# Defining the Mechanisms by Which MS4A Genes Regulate TREM2 in Alzheimer Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $629,791

## Abstract

Project Description
The complex molecular events that underlie the development of Alzheimer's disease (AD) are poorly
understood and are the key to developing targeted therapies. Our group and others have shown that rare
variants in the triggering receptor expressed on myeloid cells 2 gene (TREM2) are associated with increased
susceptibility to AD. TREM2 encodes a membrane protein that is part of a receptor-signaling complex that
modulates inflammatory responses, phagocytosis and cell survival in myeloid cells, such as microglia.
However, the specific role of TREM2 in AD pathogenesis remains unclear. CSF sTREM2 levels are increased
in patients with symptomatic AD compared to cognitively normal controls. We have recently discovered that
common variants in the MS4A locus are a major regulator of CSF sTREM2 levels. Importantly, the same allele
associated with higher CSF sTREM2 levels is associated lower AD risk and delayed age at onset. We also
identified a second, independent signal in the MS4A locus that encodes MS4A4A p.M159V, which has the
opposite effect on CSF sTREM2 levels and AD risk. Our findings that two independent signals in the MS4A
gene region have opposing effects on CSF sTREM2 levels and AD risk points to the connection between
MS4A and TREM2 biology in AD pathogenesis. The goal of this project is to elucidate the mechanisms by
which MS4A genes alter TREM2 function and drive AD pathogenesis. We hypothesize that MS4A4A is
involved in TREM2 trafficking and cleavage and that disrupted interaction between MS4A4A and TREM2 leads
to microglial dysfunction and neurodegeneration. To test this hypothesis, we will use genomic and biochemical
approaches in human brains and stem cell models. The results of this project will provide the mechanistic
framework needed to develop treatments that restore or enhance TREM2 functions in order to prevent
neurodegenerative disease.

## Key facts

- **NIH application ID:** 9999997
- **Project number:** 5R01AG062734-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Celeste Marie Karch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $629,791
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999997

## Citation

> US National Institutes of Health, RePORTER application 9999997, Defining the Mechanisms by Which MS4A Genes Regulate TREM2 in Alzheimer Disease (5R01AG062734-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999997. Licensed CC0.

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