Basic Science and Pathogenesis.

Background: Altered lipid profiles and lipid processing genes are associated with Alzheimer's disease (AD). There is a reported genetic interaction between the AD risk gene APOE and cholesterol ester transfer protein (CETP). Mice lack functional CETP which is critical to the balance of circulating lipoproteins; this imparts cardioprotective effects and may make mice resistant to AD. Additionally, previous studies in transgenic humanized CETP (hCETP) mice have demonstrated that CETP addition in mice increases expression of AD risk genes and markers of AD pathogenicity. Together, this suggests that CETP may modify AD risk in an APOE4-dependent manner. This project aims to determine molecular pathways and signatures in AD mediated by CETP with an emphasis on molecular pathways shared with APOE as a potential disease-altering mechanism.

Methods: To identify pathways shared by CETP and APOE we created molecular networks using publicly available online tools including the AD Atlas and STRING (v12.0). The Heart and Diabetes Institute Metabolomics Laboratory Portal was leveraged to perform Genome Wide Association Study (GWAS) analysis to establish changes in lipid species abundance shared by CETP and APOE genetic variants. Transcriptional signatures in several mouse models were compared to human AD gene modules to determine pathological relevance of hCETP and APOE4 mouse models.

Results: Molecular networks implicated several genes as being co-expressed suggesting they may co-function with CETP and APOE. These co-expression edges included C4A/B compliment genes, PSMB8, APOJ/CLU, and APP. GWAS analysis resulted in several notable findings including that CETP variants have a strong effect on the relative abundance of phosphatidylcholine (PC) lipid species. Additionally, while APOE4 is positively associated with total PC, the common loss-of-function variant CETP I405V (rs5882) is associated with reduced PC levels. Transcriptional changes in lipid-related transgenic and MODEL-AD knock-in mouse models exhibited significant associations with immune processes.

Conclusions: These findings indicate that both CETP and APOE influence total PC and are associated with molecular pathways of immune activation and amyloid biology. Overall this evidence suggests that CETP and APOE act on shared pathways, likely mediated by lipid metabolism and peripheral immunity, that contribute to AD susceptibility.