Traumatic brain injury (TBI) accounts for ~2.5 million emergency visits in the US each year and is a major public health concern. Individuals who experience TBI are at increased risk for Alzheimer’s disease (AD) and AD-related dementias (ADRD). Millions of individuals who play contact sports or serve in the military are exposed to repetitive head impacts (RHI) and are at increased risk for chronic traumatic encephalopathy (CTE). Our studies show that the neuropathological substrate of trauma-related dementia is heterogeneous with varying degrees of beta-amyloid, phosphorylated tau, pTDP-43, and alpha-synuclein deposition, atrophy, vascular changes, axonal and myelin loss, astrocytosis, and neuroinflammation. The type, frequency, severity, and timing of TBI and other genetic and non-genetic factors influence long-term outcomes. RHI and TBI have not been sufficiently studied in neurodegenerative brain banks, consequently, RHI and TBI prevalence, their unique contribution to AD, ADRD, CTE, and other pathologies, and their resulting clinical syndromes are not well understood. In addition, scientific research on the adverse effects of RHI and TBI exerts a tremendous effect on the public, including family decisions regarding brain donation and participation in contact sports. To address this major public health concern, this U01 will answer the following critical needs: to determine the relationship of RHI and TBI to AD, ADRD, CTE, and other pathologies, to identify the neuropathological phenotype of post-traumatic neurodegeneration, to establish the prevalence of post-traumatic neurodegeneration and CTE, to define the relationship of RHI and TBI to cognitive decline, neuropsychiatric symptoms, and parkinsonism, and to learn the impact of this scientific research on donor caregiver and families regarding the brain donation process, receipt of diagnosis, and decisions about contact sport participation. This U01 will leverage the infrastructure of our successful Traumatic Brain Injury and Repetitive Head Impacts: Contributions to AD, ADRD and CTE Neuropathology and Resulting Clinical Syndromes (McKee PI: U54NS115266) and Understanding Neurological Injury and Traumatic Encephalopathy (UNITE) studies (U01NS086659, R01AG057902). We have harmonized 6 novel brain banks and amassed 3109 well-characterized brains including (1120 (36%) exposed to RHI/TBI) - the largest collection of its kind in the world. The overarching hypotheses are: RHI and TBI will have distinct associations with AD, ADRD, CTE, and other pathologies; these effects will be modified by genetic (APOE ε4, TMEM106b, MAPT) and non-genetic (age, cardiovascular disease, social determinants of health (SDOH)); these pathologies will have direct associations with cognitive, neuropsychiatric, functional, motor and structural MRI outcomes (T1, FLAIR); and this research will impact donor caregiver and family decisions regarding brain donation and contact sport participation. Through this U01 proposal, we...