# Genetic and environmental modifiers of pathology in amyotrophic lateral sclerosis

> **NIH VA I01** · EDITH NOURSE  ROGERS MEMORIAL VETERANS HOSPITAL · 2024 · —

## Abstract

Traumatic brain injury (TBI) may be a risk factor for the development of amyotrophic lateral sclerosis (ALS). US
military veterans have an increased frequency of ALS, and the veteran population has higher head injury
prevalence than the comparable civilian population. Repetitive head impacts (RHI) are a form of mild TBI that
can lead to severe cognitive and behavioral symptoms and the progressive neurodegeneration of chronic
traumatic encephalopathy (CTE). We have shown that ALS is a relatively frequent comorbidity in CTE (4) and
that CTE occurs in a veteran population with ALS. Furthermore, genomic variation in TMEM106B may play an
important role in both ALS and CTE disease progression. We hypothesize that TMEM106B is a modifier of
disease presentation and severity in ALS and that TBI and RHI alter the associations of TMEM106B with
pathology and clinical outcomes in CTE. Currently, there are no disease modifying treatments for ALS or CTE,
and little is known about genetic modifiers of disease phenotype in ALS or CTE. This is largely because there
has not been a systematic collection of participants with ALS, CTE, and both (ALS+CTE) until now. Our
translational approach is to systematically address neurodegeneration in the world’s largest
neuropathologically-confirmed autopsy cohort of ALS and CTE subjects on the DNA, RNA, and protein levels,
with the goal of identifying novel genetic risk factors, biomarkers, and mechanisms that can be targeted for
drug discovery. We have shown that compared with ALS in isolation, comorbid ALS+CTE is associated with a
history of TBI and has a distinct clinical and pathological presentation. Furthermore, we have demonstrated
that variation in TMEM106B is associated with microglia activation, tau pathology, and clinical symptoms in
CTE. Variation in TMEM106B is also related to altered clinical outcomes in ALS, the development of
frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), and to progranulin (PRGN) levels and
modulation of inflammatory pathways. Microglial activation is an early change in both ALS and CTE and may
alter disease progression. Our hypothesis, based on our preliminary data, is that variants of TMEM106B have
disease-specific associations with altered cytokines, pathology, and clinical disease progression in ALS and
CTE. We further hypothesize that TMEM106B variation is associated with altered gene expression networks
related to inflammatory pathways that predispose to worse pathological and clinical outcomes in ALS, CTE,
and ALS+CTE. Our long-term goal is to uncover genetic and molecular mechanisms underlying the
development of ALS and CTE in the setting of TBI. The immediate goal of this research project is to test the
hypothesis that the TMEM106B risk allele leads to altered inflammatory gene expression and to determine
TMEM106B-related disease modifying gene networks and neuroinflammatory markers that may serve as
biomarkers to identify those individuals at risk for developing...

## Key facts

- **NIH application ID:** 10720893
- **Project number:** 5I01BX005161-02
- **Recipient organization:** EDITH NOURSE  ROGERS MEMORIAL VETERANS HOSPITAL
- **Principal Investigator:** Thor Stein
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10720893

## Citation

> US National Institutes of Health, RePORTER application 10720893, Genetic and environmental modifiers of pathology in amyotrophic lateral sclerosis (5I01BX005161-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10720893. Licensed CC0.

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