# Regulatory variation that affects splicing of the Alzheimer's disease risk gene TREM2

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $759,146

## Abstract

Alzheimer's disease (AD), the most frequent cause of age-related dementia, constitutes a serious burden for
the US health system and economy. In the absence substantial preventative or disease-modifying treatments,
AD frequency is increasing as the lifespan increases. Age and genetic predisposition are the largest contributors
to AD risk. A substantial fraction of genetic variation in AD are noncoding variants that regulate gene expression,
but unlike changes in protein code, impact of regulatory variants is not easily predictable. Currently known genes
and risk alleles that change protein coding sequence explain at most 30% of AD susceptibility, emphasizing the
need to investigate variants that regulate gene expression and splicing. According to recent estimates, up to
50% of all variants associated with human diseases are variants that have some effect on gene splicing.
 Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific immune molecule whose
dysfunction causes a continuum of neurodegenerative conditions. Some missense TREM2 variants, exemplified
by R47H, are transmitted as autosomal dominant traits, conferring a significant late onset AD risk. The R47H
allele is one of the strongest known contributors to the risk, with effect size similar to the APOE e4 allele. On the
other hand, biallelic loss-of-function variants that inactivate the receptor cause recessive early onset dementia,
such as Nasu-Hakola disorder (NHD). TREM2 is subject to alternative splicing, which is species-specific, but the
extent and effect of this process has yet to be comprehensively characterized. We recently identified a novel
splice isoform of TREM2 (delta e2) with altered activities due to lack of an important protein domain. In
preliminary study, we found that multiple variants that cause NHD or increase risk for AD affect TREM2 splicing
and reduce the dosage of functional transcript via competition with the abnormally spliced delta e2 isoform. We
hypothesize that a precise balance of isoforms is important for TREM2 function and that cis-regulatory variants,
in combination with protein factors variably expressed in AD microglia, reduce gene dosage and increase AD
risk. The goal of this proposal is to comprehensively characterize the TREM2 transcript repertoire in human brain
in health and disease (Aim 1), assess TREM2 variants that are present in patients with dementia for their effect
on RNA splicing and post-splicing processing (Aim 2) and analyze the interplay between AD-associated cis-
regulatory TREM2 variants and trans-acting splicing factors that are perturbed in AD brain (Aim 3). To achieve
these goals, we will use state-of-the-art long-read RNA sequencing, computational variant effect predictions,
high-throughput combinatorial library screening, and unbiased quantitative proteomics approaches. This will
generate a cis-regulatory TREM2 map at the nucleotide resolution level that will be used to annotate the
regulatory potential of...

## Key facts

- **NIH application ID:** 10774052
- **Project number:** 1R01AG084684-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Olena Korvatska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $759,146
- **Award type:** 1
- **Project period:** 2024-09-30 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10774052

## Citation

> US National Institutes of Health, RePORTER application 10774052, Regulatory variation that affects splicing of the Alzheimer's disease risk gene TREM2 (1R01AG084684-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10774052. Licensed CC0.

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