PROJECT SUMMARY/ABSTRACT Night shift work is common in the current 24-hour global society and is increasingly recognized as a risk factor for Alzheimer’s Disease (AD) and related dementias (ADRD). However, we know very little about the persistence, recovery from, or pathways through which shift work contributes to AD/ADRD. Neuronal metabolic decline (i.e., disrupted brain bioenergetics) contributes to AD/ADRD development and progression, and the repeated sleep and circadian disruptions in shift work compromise peripheral energy metabolism. This K01 proposal will advance these findings by comparing indices of Alzheimer’s disease risk and brain bioenergetics between retired night shift workers and retired day workers. N = 40 participants (n = 20 retired night shift workers, n = 20 retired day workers) ages 65-80 from an established cohort will perform neurocognitive assessments (e.g., episodic memory, executive function) and 7 Tesla neuroimaging. Structural magnetic resonance imaging will assess hippocampal, posterior cingulate cortex, and retrosplenial cortex volume and phosphorous magnetic spectroscopy will assess brain bioenergetics, including adenosine triphosphate, phosphocreatine, and inorganic phosphate. This study will compare retired night shift workers and retired day workers on cognitive function, brain volume, and brain bioenergetics, and will examine the association of brain bioenergetics with brain volume among retired night shift workers. To conduct this research, Dr. Lehrer will pursue a program of training that will advance his knowledge and skills in the assessment of Alzheimer’s disease-related cognitive function, brain structure, and neurobiology (i.e., bioenergetics and AD-specific proteinopathy). He will also learn how to integrate these methods into his emerging program of sleep and circadian rhythm and AD/ADRD research. This training, along with findings from the proposed study, will allow Dr. Lehrer to launch his career as an independent investigator studying the role that long-term sleep and circadian disruption plays in Alzheimer’s disease to inform impactful prevention efforts for retired night shift workers. Study findings could influence our approach to AD/ADRD risk among current and former shift workers, leading to early identification of at-risk individuals at the conclusion of, or even during a career in shift work. Results will inform future studies using experimental approaches to test causal relationships, inform development and dissemination of interventions, and elucidate precision medicine approaches to prevent and attenuate the clinical course of AD/ADRD. Such interventions may include potentially modifiable behavioral (e.g., sleep and circadian rhythm enhancement) and pharmacological (e.g., bioenergetics-boosting compounds) therapies for AD/ADRD intervention and/or prevention. The proposed study will generate public health-relevant data that will help to reduce AD/ADRD risk and inform behavioral and bioenerg...