The goal of this project is to analyze how Alzheimers Disease (AD)-associated mutations in a key signaling molecule, protein kinase C α (PKCα), alter its function. 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. Our mechanistic insight into PKC structure and function sets the foundation for understanding how these mutations alter the function of the enzyme to contribute to the pathogenesis of AD.