Role of ABCA-1 Activity in Brain DHA Metabolism in Carriers of APOE4 (P3.032)

Objective: Our aim is to identify that APOE lipidation by the lipid transporter ABCA-1 as a critical mechanism in brain docosahexaenoic acid (DHA) metabolism. Background: We previously demonstrated that ABCA-1 activity was lower in cerebrospinal fluid (CSF) of persons with APOE4 compared with non-carriers. Design/Methods: We employed cellular, brain imaging and clinical studies to understand the how APOE4 regulates the transport of DHA in the brain. Results: Using astrocytes expressing APOE2, APOE3 and APOE4, we demonstrate that APOE4 cells release less DHA into APOE4 lipoproteins compared with non-APOE4 cells. We identify lower ABCA-1 expression in APOE4 cells as a mechanism for the lower DHA release that can be reversed by inducing ABCA-1 expression in vitro. To understand the clinical relevance of these findings, we employed PET imaging with 11C DHA in a group of cognitively normal individuals (n=23, mean age=37). APOE4 carriers (n=9) had a 30% increase in brain DHA uptake from plasma compared to non-carriers (n=13, p=0.04). These findings suggest a DHA deficit in brains of APOE4 carriers. We then examined whether the APOE4 allele affected CSF DHA levels after DHA supplementation. CSF DHA levels of 43 participants receiving DHA (n=28) vs. Placebo (n=15) over 18 months were measured in the ADCS-sponsored DHA trial. Carrying the APOE4 allele was associated with lower increase in CSF DHA levels (p=0.07, interaction between genotype and treatment) compared with non-carriers. Conclusions: Our studies identify a novel role for APOE lipidation by ABCA-1 in DHA transport. These findings are clinically relevant as we observed deficits in brain DHA transport in younger cognitively normal APOE4 carriers using DHA PET scans, and in APOE4 carriers with dementia after DHA supplementation. Enhancing APOE lipidation using ABCA-1 agonists is a promising strategy to enhance brain DHA metabolism in APOE4 carriers. Disclosure: Dr. Horton has nothing to disclose. Dr. Umhau has nothing to disclose. Dr. Chui has nothing to disclose. Dr. Schneider has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Takeda (adjudication committee), Merck (DSMB). Consulting: AC Immune, Avraham, Axovant, Boehringer Ingelheim, Cognition, Insys, Kyowa Kirin, Neurim, Tau Rx, vTv. Dr. Schneider has received personal compensation in an editorial capacity for Alzheimer & Dementia: Translational Research and Clinical Intervention. Dr. Schneider has received research support from Yes, Biogen, Genentech, Lilly, Novartis. Dr. Harrington has nothing to disclose. Dr. Fonteh has nothing to disclose.