# Individual Predoctoral Fellowship

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2023 · $35,361

## Abstract

ABSTRACT
Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid
beta (Aβ) plaques and intracellular neurofibrillary tau tangles (NFTs) which together contribute to
neuroinflammation, neurodegeneration, and often cognitive decline. Down syndrome (DS) is the result of having
three copies of chromosome 21 (T21) from conception. The Aβ peptide is a cleavage product of the amyloid
precursor protein (APP) which is encoded by the APP gene. Given that the APP gene resides on chromosome
21, all people with DS accumulate higher levels of Aβ peptide in their brains. Accordingly, adults with DS will
develop AD pathology (DS-AD), and many go on to develop clinical dementia. DS-AD has documented
pathological differences from typical AD, including accelerated Aβ and tau accumulation and a more
heterogeneous Aβ plaque composition. While there are numerous genetic and environmental contributors to AD
risk, the APOE gene, and especially the ε4 variant (APOE4), has been identified as the greatest risk factor for
typical AD besides age itself. Inheritance of APOE4 also significantly increases risk for AD and cognitive decline
in individuals with DS. Cohort studies in people with DS have found an overall increased AD risk conferred by
APOE4, but investigations of the mechanistic role of APOE4 in people with DS are lacking. Clearly, there is an
urgent need for studies interrogating the mechanism of increased risk of AD for people with DS carrying APOE4.
The overall goal of this proposal is to elucidate the role of the APOE4 genotype in the development of DS-AD
and assess the potential of apoE4-drive Aβ fibrilization as a therapeutic target. Specifically, I will identify APOE4-
driven mechanisms and pathways that contribute to the development of DS-AD neuropathologies and assess
the efficacy of small molecular inhibitors of apoE and/or Aβ in alleviating these pathologies. To accomplish these
goals, I will develop novel human induced pluripotent stem cell (hiPSC)-based models of DS-AD that carry
APOE4. I will generate multiple human neural cell types and cerebral organoids (COs) from the hiPSCs to
determine the specific effects of APOE4 in these models of the developing and aging human DS-AD brain. I will
evaluate six validated small molecule drugs that have been shown to prevent and/or reverse apoE4-catalyzed
Aβ fibrillization in my CO model system. My overall hypothesis is that APOE4 will accelerate and enhance
the development of AD neuropathologies in hiPSC-based models of DS-AD and can be targeted with
small molecule apoE inhibitors to alleviate those AD phenotypes.

## Key facts

- **NIH application ID:** 10752036
- **Project number:** 1F31AG084295-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Breanna Dooling
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $35,361
- **Award type:** 1
- **Project period:** 2024-02-02 → 2027-02-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752036

## Citation

> US National Institutes of Health, RePORTER application 10752036, Individual Predoctoral Fellowship (1F31AG084295-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10752036. Licensed CC0.

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