# Nonlipogenic ABCA1 inducers for ADRD - Supplement

> **NIH NIH U01** · UNIVERSITY OF ARIZONA · 2023 · $373,042

## Abstract

Alzheimer’s disease and related dementia (ADRD) constitutes a growing health crisis. Equally, chronic metabolic
diseases such as type 2 diabetes (T2D) are increasing, because of the prevalence of obesity and other risk
factors. T2D is a risk factor for ADRD and both T2D and ADRD share common causal mechanisms: insulin
resistance; impaired glucose metabolism; inflammation; dyslipidemia; and impaired cholesterol mobilization. The
APOE4 allele is the greatest genetic risk factor for AD. ApoE4 is poorly lipidated and lipidation of apoE, required
for stability and positive function, is controlled by the ATP-binding cassette transporter ABCA1. Deletion of
ABCA1 in familial AD (FAD) mouse models exacerbates pathology and behavioral deficits; and rare human loss-
of-function mutations in ABCA1 increase ADRD risk. ABCA1 is a gene product of liver X receptor (LXR);
however, induction of lipogenesis in the liver (steatosis and triglyceride elevation) by LXR agonists has hindered
progress. A nonlipogenic ABCA1-inducer (NLAI) would address multiple causal factors in T2D and ADRD,
including APOE4 risk in AD. We have optimized a phenotypic drug discovery strategy for NLAIs, yielding hit
series that enhanced cholesterol mobilization, attenuated inflammation, and improved biomarkers of glucose
metabolism. One hit and an early lead derived from it (CL2-57), increased ABCA1 and APOE, without
upregulating lipogenic genes. CL2-57 administered orally in the high-fat diet (HFD) model of obesogenic T2D,
attenuated insulin resistance, reduced weight gain, and from full metabolomic analysis improved biomarkers and
lipid profiles. The goal of the parent U01 is to optimize NLAIs using phenotypic and other assays validated in
development of CL2-57. In silico and in vitro predictors of oral/brain bioavailability and SAR will guide
optimization. Oral and brain bioavailability are criteria for progression in Year 2 and in Year 4 study of a lead
candidate is planned in animal models of AD: A) in 5xFAD mice (Aβ, cognition, and disease-associated microglia)
and B) in HFD-treated mice (WT, hAPOE3-KI, and hAPOE4-KI) to identify APOE genotype specific interactions
with HFD and NLAI treatment. CL3-3 was developed from CL2-57 with improved potency for ABCA1 induction
and cholesterol mobilization. Although CL3-3 does not meet brain bioavailability criteria for progression, it was
tested in a pilot study in E3/4FAD mice (5xFAD mice crossed with hAPOE3/hAPOE4-TR mice in the lab of the
late Mary Jo Ladu) demonstrating improvement of AD biomarkers and increased brain ABCA1 without peripheral
lipogenesis. The proposed supplement will support rigorous exploration of CL3-3 in 5xFAD and hAPOE-KI mice
to define the interactions of this NLAI with FAD pathogenesis and hAPOE. This work would accelerate progress
towards a an NLAI drug candidate.

## Key facts

- **NIH application ID:** 10832305
- **Project number:** 3U01AG076450-02S1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Gregory R. J Thatcher
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $373,042
- **Award type:** 3
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832305

## Citation

> US National Institutes of Health, RePORTER application 10832305, Nonlipogenic ABCA1 inducers for ADRD - Supplement (3U01AG076450-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10832305. Licensed CC0.

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