# Investigating and targeting apolipoprotein E4 in Down syndrome-associated Alzheimer's disease

> **NIH NIH RF1** · UNIVERSITY OF COLORADO DENVER · 2023 · $2,282,487

## Abstract

PROJECT SUMMARY ABSTRACT
By the age of forty, every person with Down syndrome has Alzheimer's disease brain pathology, and most will
go on to develop Alzheimer's disease dementia, due to triplication of the amyloid precursor protein gene (APP)
that resides on chromosome 21. As the strongest genetic risk factor and greatest overall risk factor for
Alzheimer's disease in the typical population, other than increasing age itself, inheritance of the ε4 allele of the
apolipoprotein E gene (APOE) also significantly increases the risk and severity of Alzheimer's disease in people
with Down syndrome. We have found a key mechanism by which apoE promotes Alzheimer's disease: it binds
to the Aβ peptide and converts it into a toxic species that kills neurons and causes neurodegeneration, with the
apoE4 form being the most effective amyloid catalyst. In view of the essential contributions of apoE to
Alzheimer's disease, it is critical that the mechanisms underlying the enhanced Alzheimer's disease risk for
people with Down syndrome be elucidated and that new therapies be developed to effectively target its
pathogenic activity. We have developed an in vitro assay to screen the NIH Clinical Collection (NCC) small
molecule library for inhibitors of apoE4-catalyzed Aβ oligomer/fibril formation. We have identified eight hit
compounds, each of which has been tested previously in Phase I-III clinical trials for other indications and thus
have known safety profiles. In a secondary screen, we found that three out of the eight initial compounds were
non-neurotoxic inhibitors of apoE that significantly reduced Aβ and tau pathology and cell death in neurons from
two rodent models of Alzheimer's disease. Furthermore, an analysis of the National Alzheimer's Coordinating
Center (NACC) database showed use of either one of two drugs we identified as apoE inhibitors by Alzheimer's
patients was associated with improved cognition over time and increased odds of reverting to a better clinical
diagnosis from Alzheimer's disease to mild cognitive impairment (MCI) or from MCI to normal cognition, providing
translational support for their further study. Herein, we will use a panel of human induced pluripotent stem cell
(iPSC)-derived cerebral organoid (CO) models of Down syndrome and Alzheimer's disease to study the
mechanisms of apoE-induced Alzheimer's disease phenotypes and to evaluate whether our top candidate apoE
inhibitors can block the development of Alzheimer's disease phenotypes in Down syndrome. We will also develop
the first mouse model of Down syndrome expressing human APOE4 and assess the ability of our top candidate
apoE inhibitors to prevent the development of cognitive deficits, cerebrovascular damage, synaptic dysfunction,
neurodegeneration, and/or neuroinflammation in this novel model of Down syndrome-associated Alzheimer's
disease in order to inform future clinical trials. Our proposed approach should result in highly targeted Alzheimer's
disease therapies for peop...

## Key facts

- **NIH application ID:** 10658660
- **Project number:** 1RF1AG078965-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Noah Ray Johnson
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,282,487
- **Award type:** 1
- **Project period:** 2023-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10658660

## Citation

> US National Institutes of Health, RePORTER application 10658660, Investigating and targeting apolipoprotein E4 in Down syndrome-associated Alzheimer's disease (1RF1AG078965-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10658660. Licensed CC0.

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