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...