PROJECT SUMMARY The Down Syndrome – Ambulatory Research in Cognition (DS-ARC) study will develop and validate a smartphone-based digital cognitive assessment designed specifically for participants at risk for Down syndrome-associated Alzheimer’s disease (DS-AD). We will partner with sites in London, Barcelona, Munich, and Gothenburg to develop and validate this approach in different cultures and languages. Nearly all individuals with Down syndrome have elevated levels of Alzheimer’s disease (AD) biomarkers by the time they are in their 30s or 40s, though not all show symptoms of AD. It is during the pre-symptomatic and early symptomatic stages of DS-AD that an in-depth understanding of cognitive changes is crucial, as therapeutic interventions to stop, slow, or prevent disease are focused on these critical periods. Typically, prevention trials and observational studies in AD populations assess cognition with standard “table top” paper and pencil tests. But these conventional methods have several drawbacks. First, performance is influenced by day to day fluctuations in stress, fatigue, sleep patterns, and mood. Second, the testing takes place in environments that are fundamentally different from where cognition is relied upon to function in daily life. Finally, by design, cognition is typically assessed in “one-shot” in extended testing sessions on an annual or semiannual basis. The DS-ARC study will address these difficulties by developing a smartphone-based assessment solution adapted specifically for individuals with Down syndrome. This approach uses a measurement “burst” design in which participants complete very brief cognitive tests on their smartphones several times per day for one week while living in their natural environments. Instead of focusing on one of these measurements, tests are averaged across the week to provide a score that captures and normalizes natural variability and dramatically increases reliability. Studies of our original ARC assessments in autosomal dominant and sporadic AD demonstrate extraordinary reliability and strong relationships with AD biomarkers, while reducing costly and burdensome in-clinic evaluations. The study has two phases: a 2-year development phase and a 3-year validation phase. In the development phase, we will adapt an existing smartphone application called the Ambulatory Research in Cognition (ARC) app for use in DS-AD studies. This will include an iterative pilot testing process for psychometrics and task development, focus groups and user experience testing to address accessibility and compatibility concerns for DS-AD populations, and readiness audits to ensure that the DS- ARC app meets strict compliance guidelines for clinical trial applications. In Phase 2, participants complete DS- ARC assessments every 6 months and complete standard clinical, cognitive, and blood tests for AD biomarkers annually. We hypothesize that DS-ARC assessments are accessible, sensitive, and reliable indicators of co...