# Project 1 - Changes in Gut Microbiome and related Metabolome Across Trajectory of Alzheimer's Disease

> **NIH NIH U19** · DUKE UNIVERSITY · 2022 · $563,952

## Abstract

ABSTRACT – Project 1: Human Gut Microbiome, Metabolome and AD Phenotypes
Accumulating evidence characterizes Alzheimer’s disease (AD) as a metabolic disorder with several
biochemical perturbations identified. Genetic factors, gut bacteria, diet, lifestyle, and environmental exposures
all contribute to human metabolism and its dysregulation in disease states including AD. Many bioactive
metabolites, such as vitamins, short-chain fatty acids, and neurotransmitters (e.g., GABA, dopamine,
norepinephrine serotonin), are produced by the gut bacteria and thus can modulate brain function. Bidirectional
biochemical communication between the brain and the gut may contribute to neurodegenerative and
psychiatric diseases including depression and neurodegenerative diseases. Recently, a role for the gut
microbiome in the etiology of Parkinson’s disease was highlighted by Co-PI Mazmanian. Further, we show
distinct profiles in microbial metabolites in brains of AD patients, suggesting that changes to the human
microbiome alter the metabolic output of gut bacteria to send potentially disease-modifying chemicals into the
brain that may contribute to pathophysiology. In this proposal, we seek a deeper understanding of the role of
the gut microbiome in AD pathogenesis and use powerful metagenomics and metabolomics tools to define
biochemical axis of communication between the gut and brain. To implement this project we will build on large
initiatives and established infrastructures including: The American Gut Project and Human Microbiome Project
(led by Co-PI Knight), the AD Metabolomics Consortium (led by Co-PI Kaddurah-Daouk), AD Research
Centers (ADRCs), National Centralized Repository for AD and Related Dementias (NCRAD), The National
Alzheimer’s Coordinating Center (NACC), and centers of excellence in metabolomics, metagenomics,
informatics, machine and deep learning. In this proposal we seek to: 1) define compositional and functional
changes in the gut microbiome across stages of AD; 2) define metabolome differences in blood and feces
related to gut microbiome composition and function and link these to cognitive and brain imaging changes; and
3) connect blood and brain metabolomes to define biochemical and immune axes of gut-brain communication.
We will also explore the role of the gut microbiome in the development of neuropsychiatric symptoms (e.g.,
depressive phenotypes and sleep disturbances). The metabolic state of the brain in health and in disease
seems dependent on peripheral metabolic states with influences from gut metabolism. Hence, understanding
how peripheral and central metabolism is connected and linked to failures in AD is critical to the understanding
of disease pathogenesis and for development of new effective therapies to slow or prevent the disease.

## Key facts

- **NIH application ID:** 10475895
- **Project number:** 5U19AG063744-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Rima F Kaddurah-Daouk
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $563,952
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475895

## Citation

> US National Institutes of Health, RePORTER application 10475895, Project 1 - Changes in Gut Microbiome and related Metabolome Across Trajectory of Alzheimer's Disease (5U19AG063744-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10475895. Licensed CC0.

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