, followed by analysis by transcriptomics, lipidomics and metabolomics, respectively. We observed that APOE4 expression in the EC results in the differential expression of genes, lipids and small-molecule metabolites related to a number of important neurobiological systems, including neuronal activity, endosomal-lysosomal processing and bioenergetics. Follow up studies were utilized to validate and extrapolate on these finding, revealing the widespread dysregulation of each of these interconnected systems in the EC of aged APOE4 mice. These studies provide an unbiased, systems-wide look at the effects of APOE4 expression on neurobiology, which we believe will lead to a more thorough understanding of why APOE4 increases the risk of AD and how to prevent or slow the progression of AD among APOE4 carriers.