# High-Content Screen to Identify Small Molecule Therapeutics that Reduce Aberrant Lipid Accumulation in APOE4 Alzheimer's Disease

> **NIH NIH R41** · MCM6 THERAPEUTICS, INC. · 2024 · $473,216

## Abstract

Project Summary: Genome-wide association studies demonstrate that the top genes associated with
increased risk for Alzheimer’s disease (AD) are involved in cholesterol and lipid metabolism, inferring
lipid dysregulation is pathological. In particular, APOE4 is the strongest genetic risk for late-onset AD.
Individuals of European ancestry carrying two copies of the APOE4 allele have a sixteen-fold increase in AD risk
compared to a similar individual carrying two copies of the APOE3 allele. APOE is the primary cholesterol and
lipid transporter in the brain. Studies using induced pluripotent stem cells (iPSC) show that APOE4 alters
cholesterol and lipid homeostasis across multiple cell types; however, its effects are especially pronounced in
oligodendrocytes—myelinating cells that insulate and protect neurons. Histological and lipidomic profiling of
human post-mortem brains and animal models shows impaired cholesterol transport and vast lipid deposits in
APOE4-expressing oligodendrocytes. This aberrant accumulation of lipids impairs myelination, impedes amyloid
plaque clearance, and increases neuroinflammation. Despite the central role of APOE4 and lipid metabolism
in AD, no therapeutics target APOE4 or aberrant lipid accumulation. MCM6 Therapeutics’ Chief Science
Advisor, Dr. Joel Blanchard, an Associate Professor of Neuroscience at the Icahn School of Medicine at Mt.
Sinai, has developed a drug discovery pipeline that models APOE4 lipid accumulation in human
oligodendrocytes. In a small proof-of-concept screen, we discovered two mechanistically distinct drugs,
rosiglitazone and cyclodextrin, both reduce lipid deposits in APOE4 oligodendrocytes. This reduction in
intracellular lipid accumulation restored myelination in an in vitro neuron co-culture assay and improved learning
and memory in APOE4 transgenic mice. We will further optimize and apply this high-content screening
pipeline to identify therapeutics that reduce aberrant cholesterol and lipid accumulation in human
APOE4 oligodendrocytes. Aim 1, we will adapt our screening assay to 384-well plates, and perform a targeted
screen of ~2,500 lipid modifying compounds. Our high-content image analysis platform will be conducted in
collaboration with PhenoVista. We expect the focused screening approach in Aim 1 will generate early leads and
targets that we will validate and expand on with structure-activity-relationship studies. Aim 2 we will perform a
large unbiased screen of 30,000 compounds. Hits from Aims 1 and 2 will be validated via dose titration, and
identity will be confirmed by re-ordering and MS analysis. We will perform off-target analysis, functional validation
(in vitro myelination), and neurotoxicity assays in iPSC-derived human brain tissue. Through rigorous in vitro
validation of efficacy, selectivity, and neurotoxicity, we will select 3-10 lead compounds for future evaluation in
our established APOE4 humanized mouse models through extensive histological and behavioral assays,
deliv...

## Key facts

- **NIH application ID:** 11067722
- **Project number:** 1R41AG087802-01A1
- **Recipient organization:** MCM6 THERAPEUTICS, INC.
- **Principal Investigator:** Kelvin T Lam
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $473,216
- **Award type:** 1
- **Project period:** 2024-09-25 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11067722

## Citation

> US National Institutes of Health, RePORTER application 11067722, High-Content Screen to Identify Small Molecule Therapeutics that Reduce Aberrant Lipid Accumulation in APOE4 Alzheimer's Disease (1R41AG087802-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11067722. Licensed CC0.

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