# Exploring mechanisms driving microbe-induced AD risk using next generation sequence data.

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $319,499

## Abstract

Multiple lines of evidence suggest microbial infections are risk factors for Alzheimer’s disease (AD). Amyloid-β
(Aβ) peptides possess antimicrobial activity and may protect against human herpes viruses (HHV). Viral DNA
is also detectable in Aβ plaques, and HHV DNA detected in next generation sequencing (NGS) experiments is
associated with AD risk. Although neuroinflammation is the mechanism assumed to drive this association,
several questions remain. Foremost, it is unclear whether infections precede AD or are the result of an aging
immune system or AD pathology itself. The specific aspects of AD pathology that are affected by infections are
also unknown, as is the role of the host genome in mediating risk. The objective of this project is to answer
these questions by leveraging large AD cohorts with NGS data derived from blood and brain samples to detect
the presence of microbial DNA. Microbial DNA can be detected and quantified in human NGS experiments by
aligning reads that do not map to the human genome to microbial reference genomes, and depending on the
species identified, may be evidence of either an active or latent infection. Any microbe for which a reference
genome is available can be detected. The cohorts include the Alzheimer’s Disease Sequencing Project
(ADSP), the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Framingham Heart Study (FHS),
Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD), and Gwangju Alzheimer's & Related
Dementias project (GARD). The long-term goal of this project is to provide evidence that interventions targeting
microbial infections could prevent AD or slow its progression. Our central hypothesis is that infections increase
AD risk and cause observable changes to specific facets of AD pathology. We also hypothesize that variants in
the human genome mediate these processes. We will test these hypotheses through the following specific
aims. In Aim1, we will develop a pipeline to accurately quantify and match DNA fragments generated by next
generation sequencing to microbial DNA sequences, including inserted viral DNA. In Aim2, we will leverage
longitudinally followed cohorts with multi-omics data to establish a temporal relationship between infection and
AD, and test for associations between microbial DNA and AD-related traits, including biomarkers, structural
brain changes measured by magnetic resonance imaging, neuropathological traits, disease progression, brain
cell type sub-fractions, and cognitive function. In Aim3, we explore the role of the host genome in mediating
microbe induced AD pathology, including testing for associations between SNPs and microbes, and for
interactions between known AD risk variants/HLA serotypes and microbial DNA to predict AD. This project is
significant because it could provide evidence that preventing or treating infections could treat or prevent AD.
The project is innovative because it will be the first to leverage very large AD NGS cohorts, in many of ...

## Key facts

- **NIH application ID:** 10491895
- **Project number:** 5R01AG076002-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Richard Sherva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $319,499
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10491895

## Citation

> US National Institutes of Health, RePORTER application 10491895, Exploring mechanisms driving microbe-induced AD risk using next generation sequence data. (5R01AG076002-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10491895. Licensed CC0.

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