SUMMARY AND RELEVANCE Traumatic brain injury (TBI) is recognized as the strongest environmental risk factor for neurodegenerative disease, including dementia of Alzheimer's disease (AD)-type. Correspondingly, the neuropathology of survival from TBI comprises a complex array of pathologies, including production and deposition of amyloid-beta (Aβ) often in association with axonal degeneration. Of particular note, pathologies in Aβ are recognized across all survival intervals, being present in patients dying in the acute phase post injury, in a proportion of longer term survivors of moderate to severe TBI and in a majority of patients with later stage, clinically significant CTE. Derived from amyloid precursor protein (APP), soluble Aβ is widely recognized as neurotoxic. As such, Aβ clearance is closely regulated via enzymatic degradation, direct absorption into blood and perivascular drainage. As a consequence, TBI-associated pathologies in Aβ may arise through either excess production, inefficient clearance or a combination of both. A feature common to all severities of TBI is diffuse axonal injury (DAI). As a consequence, there is interruption of axonal transport in damaged axons, which we have demonstrated is associated with rapid accumulation of APP and the secretases responsible for its processing to Aβ. Thus, within hours of TBI, there is the potential for release of large pools of neurotoxic Aβ as a consequence of DAI. Of note, among our most recent observations, we have demonstrated that axonal transport interruption is not restricted to the acute phase after injury, with evidence of continued axonal degeneration and associated APP transport interruption in material from survivors a year or more from TBI. As such, through axonal injury there is potential for TBI to initiate immediate and sustained Aβ production. However, though DAI is ubiquitous and may persist years after injury, only around 30% of patents develop Aβ plaque in the acute phase after TBI; these acute plaques appearing to diminish in the months following injury. In brain parenchyma, the principal enzyme responsible for Aβ degradation is neprilysin. Intriguingly, through our unique studies in human TBI, we have shown polymorphism in the neprilysin gene is associated with risk of amyloid plaque deposition in the acute phase post TBI. However, its relationship to late post-TBI pathologies is unknown and will be addressed in this proposal. In addition to enzymatic catabolism, clearance of soluble Aβ proceeds via exchange across the blood brain barrier (BBB) and through interstitial fluid drainage along perivascular pathways. In this regard, our preliminary studies in both human tissue and animal models suggest TBI is associated with significant and persisting BBB disruption in a high proportion of patients. As such, disturbance in the vasculature following TBI, might serve to alter Aβ transport across the BBB following injury. Our proposal extends our longstanding and successf...