# The neuropathology of mild traumatic brain injury in Alzheimer disease

> **NIH VA I01** · EDITH NOURSE  ROGERS MEMORIAL VETERANS HOSPITAL · 2020 · —

## Abstract

Repetitive head impacts (RHI) lead to severe cognitive and behavioral symptoms and the progressive
neurodegeneration of chronic traumatic encephalopathy (CTE). Trauma is also a known risk factor for
Alzheimer disease (AD) and we hypothesize that a prolonged period of RHI can play a causative role in the
development of AD as well as CTE. Currently, there are no disease modifying treatments for CTE or AD, and
diagnosis of CTE can only be made at autopsy. Furthermore, little is known about the genetic and molecular
changes in CTE or in AD in the setting of RHI exposure. This is largely because there has not been a
systematic collection of more than a handful of cases of CTE, until now. Our translational approach is to
systematically address neurodegeneration in the world's largest neuropathologically-confirmed autopsy cohort
of CTE and CTE with AD (CTE-AD) 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 in CTE subjects beta-amyloid deposition is accelerated, related to areas where mechanical
stresses are greatest, and influenced by APOE allele status. Furthermore, genomic variation can play an
important role in disease progression, and stratification based on APOE allele ε4 status uncovers additional
risk alleles and predicts altered pathologies based on the underlying genetics. Our preliminary data shows that
variation in TMEM106B is associated with microglia activation, tau pathology, and clinical symptoms in CTE in
APOE ε4-negative subjects. Variation in TMEM106B is related to the development of FTLD-TDP and to
progranulin (PRGN) levels and modulation of inflammatory pathways. Many other genes implicated in AD
genetic risk are also involved in the brain's inflammatory response/immune system. We have shown that
microglial activation is an early change in CTE and have demonstrated that altered neuroinflammatory
cytokines are related to the development of tau pathologies disparately in CTE versus AD. Our hypothesis,
based on our preliminary data, is that variants of APOE and TMEM106B are enriched in CTE and CTE-AD
subjects and are associated with altered cytokines and increased levels of beta-amyloid and tau and
progression of disease. We further hypothesize that genomic variation in known AD genes will predict risk or
progression of CTE and CTE-AD following RHI exposure and that levels of beta-amyloid, tau, and
neuroinflammatory cytokines may serve as biomarkers for trauma-induced neurodegenerations. Our long-term
goal is to uncover genetic and molecular mechanisms underlying the development of AD in the setting of
multiple mild traumatic brain injuries. The immediate goal of this research project is to discover differences in
genomic variation and neuroinflammatory markers that may serve as biomarkers to identify those individuals at
risk for developing AD in the setting of trauma. This research will be crit...

## Key facts

- **NIH application ID:** 9813951
- **Project number:** 5I01CX001038-06
- **Recipient organization:** EDITH NOURSE  ROGERS MEMORIAL VETERANS HOSPITAL
- **Principal Investigator:** Thor Stein
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9813951

## Citation

> US National Institutes of Health, RePORTER application 9813951, The neuropathology of mild traumatic brain injury in Alzheimer disease (5I01CX001038-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9813951. Licensed CC0.

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