# Vascular-associated neuroinflammation in Alzheimer's disease: differential effects on disease progression modulated by underlying amyloid burden

> **NIH NIH F32** · UNIVERSITY OF KENTUCKY · 2020 · $67,446

## Abstract

PROJECT SUMMARY
 Of the modifiable factors that collectively account for over half of Alzheimer’s disease (AD) cases, the
majority are vascular risk factors (VRFs). Given that the number of AD patients is expected to double by 2040,
this situation presents an important opportunity to reduce negative impacts on public health. Clearer
understanding of the precise temporal and mechanistic alterations linking VRFs to AD may enable development
of therapeutic approaches to sever that link. The overall goal of this proposal is therefore to elucidate potentially
targetable mechanisms underlying the connection between early vascular damage and subsequent AD
pathology. Vascular inflammation is one unifying feature of many VRFs, and this can induce or propagate
neuroinflammatory changes in the brain. Considering the established role of neuroinflammation in AD
pathogenesis, it may be clinically useful to target neuroinflammatory alterations secondary to vascular insult.
This proposal will therefore test the hypothesis that vascular risk factors contribute to AD primarily by increasing
neuroinflammatory responses and altering subsequent amyloid pathology. For these studies, I will use a well-
characterized amyloid beta (Ab) overexpression mouse model of AD (APPswe/PS1dE9) along with a dietary
hyperhomocysteinemia (HHcy) model to induce vascular damage and inflammation. In Aim 1, I will induce HHcy
in AD mice within a period corresponding to prodromal AD, and in Aim 2 within a period corresponding to early
AD. In both aims l will acutely treat the vascular-associated neuroinflammation in half of the animals. I will
characterize how vascular damage and associated neuroinflammation interact with underlying Ab pathology to
produce additive cognitive deficits at different stages of AD progression. In addition, both aims will include
clinically relevant neuroimaging measures to connect pathological alterations with detectable alterations in
cerebral blood flow (arterial spin labeling) and metabolic changes (magnetic resonance spectroscopy).
Successful completion of this project will provide clinically-relevant insight into the links between VRFs and AD.
Further, it will provide proof-of-concept of the utility of targeting neuroinflammation secondary to vascular
damage as a means of preventing or delaying future cognitive decline. Ideally, such an approach will someday
be incorporated into a comprehensive strategy of managing AD risk. A carefully designed career development
plan has also been formalized that includes participation in specialty workshops, regular presentation of data,
participation in scientific meetings and enhancement of non-technical science proficiencies. An experienced
mentoring group of senior scientists, in a well-established institution for AD research, ensure that I will have
optimal opportunity to grow into a successful independent investigator devoted to AD therapeutic development.

## Key facts

- **NIH application ID:** 9869825
- **Project number:** 5F32AG058456-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** David James Braun
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2018-02-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869825

## Citation

> US National Institutes of Health, RePORTER application 9869825, Vascular-associated neuroinflammation in Alzheimer's disease: differential effects on disease progression modulated by underlying amyloid burden (5F32AG058456-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9869825. Licensed CC0.

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