# The intersection of GLP-1, gut microbiota, and brain connectivity in prodromal Alzheimer’s disease

> **NIH NIH R21** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $396,000

## Abstract

Project Summary:
Early identification of Alzheimer's disease (AD) is essential for preventing or delaying disease onset. There is
currently no effective treatment for AD, which may be attributable to multiple underlying causes. Mounting
evidence supports the notion that AD is, in part, a metabolic condition with an array of metabolic perturbations
early in the disease, even at the prototypical prodromal stage, i.e. amnestic mild cognitive impairment (aMCI).
Animal models indicate that gut- and neuropeptide Glucagon like peptide-1 (GLP-1) is a promising link within
the gut-brain axis of AD, although this peripheral-central pathway has yet to be defined in AD. We propose a
novel gut-GLP-1 interactome of prodromal AD. We hypothesize that gut specific bacterial strains will influence
GLP-1 levels and produce small metabolites that influence brain connectivity patterns in patients with aMCI.
We will test this scientific premise in two Specific Aims. In Aim 1, we will determine the relationship between
GLP-1 levels and default mode network (DMN) connectivity patterns in aMCI compared to age-matched control
cohorts. We will apply rigorous methodological design to measure pre- and post- meal testing GLP-1 levels
and assess DMN connectivity patterns using a cutting-edge functional MRI method. In Aim 2, we seek to
determine bacterial strains and metabolites associated with DMN connectivity patterns in aMCI and control
groups. We will conduct metagenomic sequencing on stool samples collected at similar times from the same
individuals assessed in Aim1. We will identify bacterial genes with potential to impact GLP-1 levels. Metabolic
markers will be correlated with DMN connectivity patterns. Together, these Aims will elucidate bacterial
metabolic biomarkers in a prodromal AD disease state that can negatively affect GLP-1 levels or activity to
affect brain functioning. We will use the data collected here to initiate a longitudinal study to follow the
progression of metabolic and neuroimaging data along with known AD pathologic biomarkers such as beta-
amyloid and tau. Our goal is to determine the specific bacterial strains and their metabolic properties that drive
the transition from normal cognitive aging to aMCI to AD.

## Key facts

- **NIH application ID:** 10352498
- **Project number:** 1R21AG075501-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** JOHN R KIRBY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $396,000
- **Award type:** 1
- **Project period:** 2022-01-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352498

## Citation

> US National Institutes of Health, RePORTER application 10352498, The intersection of GLP-1, gut microbiota, and brain connectivity in prodromal Alzheimer’s disease (1R21AG075501-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10352498. Licensed CC0.

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