# Testosterone and APOE genotype interactions following mild traumatic brain injury

> **NIH VA I01** · DURHAM VA MEDICAL CENTER · 2020 · —

## Abstract

Nearly 20% of US troops deployed in Iraq and Afghanistan conflicts are estimated to
have suffered probable traumatic brain injury (TBI). Among survivors, the loss of circulating
levels of testosterone (hypogonadism) is one of the most frequently reported deficits, and the
long-term effects may dramatically increase the risk of multiple symptoms including PTSD,
depression, anxiety, and cognitive loss. The 4 allele of apolipoprotein E is the strongest risk
factor for developing Alzheimer’s disease and is also associated with a more severe outcome
following TBI. Importantly, individuals who carry APOE4 are 10X more likely to develop AD
compared to those without the allele. Given that both TBI and testosterone loss adversely
impact neurophysiology, the purpose of this study is to test the hypothesis that APOE genotype
and testosterone interact to increase the risk of brain injury and that hormone replacement may
significantly improve outcome. We have developed a closed-head model of mild traumatic brain
injury that simulates acceleration-deceleration of the head during a collision and produces
immediate loss of consciousness, temporary motor deficits, and deficits in both spatial and non-
spatial learning that persist for at least 1-3 months following injury. These cognitive deficits are
genotype and testosterone level dependent at this time point. For this study, we will use human
APOE targeted replacement mice, a mouse model that expresses human apoE proteins under
endogenous control of the mouse promoter, to assess the effects of APOE genotype in the
presence and absence of testosterone loss on outcomes following mild repetitive traumatic
brain injury. Specifically, following repeated mild TBI, we will examine the relationship of APOE
genotype and testosterone loss on 1) cognitive and behavioral function, as well as 2) synaptic
structure and function. Finally we will investigate whether testosterone mediates brain function
via inflammatory pathways in an APOE-dependent manner following TBI. Outcomes will be
measured 3 and 15 months post-injury in sham and post-TBI gonadectomized mice in order to
examine chronic effects during adulthood and the aging process. We will also assess the effects
of hormone replacement on behavioral and physiological outcomes. As there are currently no
effective treatments that improve outcome following TBI, hormone replacement may provide a
potential therapeutic option to attenuate the onset of mental and cognitive disorders that result
from hypogonadism, especially in veterans who are genetically at risk. By studying TBI,
testosterone, and APOE in conjunction, we can investigate the possibility of personalizing
treatments to patients based on their genetic profile, with the goal of minimizing risks and
maximizing benefits.

## Key facts

- **NIH application ID:** 9989866
- **Project number:** 5I01RX002335-04
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** Rebecca C. Klein
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989866

## Citation

> US National Institutes of Health, RePORTER application 9989866, Testosterone and APOE genotype interactions following mild traumatic brain injury (5I01RX002335-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9989866. Licensed CC0.

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