Abstract People with Down syndrome (DS) develop Alzheimer disease (AD) neuropathology, including Aβ plaques and tau neurofibrillary tangles by the age of 40 years. However, the age of onset of cognitive decline, mild cognitive impairment (MCI) and dementia can occur over 10 years later, with individual variability in the age of onset. The overarching goal of ABC-DS is to understand biomarkers that predict conversion from cognitively stable to MCI or dementia and potentially the age of onset. Biomarkers in ABC-DS includes neuroimaging (MRI and PET), proteomics, metabolomics and genomics (blood/cerebrospinal fluid/DNA). In this supplement to ABC-DS, we propose to leverage the neuropathology core's collection of tissue from brain donations prospectively as well as the legacy autopsy cohort (U01AG051412, R01HD064993) to accomplish 2 aims: (1) to create an amyloid/tau/neurodegeneration framework (AT(N)) for neuropathology in clinically characterized cases with age as the dependent variable and (2) to define DS-specific gene expression changes in a spatially resolved manner. Thus, we are requesting funds to allow us to examine the brains from 30 people with DS and make comparisons to 20 age matched neuropathology-free controls (from the NIH Neurobiobank) with tissue being at UCI. Studies for Aim 1 includes a series of immunohistochemical identification of proteins of interest involving Aβ, tau, neuroinflammation, cerebrovascular pathology as well as non-AD associated pathologies (e.g. Lewy bodies, TDP-43), in brain regions involved in AD pathogenesis, with digital pathology and quantification approaches. In parallel using frozen tissue from the same cases, we will use spatial transcriptomics and the 10X genomics Visium platform to conduct single nucleus RNA sequencing. The successful completion of these studies will provide a rich dataset that can be shared and made available to other researchers, permit the testing of hypotheses related to the Projects in U19AG068054, and set the stage for neuropathology data acquisition in prospective ABC-DS brain donations.