# Biomarkers of ABCA1 mediated functions in Alzheimers disease

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $993,303

## Abstract

Carrying the ApoE ε4 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 ε4 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.

## Key facts

- **NIH application ID:** 9965709
- **Project number:** 5R01AG055770-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Hussein N Yassine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $993,303
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965709

## Citation

> US National Institutes of Health, RePORTER application 9965709, Biomarkers of ABCA1 mediated functions in Alzheimers disease (5R01AG055770-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9965709. Licensed CC0.

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