Pathogenesis of Alzheimer’s disease (AD) is directly linked to levels of the toxic amyloid beta (Abeta) peptide in the brain. Abeta levels and amyloid deposition increase in aging and in AD, yet age-dependent factors that increase Abeta levels at the synapse remain largely unknown. In large family-based genome-wide association studies (GWAS), we recently have discovered a strong association between a neurexin gene and late-onset AD, and identified a number of neurexin variants that are associated with increased risk for AD. Neurexin, a transmembrane protein, expresses mainly at the presynaptic side of the neuron and plays an essential role in synapse formation, learning and memory. Our preliminary studies also identified neurexin as a novel APP-interacting protein and have further shown that expression of neurexin in neuronal cells reduces Abeta generation. Association of neurexin with risk for late-onset AD and reduced Abeta generation with neurexin-APP binding strongly advocate for an important role of the neurexins in the pathology of AD. The goal of this project is to study the functional significance of neurexins and genetic variants in regulating amyloid pathology in aging and Alzheimer’s disease. Our studies will greatly facilitate the understanding of Alzheimer’s disease pathology and may contribute to the development of novel strategies for the prevention and treatment of this debilitating disease.