# ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia

> **NIH NIH K08** · WASHINGTON UNIVERSITY · 2020 · $168,585

## Abstract

7. Project Summary/Abstract
The goal of this mentored career development award is to facilitate the candidate's transition to independence
as a physician-scientist studying molecular mechanisms of neurodegeneration. The candidate is an MD/PhD
neurologist with a background in neurodegenerative disease research. The award will help the candidate
achieve his short-term goal, to gain research experience in the molecular pathogenesis of Parkinson disease
and dementia and facilitate his transition to an investigator with an independent laboratory. The award will also
help position the candidate to achieve his long-term goal of becoming a successful and productive physician-
scientist and a leader in academic neurology. The environment in which the proposed research will be
conducted is outstanding. The candidate's primary mentor, Dr. David Holtzman, is an internationally respected
scientist and neurologist with a proven track record of excellence in training junior faculty. The candidate's
career development plan also includes structured mentorship from multiple physician-scientists at all stages of
seniority and exposure to a rich and supportive faculty, ensuring that the candidate has role models along the
full spectrum of the career trajectory. Didactic learning, presentation of work at scientific meetings, and
rigorous training in the responsible conduct of research will ensure a balanced development. The proposed
research will examine the role of apolipoprotein E (apoE) in regulating the aggregation and pathological
spread of alpha synuclein (αSyn), a protein implicated in Parkinson disease (PD), Parkinson disease dementia
(PDD), and dementia with Lewy bodies (DLB). The aggregation of αSyn from its native monomer form into
oligomers is thought to be toxic and to contribute to neuronal dysfunction. This process is regulated by other
proteins including chaperone proteins. Several genetic studies point to the APOE ε4 allele, the strongest
genetic risk factor for Alzheimer disease, as a risk factor for developing dementia in PD as well. APOE is and
is known to regulate amyloid-beta (Aβ) pathology and individuals with PD often have comorbid αSyn and Aβ
pathology, but importantly, the risk effect of APOE in PDD and DLB appears to be independent of Aβ
pathology. The goal of this project is to test the hypothesis that apoE isoforms differentially regulate αSyn
aggregation by stabilizing a harmful oligomeric intermediate. A secondary hypothesis is that apoE regulates
the propagation of pathologic conformations of αSyn from cell to cell in vivo. The proposed experiments are
designed to elucidate a potential novel relationship between apoE and αSyn, with the ultimate goal of
identifying therapeutic targets that can be leveraged to treat diseases caused by pathologic aggregation of
αSyn. This career development award is an ideal mechanism to provide the candidate with valuable research
training which will complement his clinical focus in movement disorders an...

## Key facts

- **NIH application ID:** 10006865
- **Project number:** 5K08NS101118-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Albert A Davis
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,585
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006865

## Citation

> US National Institutes of Health, RePORTER application 10006865, ApoE Regulation of Alpha-Synuclein Pathology in Parkinson Disease Dementia (5K08NS101118-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006865. Licensed CC0.

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