ABSTRACT Down syndrome (DS) is a caused by an error in cell division resulting in an extra copy of chromosome 21. The outcome is intellectual disability, physical features, and several medical vulnerabilities. Further, DS is associated with accelerated aging processes and very high risk for Alzheimer’s disease (AD). The classic components of AD neuropathology - amyloid plaques and neurofibrillary tangles (NFTs) – are both affected by overexpressed genes that are on chromosome 21. One of these genes is APP, which produces amyloid beta (Aβ) precursor protein and, can, in abundance, result in harmful buildup of Aβ deposits (plaques) in the brain. Several other genes that are on chromosome 21, including DYRK1A, contribute to buildup of Aβ deposits and tau deposits (NFTs) as well as neuroinflammation and elevated cholesterol - all of which contribute to AD. To date, it is known that cognitive decline in DS can be detected in adults with DS who are in their 30’s and 40’s, and some declining functions are predictive of later AD diagnosis. We argue that some declines may be detectable at an earlier age, especially because AD neuropathology begins well before age 20 years in those with DS. Thus, in our parent R01 study, Early Cognitive Decline in Down Syndrome (R01HD098179), we examine decline over three years in cognitive, language, and behavioral functions in adolescents and young adults, age 15-25 years. If decline can be detected at this young age, it may be possible to develop preventive therapeutics that can potentially improve quality of life and slow the progression of early aging and AD in individuals with DS. The broad, long-term goal of the present supplement project is to add blood collection and banking to the parent study. Blood-based biomarkers that are associated with AD may help distinguish between early declines that are symptoms of accelerated healthy aging and early declines that are symptoms of pre-clinical AD. Aim 1 of the 1-year supplement project is to collect and bank blood samples from participants with Down syndrome at Time 1 of the parent study. All participants with DS who are enrolled in the parent study (N = 60) will be invited for blood draw at Time 1 of the parent study. Blood will be banked at University of California Davis. Aim 2 is to quantify biomarkers from the blood samples and create a dataset of biomarker indices. The biomarkers of interest include amyloid beta, tau, and DYRK1A protein; as well as Neurofilament Light, inflammatory markers, cholesterol/lipid levels, thyroid levels, and APOE polymorphisms. When the parent study has been completed, the biomarker data will be analyzed along with the behavioral data from the parent study to identify declines that are related to early progression to AD.

NARRATIVE The proposed supplement project will allow us to collect, bank, and analyze blood from participants with Down syndrome from the parent study. After the conclusion of the parent study, we will be able to to identify which early cognitive changes in adolescents/young adults with Down syndrome are related to blood-based biomarkers of AD. This information will increase our understanding of the time course of early aging and AD progression in DS and ultimately inform future potential interventions to slow or mitigate these conditions.