Axonal Pathology and TBI-Related Neurodegeneration (TReND) Over the last decade there has been an explosion of interest in the link between traumatic brain injury (TBI) and the development of late neurodegenerative pathologies, particularly chronic traumatic encephalopathy neuropathologic change (CTE-NC) and their association with increased risk of adverse cognitive outcomes, including Alzheimer’s disease and Alzhemier’s disease related dementias (AD/ADRD). However, the intense focus on neurofibrillary tangles in CTE-NC has come at the expense of investigation of the broader spectrum of pathologies found after all forms of TBI. Accordingly, to better reflect the complex neuropathology emerging after TBI, which includes many of the common pathologies of AD/ADRD, we have adopted the conceptual framework, “TBI-related neurodegeneration” (TReND), of which CTE-NC is just one form. We propose to examine the evolution of TReND in those with history of single moderate or severe (sTBI) or repetitive mild TBI (rTBI), which we will directly compare to the pathologies of both ‘normal’ aging and wider neurodegenerative disease, including AD/ADRD. Further, we propose to examine these changes in context of diffuse axonal injury (DAI), one of the most common pathologies found across all severities of TBI, in which we hypothesize that some axons may undergo repair, while others are driven towards degeneration. Notably, through this grant award, we have demonstrated that axon degeneration persists for decades after TBI leading to ongoing release of amyloid-beta peptides and phosphorylation of tau. We hypothesize that this smoldering axonal degeneration late after TBI presents both a driver of and a substrate pool for TReND pathology and associated AD/ADRD outcomes. We have also found that TBI induces a tau astrogliopathy with similarity to aging-related tau astrogliopathy (ARTAG) but with a pattern and distribution that is distinct from that seen in aging and AD/ADRD and may demand reappraisal of current understanding of tau pathology in CTE-NC. Finally, preliminary data indicate that females with TBI have more extensive DAI than males, suggesting there are sex- based differences in evolution of axonal pathology. It is important to note that for this proposal we will leverage the unique and unrivalled clinical datasets and tissue archives of CONNECT-TBI, an NIH U54-supported Center Without Walls, which emerged from the current grant cycle. Specifically, we propose to: 1) Document the extent and distribution of axonal degeneration and repair following all severities of and survivals from TBI; 2) Characterize the extent, distribution and progression of axonal pathology and its association with TReND; 3) Document the time course and distribution of the complex astroglial and microglial neuroinflammatory responses following TBI and their relation to ongoing axonal degeneration, white matter atrophy and the pathologies of TReND and AD/ADRD; and 4) Identify sex-associat...