Project Summary This administrative supplement is submitted in response to the NOSI for funded projects to meet NIH Down Syndrome (DS) research objectives related to NIH’s Investigation of Co-occurring conditions across the Lifespan to Understand Down syndrome (INCLUDE) project (NOT-OD-20-024). Adults with DS are at high risk for Alzheimer’s disease (AD) due to trisomy 21. However, there is marked variability in the age of onset of early Alzheimer’s disease pathology and age of onset of clinical dementia in DS. The goal of the parent R01 is to examine the effect of four lifestyle factors – physical activity, sleep, cognitive stimulation, and social engagement – on imaging and biofluid biomarkers of AD, cognitive decline, and clinical AD status in adults with DS. The parent R01 includes three study sites and enrolls 140 adults with DS who are also enrolled in the NIH- funded Alzheimer’s Biomarker Consortium in DS (ABC-DS; U19 AG070043). The goal of the administrative supplement is to strengthen the parent R01 by increase sample number but also by increasing sample socio- demographic diversity. This larger and more diverse sample will then be leveraged to conduct new mediational analyses to elucidate pathways between lifestyle factors and AD in DS. The supplement is also aimed at testing advanced analytic methods for accelerometer data as a non-invasive biomarker of sleep and physical activity in DS. To accomplish these goals, the supplement involves enrolling 40 additional adults with DS into the parent R01 by including a new study site (University of California-Irvine). Lifestyle data will be collected on this new cohort at one time point. Information on physical health, sleep, cognitive stimulation, and social engagement will be collected using self/informant report and objective measures (actigraph and WatchPAT). Data collection of lifestyle factors will correspond in time with ABC-DS data collection of AD biomarkers (PET Aβ, PET tau, PET FDG, structural and functional MRI, and CSF Aβ and tau, and blood), cognitive functioning, and dementia symptoms and status. The specific aims of the administrative supplement are to: 1) Increase the number and sociodemographic diversity (geographical location, race, and age) of participants from ABC-DS enrolled in the parent R01; 2) Test mediational models of the pathways through which lifestyle factors influence AD pathology, cognitive decline and the timing of the transition to MCI and AD dementia in DS; and 3) Compare strategies for processing and analyzing accelerometer data as a biomarker of physical activity and sleep disruptions in adults with DS. Information from the supplement will help determine if lifestyle is an important modifiable resiliency mechanism for delaying AD in adults with DS.

Project Narrative Adults with Down syndrome are at high risk of developing Alzheimer’s disease. The parent R01 addresses this public health crisis by investigating the effect of modifiable aspects of lifestyle (physical activity, sleep, cognitive stimulation, and social engagement) on biomarkers of Alzheimer’s disease and cognitive decline in adults with Down syndrome. This supplement builds on this effort by increasing the sample size and diversity and employing new innovative mediational analyses and methods for non-invasive biomarkers of sleep and physical activity in everyday life.