PROJECT SUMMARY/ABSTRACT Liver transplantation (LT) is the optimal treatment for individuals with end-stage liver disease (ESLD). Older adults (age≥50) now receive one third of all deceased donor LTs and are at elevated risk for post-LT delirium and cognitive dysfunction due to the stress of surgery, post-LT ICU stay, and immunosuppression. Delirium occurs in 10-47% of LT recipients and is associated with 4-fold higher in-hospital mortality. Delirium is also a risk factor for cognitive decline and Alzheimer’s Disease and related dementias (ADRD). These neurocognitive outcomes are manifestations of an underlying inflammatory state and potentially preventable complications, but no modifiable risk factors have been identified to date among older liver transplant recipients. Frailty, a syndrome conceptualized as the body’s inability to efficiently respond to chronic and acute stressors, is seen in 33% of older LT candidates and is a modifiable state. We developed a validated, LT-specific physical frailty measure [Liver Frailty Index (LFI)] and found that frailty is associated with increased waitlist mortality and post-LT acute rejection. Though mechanistic understanding of these relationships is limited, they might be due to poor reserve and underlying inflammation, the same risk factors underlying delirium, cognitive dysfunction, and ADRD. Therefore, frailty may further increase the risk of delirium, cognitive dysfunction, and ADRD among older recipients. Identifying frailty components and delirium characteristics (length, subtype, severity) associated with increased ADRD risk can inform future research to reduce ADRD among older LT recipients. To investigate the association between pre-LT frailty and post-LT ICU delirium, cognitive dysfunction, and ADRD in older LT recipients, we plan to leverage an ongoing NIA R01-funded multicenter cohort study of older LT recipients to accomplish the following aims: (1) To quantify the association between pre-LT frailty and post- LT ICU delirium among older recipients; (2) To determine whether pre-LT frailty is associated with differences in older recipients’ cognitive function at 3-6 months after LT; and (3) To evaluate the association between pre- LT frailty and post-LT ADRD risk among older recipients. Delirium assessments being performed in the ICU at UCSF will be initiated at Johns Hopkins Hospital (JHH) through the efforts of the trainee. Cognitive dysfunction assessments will be performed post-LT on all participants; Dr. Ruck will perform these assessments at JHH. Our group’s expertise in frailty and delirium in transplantation and utilization of an ongoing longitudinal cohort study make us uniquely able to robustly explore frailty as a predictor of neurocognitive complications including delirium and ADRD in older LT recipients. We hypothesize that frailty is associated with higher risk of post-LT delirium, cognitive dysfunction, and ADRD among older LT recipients. If the proposed aims are achieved, we wi...