Project 1 Abstract An overarching theme of the Alzheimer's Disease Biomarkers-Down syndrome (ABC-DS) program is to characterize Alzheimer disease (AD) in Down syndrome (DS) and to determine if it has a pathological progression comparable to late onset AD (LOAD) and thus can inform translational research focused on prevention and treatment for all people with AD. People with DS are at extremely high risk of AD in middle age due, at least in large measure, to lifelong overexpression of the gene coding for APP, located on Chr. 21. A hypothesized model has been proposed for LOAD consisting of early amyloid (A) deposition followed by tau (T) deposition and then neurodegeneration (N) (AT(N)). Inflammation and cerebrovascular disease (CVD) are more common in adults with DS and may modify the AT(N) framework. Project 1 utilizes outcomes collected by ABC- DS Cores to follow the conversion of adults with DS from when they are clinically unaffected by AD to progression of incident MCI-DS and subsequent dementia. This project will determine if the AT(N) framework is descriptive of AD progression in adults with DS and, if different, in what way. A second priority is to determine if AD risk and progression is modified by certain risk factors. Aim 1 examines the AT(N) framework with regard to the development of symptomatic cognitive decline (MCI-DS/Dementia). We hypothesize that early changes in amyloid (A) are followed by changes in neurofibrillary pathology (T) and then changes in neurodegeneration (N). We predict the overall sequence of events that leads to symptomatic cognitive decline in DS is similar to AD in other at risk AD populations but quantitative differences will be present in the time span over which these events occur. Aim 2 examines the contribution of selected factors that modify the risk or progression to cognitive decline (MCI-DS/dementia) and in the AT(N) framework to lead to individual variability in DS. We hypothesize that inflammatory changes and cerebrovascular disease (CVD) modify the risk of amyloid and tau deposition. Furthermore, we hypothesize that sex and commonly co-occurring medical conditions (e.g. seizures, hyperlipidemia, obesity, and sleep apnea) may contribute to the heterogeneity in the age at onset of MCI-DS and/or the rate of progression from MCI-DS to dementia. Aim 3 examines select factors that contribute to within- population variability in AD vulnerability in collaboration with Projects 2 and 3. Results from this Project could contribute to efforts to discover effective intervention(s) within this high risk population and for AD more broadly.