Project Summary Exposure to surgery with general anesthesia has been associated with cognitive dysfunction in older adults. This post-operative cognitive dysfunction has been studied across elective surgical populations, and when persistent, represents an Alzheimer’s Disease and Related Dementia (ADRD). Our group recently published on the impact of surgery and anesthesia exposure on ADRD in a prospective multicenter cohort study of >1,000 medical and surgical intensive care unit (ICU) patients without pre-existing dementia. Controlling for pre- and in-hospital patient characteristics, we demonstrated that neither surgery with anesthesia exposure, nor age, was independently associated with ADRD at 12 months. This controversial lack of association between surgery and ADRD requires reproducibility in other populations, and has never been studied in a large critically injured cohort. Injured patients vary significantly on their age, illness severity, and need for surgery. Timing, frequency, and type of surgery are also variable as many of these patients have multisystem injuries. There have been no studies investigating surgery-specific or dose-dependent relationships of surgery with anesthesia on the development of ADRD. Injured patients also may sustain traumatic brain injury, delirium, coma, and sedation which all may influence future ADRD. Neuroinflammation is one proposed mechanism of cognitive dysfunction after surgery, primarily in pediatric cohorts. The impact of neuroinflammation is unclear in a critically ill injured elderly cohort. Some work in uninjured critically ill patients has demonstrated association of ADRD and neuroinflammatory biomarkers such as high mobility group box-1 (HMGB1) or S100B, but has not been studied in the injured adult. Impact: The ADRD after Injury in the Elderly Study will be the first to investigate the effects of surgery and anesthesia exposure on ADRD and associated neuroinflammation in critically injured patients controlling for age, co-morbidities, pre-injury education level, injury severity, type of neurologic injury (i.e. traumatic brain injury, delirium), with a specific focus on the elderly. This study will feature a 450-subject nested prospective cohort investigation within my Primary Mentors’ R01 cohort of 900 critically injured patients. This will provide me with a unique opportunity to lead my own nested cohort investigation while leveraging the essential infrastructure of the Parent cohort and pursuing advanced training via a Master in Public Health.