PROJECT SUMMARY / ABSTRACT There has been considerable concern regarding the long-term effects of traumatic brain injury (TBI), largely driven by reports of neurodegenerative proteinopathies associated with participation in contact sports. In addition, increasing epidemiological data indicates that even a single moderate or severe TBI can increase the risk of dementia. While there has been a particular focus on the role of tauopathies following TBI, our group and others have demonstrated often complex and diverse neuropathologies with late survival post-injury in some individuals. However, the mechanisms driving these pathologies are poorly understood. In addition, to date there has been limited success in attempts to model both the neuropathological and clinical features of post-TBI neurodegeneration. As such, in order to permit mechanistic and translational studies of TBI-related neurodegeneration, there is a pressing need to develop preclinical models that recapitulate the complex pathologies and clinical phenotypes in the chronic phase post-injury. To address this critical knowledge gap, we propose an iterative design to develop novel gyrencephalic models of post-TBI ADRD. Three novel and distinct injury paradigms are proposed to represent repetitive mild exposures, as well as diffuse and focal TBI. We propose carefully considered biomechanical inputs relevant to real-world scenarios, with rigorous characterization of the nature and progression of neuropathological outcomes up to 1 year post-injury. The clinical relevance of pathologies will be determined via parallel and standardized comparisons with well-characterized human tissue samples from the CONNECT-TBI archive. Face validation will be determined through novel cognitive assessments, with additional validation attained via measurement of advanced neuroimaging and blood biomarker outcomes. Critically, reproducibility will be assessed at a second site. If successful, the development of a model with validated clinical relevance will provide a vital platform to study TBI-related neurodegeneration, including the assessment of novel diagnostics, and potential therapeutic interventions. Moreover, studying the evolution of pathology following the initiating injury may offer critical insights to the pathogenesis of TBI-related neurodegeneration.