PROJECT SUMMARY Endocrinopathies, sleep disorders, cognitive issues, cardiovascular conditions, sensory impairments, and ability differences not only impact the quality of life of individuals with Down syndrome (DS) and their caregivers but can intersect to magnify the threats of these co-occurring conditions. Moreover, individuals with intellectual disabilities face additional barriers surrounding healthcare access and their decision-making involvement that can jeopardize their health. The dearth of observational studies that richly detail co-occurring conditions, social determinants of health (SDoH), and the ableism individuals with DS experience represents a major challenge to providing clinical care to individuals with DS. Our long-term objective is to partner with clinicians, researchers, individuals with DS, and caregivers across the country to establish a diverse cohort of individuals with DS for comprehensive longitudinal phenotyping including multi-omics and to develop an infrastructure for intervention studies. This multi-center, multi-disciplinary collaborative team will engage individuals from infancy through young adulthood to undergo blood sample collection, imaging studies, qualitative interviews, questionnaire completion, sleep assessments, and remote physiologic monitoring while subsets will undergo additional specific procedures with the goal of rich longitudinal phenotyping across multiple systems: Endocrine: thyroid and gonadal function Cardiometabolic: lipids, inflammation, meal-related glucose excursion, insulin secretion & sensitivity Cardiovascular: blood pressure, arterial stiffness, and left ventricular mass and function Nutrition: anthropometrics, body composition, bone density, nutritional intake, and appetite/satiety Sleep: obstructive and central sleep apnea, hypoventilation, participant and caregiver sleep quantity and quality Physical Activity: sedentary, light, moderate, and vigorous activity Neurocognitive: caregiver reported and objectively assessed measures, peripheral blood Alzheimer disease markers, audiology, brain MRI, secondary analyses of sleep study EEG SDoH: family education, income, English proficiency, medical literacy, neighborhood characteristics Ethical Issues: decision-making involvement, experiences with ableism, and healthcare access Electronic Health Information: diagnoses, medications, procedures, labs, and imaging Multi-omics: genome, transcriptome, proteome, metabolome Procedures will be repeated at a cadence that depends upon baseline age (<15y, every 12-18 mo) or (>15-30y, every 24-30 mo), baseline results, pre-existing co-morbidities, and subsequent interventions. Community members will help inform study design and the specific procedures to be undertaken will be tailored to the abilities of individuals with DS and to minimize participant and caregiver burden.