Treatment options for Alzheimer?s disease have been elusive, in large part because the molecular mecha- nisms underlying AD remain unclear. Genome-wide association studies (GWAS) have uncovered genomic loci associated with increased risk of AD; however, the exact causal variants within these loci and the genes they affect have been difficult to determine. While many lines of evidence suggest that these variants alter transcriptional regulatory networks in microglia, primary human microglia are hard to acquire and intrac- table for many genome-editing, genomic, and high-throughput technologies. The overall objective of this proposal is to determine how AD causal SNPs alter microglia regulatory networks. Using microglia derived from human induced pluripotent stem cells, we will define transcriptional regulatory networks in resting and activated microglia (Aim 1), identify the causal SNPs within each AD GWAS locus (Aim 2), and determine the genes affected by AD-associated SNPs (Aim 3). Accomplishment of the goals set forth here will establish a cell culture model of microglial response to AD stimuli, determine the causal AD variants at each GWAS locus, and identify the genes impacted by AD-associated SNPs. These results will have a positive impact because they will identify the key genes involved in AD pathogenicity, providing a foundation for further studies towards the development of tools to diagnose, prognose, and treat AD.
The proposed research will identify new genes and genetic variants that increase risk of Alzheimer?s Disease. Our work will break down existing barriers by massively increasing the speed, throughput, and accuracy with which we can identify causal SNPs and their mechanisms of action. This will provide new Alzheimer?s Disease risk genes for further study and drug development, establish a tractable biological system in which to study these genes, and establish a new paradigm for GWAS SNP interpretation that can be applied to other cell types and other diseases.
