Clinical Core Abstract Virtually all adults with Down Syndrome (DS) have neuropathological changes consistent with Alzheimer Disease (AD) by age 40, including deposition of β amyloid peptide (Aβ) in diffuse and neuritic plaques, and most will develop clinical dementia by their late 60s.The high risk for AD has been attributed, at least in part, to triplication and overexpression of the gene for amyloid precursor protein (APP) on chromosome 21, leading to elevated levels of Aβ peptides The ABC-DS study is designed to understand the pathophysiological and clinical changes in adults with DS as they experience progression of AD from its earliest preclinical stages through frank dementia. The purpose of the Clinical Core is to provide participants with DS (and sibling controls), clinical data, and biological specimens to enable the goals of each project. This ultimately involves providing a best practice profile of abilities and health status to arrive at a valid clinical classification of dementia status. The Core will undertake the longitudinal assessment of a cohort of 720 individuals to maintain an active cohort of 550 adults with DS and 50 sibling controls. Over the course of this five-year project, participants will be seen for up to four evaluations (separated by 16 months). Data collection will include neuropsychological evaluations, caregiver questionnaires of functioning and possible dementia symptoms, a physical/neurological examination, blood for genetics, lipidomics and proteomics analyses, MRI and PET scans (amyloid, tau, FDG) and LP. The accumulating clinical data will be entered comprehensively into the ATRI database so it can be available for correlative analyses with the rich biological data generated from the same participants in Projects 1-3. The prospective clinical data will form the basis of cross sectional and longitudinal analyses of potential biomarkers and will enable the phenotypic correlations essential to understanding how they relate to disease risk, onset, severity, progression, and symptoms.