Project Summary/Abstract Neurodegenerative disease mechanisms encompassing Alzheimer’s disease (AD) are complex and have remained largely unknown to date despite the identification of risk factors and genetic mutations associated with the disease. Oligodendrocytes (ODCs) have critical roles in the central nervous system where they ensheath axons to allow rapid saltatory conduction and also provide metabolic support to neurons. Although a largely homogeneous oligodendrocyte population is thought to execute these functions throughout the brain, recent reports suggests that ODCs are highly diversified cell populations in the brain. Using systems biology approach, that integrates multi-omics data from human pathological specimens and mouse models of AD, this project aims to generate single-cell resolution genome-wide maps of transcriptional and regulatory networks in ODCs associated with AD. The project represents a major advance in the field by taking a comprehensive approach to data-driven discovery to identify highly conserved regulatory programs of AD. In parallel, the project aims to understand the role of sterol regulatory-element binding proteins (SREBPs) in AD using functional genomic approaches. Finally, the project will identify novel cell-type specific transcriptional regulators of AD using cutting edge approaches to data science.