# Gut barrier function in Alzheimer’s disease

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $748,156

## Abstract

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 expected to lead to the development of novel therapeutic strategies for AD and
related deme...

## Key facts

- **NIH application ID:** 10350685
- **Project number:** 5R01AG070973-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Barbara Brigitta Bendlin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $748,156
- **Award type:** 5
- **Project period:** 2021-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10350685

## Citation

> US National Institutes of Health, RePORTER application 10350685, Gut barrier function in Alzheimer’s disease (5R01AG070973-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10350685. Licensed CC0.

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