ABSTRACT This is an application for a 1-year administrative supplement to U19 AG068054 “Alzheimer Biomarker Consortium – Down Syndrome” (ABC-DS, PI: B. Handen, E. Head). This “analysis-only” proposal will build upon an impressive body of multidisciplinary work that has utilized Positron Emission Tomography (PET) imaging of individuals with Down Syndrome (DS) to reveal age-related, DS-specific, and Alzheimer’s disease (AD)-related neuropathophysiological changes in FDG metabolism and amyloid-beta (Aβ) and tau protein deposition. The emergence and progression of AD in DS has been an important focus of many of these studies that were performed in large part by members of the ABC-DS consortium. In this research, we will develop a multivariate multimodal analysis framework that will better leverage the complexity and richness of multimodal neuroimaging datasets to provide improved spatiotemporal mapping of Aβ and tau accumulation and enable more sensitive detection of early and progressive pathophysiological changes in DS, relative to prior assessments. The specific aim is to perform joint pattern analyses of baseline and longitudinal Aβ and tau PET neuroimaging data acquired in sibling controls and individuals with DS to identify spatiotemporal patterns of Aβ and tau uptake that are more sensitive to progressive pathophysiological brain changes, than prior methods. We will apply multiset canonical correlational analysis (MCCA) and orthogonal signal correction (OSC) to Aβ and tau data acquired at baseline and 16-month longitudinal follow-up in sibling controls and individuals with DS (across the continuum of cognitively stable, mild cognitive impairment, and AD continuum). We will evaluate these patterns with consideration of other pathophysiological markers, cognitive status, and demographic and genetic variables. Assessment of early/preclinical change will include examination of Aβ striatal patterns and early detection of tau deposition in entorhinal cortex in the context of subsequent detection of tau spread to cortical areas with disease progression. We will also evaluate the relationship of Aβ and tau to other pathophysiological markers (e.g., MRI volumetric measures), to cognitive performance and include covariates (e.g., age, education, and genetic risk factors), in consideration of factors contributing to the biological and clinical heterogeneity in DS. This work will provide a more comprehensive and personalized evaluation of the individual’s status. The analysis platform will be shared to facilitate feasible multimodal analyses and promote novel multimodal science, multimodal hypothesis development, and multidisciplinary ABC-DS collaboration. This research is highly relevant to the goals and priorities of both the parent ABC-DS grant (U19 AG068054, “Alzheimer Biomarker Consortium – Down Syndrome”) and the INCLUDE project.