The goal of this project is to analyze how Alzheimer’s disease (AD)-associated mutations in a key signaling molecule, protein kinase C α (PKCα), contribute to disease pathogenesis. PKCα plays a pivotal role in tuning the signaling output of cells and, as such, is frequently mutated in human cancers. The Alzheimer’s Genome Project™ led by Tanzi and colleagues has identified unique mutations in PKCα that co-segregate with AD in families with the disease. In the preceding funding period, structure/function and cellular studies revealed that a rare variant in PKCα identified in seven members of four unrelated families results in gain of function. This is in marked contrast to the mutations in human cancers that are loss of function. These data reveal that this Alzheimer’s disease-associated mutation increases the signaling by PKCα, identifying PKCα as a novel therapeutic target. The proposed research aims to examine other variants of PKCα that co-segregate with Alzheimer’s disease, use genome editing to examine how one mutant allele affects cellular signaling and disease outcome in animal models, and analyze whether PKCα signaling is amplified in brains from Alzheimer’s disease vs. non-disease humans.