Background and Significance: Down syndrome is a condition in which a person is born with an extra copy of chromosome 21. The condition is associated with intellectual disability, a characteristic facial appearance, and weak muscle tone (hypotonia), particularly in infancy. People with Down syndrome may have a variety of birth defects; about half of all affected children are born with a heart defect, and some also have intestinal atresias. Individuals with Down syndrome have an increased risk of developing several medical conditions, including childhood leukemias, hearing and vision problems, gastroesophageal reflux, diabetes, obesity, hypothyroidism, and celiac disease. The rate of Attention Deficit/Hyperactivity Disorder (ADHD) is three to five times higher than in the general population, and other neurological conditions such as seizures, autism, and behavioral problems are also more common in those with Down syndrome. Individuals with Down syndrome have an increased risk of infections such as pneumonia, due in part to immunological differences, airway anatomical factors, and comorbidities such as heart defects and pulmonary hypertension. About half of adults with Down syndrome develop Alzheimer’s Disease (AD), and the risk increases with advancing age (generally starting around the mid-50s or later). At the same time, people with Down syndrome are “protected” from other common conditions in the adult population, such as hypertension, coronary artery disease, and most forms of solid tumors such as breast cancer. Despite increases in lifespan among individuals with Down syndrome, opportunities for them to participate in medication trials have been hampered by difficulties in recruiting large enough clinical cohorts, limited knowledge of appropriate endpoints and outcome measures for this population, lack of stratification to identify positive responses to medications above placebo effects, and lack of resources to sustain a clinical trials program for the long-term that would allow new therapeutics to be tested. One of the potential barriers to drug development trials for drugs to be used by people with Down syndrome is the limited and/or lack of knowledge of how these individuals may metabolize drugs, including basic knowledge about pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenomics (PGx) in Down syndrome populations. For example, children with Down syndrome require lower doses of cytotoxic drugs to treat their leukemia. NIH’s new INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) project may help to address some of these questions. The project is a comprehensive, trans-NIH strategy to address critical health and quality-of-life needs for individuals with Down syndrome. The main goals of the INCLUDE project are: to support clinical trials on conditions and diseases that disproportionately affect people with Down syndrome, both to accelerate the development of new therapies tailored ...