PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is the greatest environmental risk factor for Alzheimer’s disease (AD). Although both neurological conditions share many of the same pathological hallmarks including neurodegeneration, the underlying mechanisms that establish this relationship between TBI and AD are not well understood. Acute TBI transitions into chronic TBI, which is characterized by progressive neurodegeneration. The pathophysiologic events associated with the transition of acute TBI into a chronic neurodegenerative condition can last for months, years, or even a lifetime and are also thought to be associated with the pathogenesis of AD after TBI. Investigating the mechanistic link between acute TBI, chronic TBI, and AD is important as there are currently no therapeutic strategies to protect patients. My proposed interdisciplinary project aims to address this knowledge gap by assessing the interplay between TBI, hematopoietic stem cell (HSC) dysfunction, chronic neurodegeneration, and AD. Specifically, I am testing the novel hypothesis that acute TBI induces changes to HSCs that in turn play a role in impairing the immune system and propagating chronic neurodegeneration after TBI, and that these TBI-induced alterations are related to the increased risk of AD after TBI. HSCs generate the entire spectrum of blood and immune cells, and my preliminary studies thus far indicate that TBI induces major changes to HSCs, including impaired HSC function, disrupted blood cell counts, and elevated inflammatory markers. This study employs a clinically relevant model of TBI, cytometric analyses, and immunohistochemical approaches to generate a deeper understanding of hematopoietic dysfunction in TBI and AD and the implications of this dysfunction on the immune system and chronic neurodegeneration. Furthermore, this proposal is tailored for a physician-scientist in training as it investigates the underlying mechanisms by which acute TBI transitions into a chronic neurodegenerative condition, with implications for novel therapeutic targets for reducing neurodegeneration after TBI and protecting TBI patients from developing AD.