ABSTRACT Down syndrome (DS) is the most common genetic cause of intellectual disability and occurs in about 1 in 700 infants. Adults with DS are at high risk for premature cognitive decline and increased incidence of Alzheimer’s disease (AD). Virtually all individuals with DS over 30 years of age have the hallmark AD neuropathology of beta amyloid plaques and neurofibrillary tangles. Certain cognitive functions decline in DS between 30 and 40 years old and the decline is predictive of later AD diagnosis, yet few longitudinal studies have examined younger individuals. Individuals with DS in late adolescence and early adulthood likely have begun to exhibit neuropathology of AD, but AD diagnosis itself is extremely rare. The broad, long-term objective of the parent project, Early Cognitive Decline in Down Syndrome (R01HD098179), is to identify cognitive skills that show early decline in individuals with DS during late adolescence into early adulthood. This longitudinal study, conducted at the University of Alabama (UA) and the University of California Davis (UCD), will enroll participants with DS aged 15-25 years and follow them for three years. The goal of the proposed supplement is to add neuroimaging to the existing parent R01, and thereby help to contribute to the identification of a set of unique indicators of early cognitive decline and that foreshadow subsequent AD in individuals with DS. Neuroimaging markers will also be evaluated in conjunction with blood biomarkers for AD collected through the first administrative supplement. Aim 1 of the present supplement is to acquire structural, diffusion, perfusion, and resting state fMRI scans in 30 participants with DS at each site (60 total) using innovative strategies designed to help individuals with intellectual disability participate in MRI research. Imaging will coincide with the first time point of behavioral data collection from the parent grant. Aim 2 is to quantify multi-modal anatomical and vascular neuroimaging biomarkers of AD, including cortical morphometry, hippocampal subfields, white matter microstructure and cerebrovascular disease, cerebral blood flow, and network connectivity using image processing pipelines developed by the UC Davis Alzheimer’s Disease Research Center Neuroimaging Core. Neuroimaging biomarkers will be assessed in relation to concurrent cognitive and behavioral measures as well as in relation to blood biomarkers such as plasma concentrations of Aβ, tau protein, and neurofilament light chains (NfL). At the conclusion of the parent R01, neuroimaging biomarkers will be evaluated as predictors of cognitive decline assessed through the parent R01 over a three- year period after the MRI scan. Quantified neuroimaging data and raw images will be made available for sharing with other researchers through the INCLUDE Data Coordinating Center (DCC). Adding AD-sensitive MRI indices has the potential to greatly enhance the value of the neurocognitive, behavioral, and blood-based indicators of decline and risk already being collected.

NARRATIVE This neuroimaging supplement will allow us to acquire multimodal MRI scans and quantify neuroimaging biomarkers of early decline in adolescents and young adults with Down syndrome that may foreshadow the subsequent transition into Alzheimer’s Disease. The participants will be recruited and evaluated through the parent R01. Adding AD-sensitive MRI indices has the potential to greatly enhance the value of the neurocognitive, behavioral, and blood-based indicators of decline and risk already being collected. Identifying the earliest, non-invasive biomarkers for neurodegenerative decline will aid in intervening as early as possible, potentially prior to behavioral indications of cognitive decline. .