PROJECT SUMMARY Our proposed research is expected to identify genetic factors that underlie disordered sleep associated with Alzheimer's disease (AD), and determine if they are intervenable to stave off cognitive symptoms. Detection and validation of these genes will promote possible treatments through discovery of new targets and biological pathways that may aid in alleviating disease burden and improving quality of life in humans. The data generated in this proposal will also be cross-checked with available datasets from human cohorts and postmortem samples, such that advances in our current understanding of the networks and mechanisms in mice can be understood in the context of human AD. We will leverage advanced mouse models to identify molecular and cellular mechanisms underlying the bidirectional relationship between AD pathology and disruptions in sleep. In Aim 1, we will identify genes and molecular networks associated with sleep loss in a large population of AD mice that better model human AD. In Aim 2, we will translate genes and networks underlying variation in sleep loss to human AD cohorts. Finally, in Aim 3, we will validate genetic and modifiable factors associated with sleep loss and dysfunction, and determine their effects on onset and progression of memory deficits in powerful AD models.