PROJECT SUMMARY The incidence of Alzheimer’s disease (AD) and dementia continue to rise, leading to increased burden on our healthcare system. It is therefore imperative to have a comprehensive understanding of the causative mechanisms for improved treatment strategies, and potential markers for early detection and intervention for AD. One causative mechanism of neurodegenerative pathophysiology is aberrant proteolytic processing. A well- studied example of this is the proteolytic processing of amyloid precursor protein, which can lead to an increase in amyloid-β peptides, which in turn form aggregates. I aim to investigate the global role of proteolytic processing in AD by looking for differential proteolytic processing products, and by determining protease activity and specificity for a couple specific proteases implicated in disease. This will be accomplished by development and application of several different, but complementary, computational and mass spectrometry proteomics methods to investigate endogenous protease and substrate abundance profiles and cleavage motif specificity.