Abstract Metabolomics is an emerging area of systems biology which aims to comprehensively analyze a wide array of metabolites in biological samples. The metabolome consists of a vast number of different classes of compounds, such as amino acids, lipids, organic acids and nucleotides. Elucidation of metabolic alterations using liquid chromatography (LC) coupled with mass spectrometry (MS) has increased our understanding of early pathway perturbations associated with neurodegeneration and enabled the development of predictive biomarkers of pre- clinical dementia. The overarching goal of the parent ABC-DS (Alzheimer’s Biomarkers Consortium - Downs Syndrome) award is to characterize Alzheimer’s disease (AD) in people with Down syndrome (DS); specifically projects 2 and 3 aim to translate outcomes to a precision medicine framework and expedite clinical trials via harmonization of clinical and neuropsychological outcomes with biofluid characterization and genetic measures. However, identification, verification and validation of blood based biomarkers specific to AD pathology is constrained by matrix effects and a large linear dynamic range that obscures the ionization and detection of low abundance compounds that could otherwise be powerful indicators of onset and progression of pre-clinical dementia in the DS cohort. We are requesting funds for the purchase of the 7500 QTrap® LC-MS/MS system (7500 QTrap hereafter), a next generation triple quadrupole mass spectrometer (MS) that is urgently needed for expanding our quantitative MS capabilities for the ABS-DS consortium projects. Our recent work has shown that metabolites belonging to energy metabolism and beta-oxidation pathways show significant dysregulation in people with DS and AD. The requested 7500 QTrap will help to strengthen biomarker discovery, verification and validation workflows for proposed biomarker studies detailed in Projects 1, 2 and 3 of the ABC-DS program. This equipment supplement will be used to primarily support our NIA-funded U19 (1U19AG068054-01) project by prioritizing U19 samples for analysis. When available, it may be used in other program related studies, such as our NIA-funded (R01AG058644) project. This system combines the requisite attributes of speed, robustness, dynamic range, and minimization of cross-contamination that is necessary for successful quantitative interrogation of metabolomic samples using LC-MS. The 7500 QTrap will be a significant technological advancement for targeted metabolomics workflows due to dramatic enhancements in sensitivity (102 to 104) and resolution as well as improved analytical pipelines for downstream data analysis and processing. Taken together, this would augment the detection of small molecules with improved sensitivity and expand the scope of biofluid biomarker characterization objectives of the parent award, in compliance with the FDA-MDDT program for developing biomarkers with translational value. This instrument will be housed at the metabolomics core facility in Georgetown University.

Overall Project Narrative Alzheimer's disease (AD) is a major public health crisis for our aging population. People with Down Syndrome (DS) are at high risk for AD and because of their unique biology and provide an unparalleled opportunity to develop biomarkers of preclinical AD. Reliable biomarkers of preclinical AD will enable new options for intervention and promote health for people with DS and in the general population.