Abstract Down syndrome (DS) is associated with an elevated likelihood of co-occurring psychiatric conditions, including autism spectrum disorder (ASD). At present, little is known regarding the mechanisms that underly co-occurring DS and ASD. Advancing the scientific knowledge base in this area could facilitate the potential discovery of measurable biomarkers associated with early identification of ASD risk and also inform groundbreaking biomedical treatments targeting underlying molecular processes. This Administrative Supplement will expand the scope of parent project #R01HD110542 (Autism in Young Children with Down Syndrome) to identify early biosignatures associated with early ASD-related dimensions in young children with DS. To do so, this project will build on the parent study’s prospective design by collecting blood samples concurrently with study visits, and examine the link between early ASD features and multi-omics signatures in the transcriptome, proteome, and metabolome. Findings from the proposed Administrative Supplement project could facilitate the potential discovery of measurable biomarkers associated with early identification of ASD risk and inform groundbreaking biomedical treatments targeting underlying molecular processes. This study expansion will directly address the NIH INCLUDE objective of identifying the “unique combination of risk and resiliencies [to] inform medical advances for individuals with Down syndrome” and to improve health and well-being in this population.