Supplement Abstract Virtually all Down Syndrome (DS) patients shows neuropathology and cognitive impairment at an accelerated rate as they age, ultimately progressing to Alzheimer’s disease (AD) in older years. Irrespective of so many advances in DS research, we still lack a substantial understanding of AD treatment in the DS patients. In this supplement, we propose to accelerate testing validated protein biomarkers for AD using our established proinflammatory endophenotype analysis in bio-banked samples from the previously completed clinical trial, “Vitamin E in Aged Persons with Down Syndrome.” The study will permit us to understand the inter-relationship between immune signals in DS-AD individuals. In addition, will assist to connect the dots between how prevailing immune signals may impact anti-inflammatory effects on AD biomarkers. The overall objective of our project is to represent a specific subgroup of DS showing a plasma-based proinflammatory endophenotype which would most likely respond to potent anti-inflammatory therapy. We aim to validate inflammatory endophenotype in DS-AD patients and assess changes in AD pathology and neurodegeneration in native plasma and neuronally derived exosomes, both at baseline and longitudinal samples. Utilizing Quanterix Simoa platform HD-X analyzer technology as well as a Nanoparticle Tracking Analyzer Malvern NS-300 instrument, we will be able to accelerate the progress of Aims 1 and 2 to overcome pandemic-related delays as well as maximize high capacity, validated technologies with enhanced capabilities to achieve study aims.

PROJECT NARRATIVE Down Syndrome (DS) is an Alzheimer’s disease related disorder (ADRD) that involves traditional ADneuropathology and cognitive impairment at an accelerated rate. We propose to use well- characterized, biobanked plasma samples from the Vitamin E in DS trial to characterize AD biomarkers and develop a precision medicine approach for use of anti-inflammatories in DS trials. In this proposal we will utilize our expertise in high throughput proteomics and analytics to better characterize our sample set and expand the database for this trial.