Project Summary/Abstract Epidemiological evidence points to a relationship between traumatic brain injury (TBI) and Alzheimer’s disease; however, many experimental studies fail to show this, with some even reporting a reduction in Alzheimer’s-like pathology over time. Most of these studies utilize mouse models with genetic mutations associated with early onset Alzheimer’s disease. This strategy largely ignores the relationship between TBI and development of late- onset Alzheimer’s disease (LOAD), which is much more prevalent in clinical populations. As a result there is a gap in defining biological pathways linking TBI and LOAD. Here, we propose to define the response to TBI in a novel mouse model of Alzheimer’s disease created by the Model Organism Development & Evaluation for Late- Onset Alzheimer’s Disease (MODEL-AD) consortium that became available in 2019- APOE4/Trem2*R47H. APOEϵ4 and Trem2*R47H are closely linked to immune signalizing in the brain and highly associated with development of LOAD. Moreover, recent evidence suggests that TREM2 binds to APOE and that the TREM2 R47H variant reduces this affinity. Indeed, Aβ clearance is more efficient for TREM2 and microglia when it is bound to APOE, and TREM2-deficient microglia show impaired uptake of Aβ. Together, these data suggest that APOE and TREM2 may influence LOAD through inflammation and impaired debris clearance. This process may be critical in linking TBI to Alzheimer’s disease as well. We hypothesize that TREM2*R47H will directly affect the microglial response to TBI and promote the appearance of Alzheimer’s disease-like pathology in humanized APOE4 mice. In Aim 1, we will define the neuropsychiatric, neuroinflammatory, and neuropathological effects of TBI or sham injury in APOE4/Trem2*R47H mice at 7, 30, and 120 days post-injury (DPI). In Aim 2, we will delineate changes in whole brain as well as microglia specific transcriptome with RNA sequencing at 7 and 30 DPI in APOE4/Trem2*R47H mice. These studies build on our expertise in TBI and neuroinflammation, and provide an opportunity to examine the relationship between TBI and Alzheimer’s disease in a clinically relevant model. Upon conclusion, we will have a detailed phenotypic characterization of APOE4/Trem2*R47H mice in response to TBI and identify microglia specific transcriptome changes that may substantially influence chronic recovery. These data will be essential in future proposals aiming to improve outcome after TBI.