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CIRCUITS: Functional Analysis of Alzheimer’s Disease Risk Genes Using Human-Induced Pluripotent Stem Cells

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The vast majority of people with Alzheimer’s disease (AD) suffer from the sporadic, or late-onset form, which causes remain completely unknown. From studies involving thousands of people, researchers have identified a number of genetic variants that may increase one’s risk for sporadic AD. However, little is understood regarding why these small changes impact one’s risk to develop AD. In this work, we will use the cutting-edge genome editing technique CRISPR/Cas9 to introduce AD-associated genetic variants identified through genome-wide analysis into reprogrammed human stem cells. We will differentiate human stem cells harboring these variants into various cell types populating the brain—including neurons, astrocytes and microglia—and study the effects of these variants in these different cell types. The proposed study will provide mechanistic insights into why some genetic variants found in the population may predispose some individuals to an increased risk for AD.