PROJECT 2 ABSTRACT The overall goal of Project 2 is to identify and characterize genetic factors in Down syndrome (DS) that contribute to the individual variation observed in three states of key symptomatic cognitive decline – unaffected (preclinical), mild cognitive impairment (prodromal), and dementia – as characterized in Project 1. Project 2, in turn, will help to delineate clinical subtypes and their progression to establish an efficient and parsimonious set of biomarker profiles that can be applied to the practice of precision medicine, which is the main goal of Project 3. Virtually, all adults with DS develop Alzheimer's disease (AD)-associated neuropathology by 40 years of age, with the risk of AD increasing rapidly from the late 40s or the early 50s. Yet, there is a wide range of age at onset of AD and severity of AD, and some adults with DS do not develop AD even at older ages. As the life expectancy of individuals with DS is reaching 60s and beyond, AD in this cohort is becoming a public health problem. With recent advances in assays for blood- and CSF-based biomarkers along with non-invasive imaging techniques, our objective is to accurately assess the risk of dementia by defining the molecular signatures associated with the progression of dementia and identify risk and protective genetic factors and their pathways using state of the art technologies. This study may help to discover causal and protective factors in the general population. To accomplish the main goal of the study, we propose to leverage existing longitudinal biomarker, imaging, and clinical data to identify genomic, transcriptomic, proteomic, and metabolomic factors that influence the amyloid, tau and other neurodegenerative pathways that influence the development of AD in adults with DS. Specifically, we will: (1) identify genetic loci that are associated with symptomatic cognitive impairments, including mild cognitive impairment (MCI) and dementia in adults with DS; (2) further examine genetic loci that contribute to variation in AD-related endophenotypes, including blood- and CSF-derived multiomic biomarkers, neuroimaging markers, and clinical phenotypes; (3) replicate candidate genetic loci identified from the ABC-DS cohort in several external cohorts, including an independent cohort of DS adults (PI: Silverman), the high-risk Dominantly Inherited Alzheimer Network (DIAN) cohort and the Alzheimer's Disease Genetics Consortium (ADGC); and (4) perform integrative analysis using the genetic and non-genetic factors identified in Projects 2 and 1, respectively, to identify highly predictive biomarkers that can be used in clinical trials.