Traumatic brain injury (TBI) is recognized as a modifiable risk factor for neurodegenerative diseases, including Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). As such, there has been an explosion of interest in the link between TBI and the development of late neurodegenerative pathologies, particularly chronic traumatic encephalopathy neuropathologic change (CTE-NC). However, the intense focus on CTE-NC has come at the expense of investigation of the broader spectrum of pathologies found after all forms of TBI. Accordingly, we have adopted the conceptual framework, “TBI-related neurodegeneration” (TReND), of which CTE-NC is just one form. Notably, studies in TBI offer a unique opportunity to discover mechanisms of neurodegeneration, since the initiating event or events – ‘time zero’- are known, thereby permitting the temporal examination of the progression of pathology. Indeed, for over two decades, our group has led the meticulous description of multiple neurodegenerative pathologies in individuals with a history of repetitive mild TBI or single severe TBI. In 2019, we established a NINDS-supported U54 center without walls, CONNECT-TBI, which has become internationally recognized for its success in coordinating prospective tissue banking in TBI, across all injury severities and exposures. To date, CONNECT-TBI has gathered unrivaled clinical datasets and tissue archives, including over 1000 prospectively collected cases across participating centers. Here, as we enter our final year of U54 support for CONNECT-TBI, we propose the next phase initiative; “Transdisciplinary Research Accelerating Neuropathology Studies and Facilitating Open Research Methods in TBI” (TRANSFORM-TBI). This initiative seeks to continue and expand the CONNECT-TBI Archive, which we will leverage to explore relationships between TReND, pathologies of AD/ADRD, and their contribution to late clinical outcomes. We also propose to democratize access to this resource to accelerate the discovery of TReND pathologies and their significance. In so doing, we have established an expert, multidisciplinary team of 26 investigators across 12 sites who will identify associations between the extent and type of neuropathological changes emerging following exposure to TBI of all severities (repetitive mild to single severe) and exposures (including sports, military, intimate partner violence). These neuropathological findings will then be compared with extensive clinical datasets to assess potential clinical correlations. Specifically, we aim to, 1) Explore the pathologic heterogeneity of TReND, including the prevalence and spectrum of AD/ADRD pathologies in late survival from TBI, 2) Characterize TReND-associated glial pathology and contrast it with the glial pathology of wider AD/ADRD, 3) Examine TReND associated clinical phenotypes and their distinction from those of aging and wider, non-TBI related AD/ADRD, and 4) Establish a Digital Slide Archive and Open Research Environment (Digital SCOPE) to support innovative, investigator-led studies across the global research community.

Traumatic brain injury (TBI) is recognized as a risk factor for neurodegenerative diseases, including Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD). Here, we propose to continue the expansion of the internationally recognized brain bank and clinical data archive, CONNECT-TBI, via a new initiative, TRANSFORM-TBI, which will also explore relationships between TBI and AD/ADRD pathologies as well as their contribution to late clinical outcomes.