Delirium is an acute brain dysfunction characterized by disturbances in attention, awareness, and cognition. Patients with Alzheimer’s disease and related dementias are at increased risk of developing delirium. Patients who experience delirium are at higher risk of being diagnosed with cognitive impairments that approximate Alzheimer’s disease and related dementias. This association between delirium and Alzheimer’s disease and related dementias suggests a shared pathophysiological mechanism. Thus, studies of pathophysiological mechanisms underlying delirium are expected to lend fundamental new insights into Alzheimer’s disease and related dementias. Evidence suggests that sleep deprivation may be a modifiable risk factor for the development of delirium and Alzheimer’s disease. This is because sleep deprivation is associated with activation of the inflammatory cascade with the acute release of inflammatory mediators such as interleukin-6 into the bloodstream. These inflammatory mediators trigger a maladaptive neuroinflammatory response that is driven in part by activated glia. Thus, sleep deprivation may be a modifiable risk factor for the development of delirium and Alzheimer’s disease and related dementias. However, pharmacological treatment with no current medication (benzodiazepines, antipsychotics) induces natural sleep or directly modulates systemic and neuroinflammation. We have found that biomimetic sleep, defined here as pharmacological induction of rapid eye movement sleep (REM) and non-REM I-III sleep states using dexmedetomidine, can now be achieved in humans. Our Specific Aims seek to: (1) investigate the benefits of biomimetic sleep for reducing the incidence of delirium and cognitive impairment in a randomized controlled trial; (2) investigate the cellular and molecular mechanisms of delirium using combined Positron Emission Tomography/Magnetic Resonance imaging and serum metabolic profiling; and (3) investigate predictors of delirium from perioperative electroencephalogram recordings. At the conclusion of these studies, we will have expanded our knowledge of the pathophysiology of delirium, evaluated a new preemptive therapeutic strategy for delirium, suggested neurophysiologically based monitoring strategies to preemptively identify patients at high risk for developing delirium, and enabled continued investigation into the pathophysiology delirium and Alzheimer’s disease and related dementias.