PROJECT SUMMARY There are currently no therapeutic options to slow or stop the progression of Alzheimer’s Disease and Alzheimer’s Disease-related Dementias (AD/ADRD) and this partly due to the complexity of these diseases and the inability to identify high-risk individuals and implement early interventions. AD/ADRD are typically associated with memory deficits, but additional symptoms include cognitive impairments, motor deficits and changes in mood are also commonly seen. In particular, motor deficits seen in individuals with AD/ADRD can have a dramatic impact on quality of life with severe cases resulting in accidental injury or individuals becoming bed bound. Importantly, sleep disruption is also prevalent in individuals with AD/ADRD and it has been shown to contribute to AD/ADRD symptoms. As the population continues to live longer, and as sleep deprivation levels continue to rise in nearly all age groups, it is critical that we understand the molecular mechanisms impacted by sleep deprivation in AD/ADRD. One potential avenue of research that connects sleep deprivation and AD/ADRD at the molecular level is Protein Kinase A. PKA activity is important in sleep/wake states and is also dysregulated in AD/ADRD, and recent results obtained using mice with a mutation in a PKA subunit, Prkar1b, revealed that mice aged 15 months or older exhibited motor deficits. What remains unknown is how sleep deprivation may impact already disrupted PKA activity at different ages representing the pre-clinical and clinical phases. The overall objective in this supplement proposal is to identify the impact of a gene-environment interaction between a Prkar1b mutation and sleep deprivation on behavior and the phosphorylome at different ages of an already generated mouse model relevant to AD/ADRD. The central hypothesis is that sleep deprivation, in the presence of the Prkar1b mutation, exacerbates aberrant PKA activity at earlier ages, which promotes neurodegeneration, and results in behavioral deficits. The rationale for the proposed research is that a mechanistic determination of how PKA activation becomes dysregulated prior to the emergence of neurodegenerative symptoms may provide the basis for the identification of PKA-specific therapeutic targets. We will use already generated Prkar1b mice at three ages (2-4 months old, 10-12 months old, and 16-18 months old) to study behavioral changes and phosphoproteomics in the hippocampus, a region particularly susceptible to sleep deprivation. The proposed research is potentially innovative because it utilizes the Prkar1b-L50R mutation, with known links to AD/ADRD symptoms in both humans and mice. The proposed project is significant because detection and treatment of the role of sleep in AD/ADRD may increase treatment effectiveness and efficacy, thereby improving the outcome of individuals with AD/ADRD.