Project Summary/Abstract Sepsis is a common cause of acute illness hospitalization affecting more than 20 million patients each year. It has a mortality rate of up to 40% and a high burden of cognitive impairment in surviors. Following critical illness, 26% of patients without pre-existing cognitive deficits will have cognitive function scores similar to mild Alzheimer's disease. Alzheimer's Disease and Related Dementias (ADRD) are the greatest cause of disability, and the sixth leading cause of death, in the country. Annual costs approach $1 trillion. Delirium is a sudden state of confusion that is common in sepsis and associated with increased morbidity, mortality and acquired long-term cognitive decline. Although there are substantial costs to both conditions - personal, financial and societal - delirium and ADRD are bereft of therapies. There is an established bidirectional clinical predisposition of dementia to delirium and vice-versa; however, the underlying mechanisms for this effect are unknown. Studying pathological changes associated with delirium offers a unique opportunity to understand how acute accumulations of neurodegenerative and tau pathologies may contribute to disease pathogenesis and lead to long-term cognitive decline. We will investigate the inter-relationship of acute brain dysfunction and delirium, cognitive decline and ADRD pathologies. We will investigate whether plasma biomarkers for neuronal injury (neurofilament light) or phosphorylated tau disease (a biomarker of Alzheimer's disease) are associated with acute brain dysfunction and delirium during, or cognitive decline following, sepsis-associated critical illness. We will also investigate the role of inflammation (and clinical factors) to drive changes in neuronal injury and tau disease, as we investigate the mechanisms of delirium and accumulation of ADRD pathologies. These investigations will fundamentally illuminate the mechanisms through which delirium, resulting from critical illness, may lead to cognitive decline as well as provide novel insights into the pathogenesis of delirium. We address the most critical question in our field: how does delirium exacerbate cognitive decline? We leverage our NIH-funded MENDS2 study to address these questions in a feasible and efficient way, analysing 1526 samples that are already biobanked. All the necessary clinical data required for this project are collected and ready to be analysed. Through understanding the mechanisms of delirium and ADRD, including the interaction of neurodegenerative and tau pathologies and inflammation, we will identify potential therapeutic approaches to prevent increases in ADRD-related pathology. We will also provide important information on whether screening for ADRD pathologies during acute illnesses may identify subjects at risk for cognitive decline and identify novel approaches to mitigate the increases in pathology. Our long-term aim is to limit the cognitive burden of acute and critical il...