This application will combine the neuroimaging expertise of the investigator with new knowledge of biomarkers for aging pathology, advanced computational methods and Down syndrome clinical translational research. The goal is to produce a unique skill set which will be used to advance the candidate’s career as an independent lifespan developmental cognitive neuroscientist focusing on Down syndrome. Neurodegenerative changes associated with Alzheimer's disease (AD) are present in almost all individuals with Down syndrome by age 40 years, and the lifetime risk of developing dementia is more than 90% in this population. Understanding patterns of neuropsychiatric and pathological brain changes before AD diagnosis is critical in order to facilitate interventions prior to onset of irreversible neuropsychiatric and pathological brain changes. Yet charting of pathological brain changes and diagnosis of dementia is extremely challenging in individuals with DS who have brain and neuropsychological differences present through the lifespan. Here we propose a computational neuroscientific framework in which we will utilize conventional resting state functional MRI, advanced quantitative MRI and multimodal biomarker data to disentangle brain and neuropsychological changes specific to DS and AD (within the context of DS). Specifically, we will test the overarching hypothesis that whole brain connectivity (i.e. connectomes based on resting state functional MRI) and brain microstructure (quantitative MRI) represent intermediate phenotypes between primary brain pathologies and neuropsychological outcomes in DS and AD. First, we will leverage data from the Alzheimer's Biomarkers Consortium — Down Syndrome (ABC-DS) to identify connectome-wide signatures specific to DS, and a separate set of signatures specific to AD in the context of DS. Then, we will examine relationships between connectome-wide signatures and AD pathology within the amyloid, tau and neurodegeneration (ATN) framework. Next, we will examine relationships between connectome-wide signatures and critical neuropsychological functions including memory, social cognition, and executive function dimensionally. Finally, we will enroll a novel cohort of adults with DS and collect complementary advanced MRI studies (not available in ABC-DS) and fluid biomarkers, to examine brain microstructural properties which may be more a) sensitive to neurodegenerative changes when compared to traditional MRI and b) complementary to PET imaging. Together, the results of this proposal will advance a mechanistic understanding of DS- and AD-specific pathological brain changes and how reorganization of functional networks relate to neuropsychological changes. Further, these data form the basis for a follow-up R01 combining ABC-DS emerging longitudinal data with advanced complementary MRI and multimodal biomarkers.