# Investigating the strain-specific role of Bacteroides in the etiology of Alzheimer's disease

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $434,860

## Abstract

PROJECT SUMMARY
While an infectious etiology has been proposed to be involved in the initiation and progression of Alzheimer’s
disease (AD), more evidence is needed to support the roles of specific infectious agents and to identify
mechanisms by which they act. Given the chronic nature of AD and based on our discoveries in animal models
of AD, we hypothesize that a chronic and sub-acute infection with specific Bacteroides strains contributes to AD
by affecting Ab and tau phosphorylation, aggregation, and clearance, and contributing to neuronal toxicity. In
support of our hypothesis, we were the first group to demonstrate that Bacteroides not only correlated with Ab
levels in the brain, but actually increased amyloid plaques when administered to animal models of AD. Strikingly,
Bacteroides is elevated in AD, correlates with CSF levels of Ab42 and phospho-tau, and is associated with
markers of gut inflammation in AD patients, suggesting a direct relevance to human disease. In our preliminary
data, we found that B. fragilis affected cortical expression of genes involved in APP and tau phosphorylation that
promote their aggregation, as well as genes related to memory and neuronal death. We also found that
Bacteroides downregulated microglial genes important for the clearance of Ab. Depletion of Bacteroides with
metronidazole decreased amyloid plaques, increased cortical expression of insulin degrading enzyme, which
can degrade Ab, and affected genes involved in multiple protein degradation pathways. We found that
Bacteroides could impair macrophage Ab phagocytosis in vitro and in vivo. Importantly, we found that transfer
of human gut microbiota from AD patients into mice affected similar microglia genes involved in protein
degradation and clearance, as well as pathways related to neuronal cell death, suggesting that the AD gut
microbiota may harbor infectious agents that contribute to the disease process. Because Bacteroides species
are highly prevalent in humans and exhibit a high degree of functional variation among strains, it is not likely that
all Bacteroides contribute to AD. In this proposal, we will modify Koch’s postulates to detect Bacteroides strains
associated with AD vs. healthy controls and non-AD dementia controls, isolate these strains in pure culture, and
use in vitro assays to optimize strain selection for in vivo studies. We will then transfer AD-derived strains to WT
mice and animal models of AD, measure AD pathology, and re-isolate our AD-derived strains to determine
whether they play a causal role. To investigate potential mechanisms, we will also investigate whether AD strains
can affect APP and tau aggregation and clearance, neuronal toxicity, or disrupt transcriptional networks in
microglia and neurons. By investigating the molecular and functional diversity in Bacteroides in AD, our studies
have the potential to identify novel pathogenicity factors in Bacteroides that could be used both for the diagnosis
and treatment of AD.

## Key facts

- **NIH application ID:** 10492004
- **Project number:** 5R01AG076008-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Laura Michelle Cox
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $434,860
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10492004

## Citation

> US National Institutes of Health, RePORTER application 10492004, Investigating the strain-specific role of Bacteroides in the etiology of Alzheimer's disease (5R01AG076008-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10492004. Licensed CC0.

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