Analyzing the Genetics Underlying Sleep Problems in Alzheimer’s Disease

The goal of the project is to identify human-relevant genes that underlie an individuals’ risk to develop Alzheimer’s-related sleep problems and test those as interventions to restore sleep. Sleep dysfunction often precedes the emergence of cognitive deficits in AD and has a strong genetic basis. In aim 1, I will assess sleep behavior in a population of genetically diverse AD mice as they age, followed by genetic mapping analysis to identify genes involved in disordered sleep. In aim 2, I will use genome editing to test for a causal link between candidate gene expression on sleep duration and quality, and the onset and progression of memory deficits. These analyses will yield novel targets for therapeutic interventions to promote healthy sleep and delay or prevent dementia.

Sleep problems are common in Alzheimer’s disease (AD) patients and are thought to influence disease severity and progression. The work proposed here seeks to identify genes that underlie an individuals’ risk for developing Alzheimer’s-related loss of sleep using a well-characterized, genetically diverse mouse model of AD that better models the complexity of human genetic diversity. Traditional mouse models of Alzheimer’s disease have provided substantial insights into possible mechanisms causing sleep loss in Alzheimer’s disease. However, these model lacks the genetic diversity required to identify genes conferring individual risk to develop AD-related sleep loss and subsequent cognitive decline. The results from the studies we propose will significantly extend current knowledge and have the potential to identify specific gene targets with the potential for translation to therapies for the elderly population suffering from various neurodegenerations.

The current proposal will be the first to identify novel genetic factors regulating disordered sleep by using a translationally relevant model system that incorporates genetic diversity into a model of AD. I will leverage MPRA and CRISPR-based screening tools to identify genomic variants associated with sleep disorder and their gene targets in vitro. A major innovation of the proposal is the use of bioinformatics tools to prioritize identified candidates by their relevance to humans. Candidate genes will be targeted to test whether they delay AD progression in vivo by improving sleep.

The proposed work will identify translational gene targets that will alleviate sleep problems associated with aging and Alzheimer’s disease. Additionally, we will assess whether novel gene targets discovered here are also potent targets to reduce Alzheimer’s disease-related cognitive decline. Success will lead to improved understanding of the genetic contribution of sleep loss to onset of dementia. Ultimately, our objective is to identify gene candidates or gene pathways that can be further investigated as therapeutic targets for Alzheimer’s disease related sleep loss.