# Exploring the role of Imidazole Propionate on Alzheimer’s Disease and Related Dementias

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $223,260

## Abstract

Project Summary:
Alzheimer's Disease (AD) and AD Related Dementias (ADRD) continue to present serious challenges in the aging
population and there is a significant need to identify and reduce risk factors. A well-recognized and promising
approach to reducing AD/ADRD comprises reduction of vascular injury often found to occur concomitantly with AD
pathology. Less appreciated facets of this disease include large systemic changes in physiology, including
alterations in the gut microbiome that occur with age and disease. Recent studies from our group and others
suggest that gut microbes play a key role in shaping vascular biology and AD pathology. Gut microbes influence
the host in part through production of metabolites that act on specific receptors expressed in distant organs,
impacting multiple cellular signaling cascades, including inflammation, thrombosis, and cellular senescence. Our
research group has recently identified associations between plasma levels of the gut microbiome-derived
metabolite imidazole propionate (ImP) and increased cerebrospinal fluid levels of neurofilament light chain (NfL),
a biomarker of neurodegeneration. Increased ImP was also detected at higher levels in individuals with accelerated
decline in performance on tests of executive function. Furthermore, we discovered that ImP impairs endothelial
cell function and disrupts the integrity of the blood-brain barrier (BBB). Validating these associations and
establishing causal and mechanistic links with AD-pathology will have significant translational impact as there is a
toolkit at our disposal to change the gut microbiome, including dietary changes, fecal transplants, and small
molecule inhibitors targeting the bacterial ImP production pathway, which is not present in the host. The central
hypothesis of this proposal is that ImP modulates AD and ADRD progression by altering vascular
endothelial function and BBB permeability. To test this hypothesis, we will characterize the relationship
between ImP, BBB disruption, and AD pathology in conventional and gnotobiotic mouse models of disease. We
will also leverage existing samples and data collected among participants in the Wisconsin Alzheimer’s Disease
Research Center to determine the extent to which ImP is associated with fluid AD biomarkers and vascular injury
as measured by MRI. The examination of the microbiome as a critical component that shapes AD/ADRD pathology
through its effects on vascular function represents a novel perspective that we are uniquely positioned to examine.

## Key facts

- **NIH application ID:** 10984658
- **Project number:** 1R21AG089348-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Barbara Brigitta Bendlin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $223,260
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984658

## Citation

> US National Institutes of Health, RePORTER application 10984658, Exploring the role of Imidazole Propionate on Alzheimer’s Disease and Related Dementias (1R21AG089348-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10984658. Licensed CC0.

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