PROJECT SUMMARY This study will provide novel insights on cognitive trajectories among new liver transplant recipients, and the impact of cognitive function on self-management, health behaviors, and patient outcomes. The prevalence of cirrhosis and end-stage liver disease (ESLD) in North America is estimated at up to 1,000 per 100,000 population and has nearly doubled over the past two decades with baby boomers (born 1945-1965) accounting for half of cases. From 2009 to 2016, there has been a 65% increase in cirrhosis mortality in the U.S. Decompensated cirrhosis has a 5-year survival of only 34-56% with liver transplantation (LT) as the only life- saving option. By 2033, LT demand will increase by 23% and per-patient LT-associated costs will rise from $1.4 to $2.1 million, resulting in a total of $26.7 billion in transplant-related medical expenses over a 10-year time horizon. To maximize the benefits of LT, liver transplant recipients (LTRs) must have strong self-management skills to navigate health systems, adhere to clinical monitoring, and take complex, multi-drug regimens. All of these tasks require formidable cognitive abilities for active learning and problem solving. LTRs are at higher risk for poorer cognition due to high prevalence of pre-transplant cognitive impairment (hepatic encephalopathy), multiple chronic conditions, alcohol use, and increasing age. The cognitive status of LTRs over time could affect self-management and transplant outcomes, yet these issues have not been thoroughly investigated. Our proposed cohort study (`LivCog') will longitudinally characterize cognitive performance using the NIH Toolbox among 450 new LTRs from 3 diverse transplant centers, beginning at transplant waitlisting and then at 1, 4, 12, and 24 months post-LT. We will also serially assess self-management skills, physical function, health behaviors, patient-reported and clinical outcomes. Potentially modifiable post-transplant targets will be investigated, including caregiver support, physical activity, sleep, and treatment adherence to understand causal pathways that could inform future health system responses. Our specific aims are to: 1) assess pre to post-LT cognitive trajectories and identify risk factors for persistent cognitive impairment, 2) evaluate associations between cognitive function and self-management skills, health behaviors, functional health status, and post- transplant outcomes, and 3) investigate potential mediators and moderators of associations between cognitive function and post-transplant outcomes. Our proposed LivCog study will fill critical gaps in understanding cognitive recovery and function, risk factors and consequences of cognitive impairment among LTRs. Findings will directly inform future interventions to improve post-transplant outcomes.