# Gut barrier function in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $249,997

## Abstract

SUMMARY______________________________________________________________________________
The age-related processes that contribute to Alzheimer's disease (AD) development, particularly in the prodromal
period, are incompletely understood. Age-related reduction in gut microbiome alpha-diversity is apparent in the
majority of older adults, and is suspected of contributing to brain changes, including the development of
neurodegenerative disease. Our team published the first comprehensive report describing differences in the gut
microbiome observed in AD dementia, including reduced diversity in gut microbiota and altered composition in
people with AD dementia compared to age-matched controls. Furthermore, we found that differentially abundant
genera were associated with cerebrospinal fluid biomarkers of AD, even among individuals who were cognitively
unimpaired. Several studies in mouse models of AD indicate that gut microbiota play a role in the development
of AD neuropathology, however to date, the mechanisms underlying these effects are virtually unknown.
Recently it has also become clear that the innate immune response in AD plays a critical role in mediating the
pathology associated with AD; however the interplay between systemic changes and the innate immune
response in AD are not well understood, nor is it known how these factors impact the progression of AD
pathology. Our overarching goal is to determine the extent to which alterations in the composition of gut
microbiome exacerbate and/or accelerate the development of AD pathology. This proposal is based on the
central hypothesis that age-associated gut dysbiosis and inflammation weaken gut barrier function, which in turn
leads to the systemic dissemination of microbial components, driving an immune response and system wide
changes that worsen AD pathology. To test this hypothesis we propose to study well-characterized participants
enrolled in the Wisconsin Alzheimer's Disease Research Center as well as conventional and gnotobiotic APPPS1
mice, to address the following specific aims: 1. Determine the longitudinal relationship between gut microbiome
(metagenome), gut inflammation and permeability, and the development of AD pathology in human participants,
and 2. Determine the effects of modifying gut permeability on AD pathology in mice. We expect that alterations
in gut microbiome composition and gut permeability exacerbate AD pathology in humans, and that impairment
of intestinal barrier function and increased gut permeability alters brain homeostasis and exacerbates AD
progression in mouse models of AD. Our research group has been working to determine the role of gut
microbiome in the development of AD pathology for the past 5 years, and we are perfectly poised to address the
proposed aims. We will leverage our expertise in clinical AD, neuroimmunology, and gut microbiology/gnotobiotic
mouse models to successfully carry out the proposed project. Completion of the proposed experiments is
expec...

## Key facts

- **NIH application ID:** 11082892
- **Project number:** 3R01AG070973-04S1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Barbara Brigitta Bendlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,997
- **Award type:** 3
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11082892

## Citation

> US National Institutes of Health, RePORTER application 11082892, Gut barrier function in Alzheimer's Disease (3R01AG070973-04S1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/11082892. Licensed CC0.

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