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.