Carrying the ApoE ?4 allele and low HDL cholesterol diabetic dyslipidemia are risk factors of Alzheimer?s disease (AD). How low HDL cholesterol levels or ApoE4 HDL proteins increase AD risk is far from being completely understood. The efflux of cholesterol and lipids to ApoE-containing lipoproteins is the first step in the formation of brain HDL. ABCA1 is a major transporter of lipids to ApoE-containing lipoproteins. In AD mouse models, the absence of the ABCA1 gene decreases brain HDL and increases brain amyloid deposition. Conversely, facilitating ABCA1 lipid transport decreases amyloid plaques and improves cognition. In humans, loss-of-function mutations in the ABCA1 gene are associated with increased AD risk. Therefore, targeting ABCA1 is a promising therapeutic strategy in AD. One promising therapy is the ApoE mimetic peptide ?CS- 6253?. CS-6253 enhances the rate of ABCA1-driven efflux of cholesterol and phospholipids from cells to form HDL. Using a novel approach, we examined the capacity of cerebrospinal fluid (CSF) to transport cholesterol from cells expressing the ABCA1 transporter and demonstrated significantly reduced ABCA1 mediated cholesterol efflux capacity in participants with mild cognitive impairment and AD compared to healthy controls. Our preliminary data reveal decreased cholesterol efflux capacity in cognitively healthy older ApoE ?4 carriers compared to non-carriers. We hypothesize that this functional capacity of CSF can serve as a biomarker providing unique information regarding pathophysiology of AD and identifying participants that could be benefit from ABCA1 agonist treatments. In this project, we propose to (1) determine the effect of the ApoE mimetic peptide ?CS-6253? on the capacity of CSF to efflux cholesterol and lipids out of ABCA1 expressing cells and ApoE lipidation ex vivo, (2) determine ABCA1 mediated cholesterol efflux capacity and ApoE lipidome composition of HDL from existing 107 CSF and serum samples obtained of cognitively healthy older participants, and (3) determine whether ABCA1 mediated cholesterol efflux capacity of CSF and serum HDL is associated with rapid memory decline after 4 years of longitudinal follow-up. This project will take advantage of the clinical research infrastructure and existing samples afforded to us by the USC Alzheimer?s Disease Research Center. Achieving our aim will identify ABCA1 mediated cholesterol efflux capacity as a novel biomarker in AD and a potential target for personalized AD interventions.

Public Health Relevance

Aging and ApoE e4 genotype are among the strongest risk factors for developing Alzheimer's disease. The goal of this project is to identify whether reduced ABCA1 mediated cholesterol transport functions of apoE proteins in cerebrospinal fluid of cognitively healthy older adults is associated with accelerated cognitive decline. This project will help identify a mechanistic biomarker for apoE personalized therapies in AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ETTN-E (55)R)
Program Officer
Hsiao, John
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University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Yassine, Hussein N; Braskie, Meredith N; Mack, Wendy J et al. (2017) Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ?4 Carriers: A Review. JAMA Neurol 74:339-347
Yassine, Hussein N (2017) Targeting prodromal Alzheimer's disease: too late for prevention? Lancet Neurol 16:946-947
Yassine, Hussein N; Schneider, Lon S (2017) Lessons from the Multidomain Alzheimer Preventive Trial. Lancet Neurol 16:585-586