PROJECT SUMMARY/ABSTRACT Down syndrome (DS) is the most common genetic cause of intellectual disability, with virtually all DS individuals having AD by age 60. Despite exciting advances over the past 20 years in our understanding of DS and how genetics confer susceptibility for AD, there have been few clinical trials to treat AD in the DS population (DS-AD) and currently no means to clinically impact disease progression. We hypothesize that the biological makeup of DS-AD is as heterogeneous as the sporadic AD population and that identifying specific subsets of DS-AD for particular treatments will yield meaningful therapeutic responses. We propose to test a validated biomarker for sporadic AD, our established proinflammatory endophenotype analysis. This analysis will allow for an understanding of differences in immune signaling between DS-AD individuals and how this may impact anti- inflammatory effects on AD biomarkers. For this study we will leverage biobanked samples from the previously completed Phase 3 clinical trial, “Vitamin E in Aged Persons with Down Syndrome (NCT00056329).” For our proposed work we will employ high throughput proteomics on native plasma and exosome subpopulations to validate new techniques and develop a framework for designing better therapeutic trials for DS-AD