PROJECT SUMMARY In addition to intellectual disability, individuals with Down syndrome (DS, Trisomy 21, Ts21) have an increased risk for many other health conditions, including Alzheimer’s disease (AD). DS is the leading genetic risk factor for AD, and nearly 90% of individuals with DS develop AD (DS-AD). Beta-amyloid (Aβ) plaques and tau tangles, characteristic AD pathology, begin accumulating in DS brains earlier than in the general population, and most individuals with DS are diagnosed with DS-AD in their early to mid-50s. Basal forebrain cholinergic neurons (BFCNs), involved in arousal, learning, attention, and memory, are a susceptible population prone to degeneration in DS-AD as well as other neurodegenerative diseases, including AD, Parkinson’s disease (PD), and Dementia with Lewy bodies (DLB). Little is known about BFCN development and molecular mechanisms underlying vulnerability. Limited analysis of human DS tissue suggests fewer BFCNs populate the basal forebrain, however, it remains unclear whether the reduction is due to developmental deficits, accelerated degeneration, or a combination of both. The goals of the F99 pre-doctoral proposal are to 1) determine whether fewer BFCNs and AD pathology are present in the early postnatal DS basal forebrain, 2) identify underlying molecular signatures that may contribute to the susceptibility of BFCNs later in life, and 3) model BFCN development in vitro using isogenic of Ts21 and control induced pluripotent stem cells. The goals of the K00 post-doctoral proposal are to 1) analyze tissue across the lifespan at different disease stages to determine the temporal order of AD pathology accumulation in the DS basal forebrain, and 2) sequence basal forebrain tissue from DS-AD, AD, PD, and DLB to determine if shared mechanisms underlie BFCN vulnerability across several neurodegenerative diseases. This F99 proposal will be the first study of human DS post-mortem tissue to reveal early deficits in DS BFCNs, suggesting deficits in DS BDCN development. Elucidating early post-natal deficits in DS BFCNs may inform early interventions and improve BFCN health across the lifespan. The K00 proposal will be the first cross-sectional study of human DS post-mortem tissue to reveal early emerging pathology and molecular mechanisms contributing to the susceptibility of BFCNs in the basal forebrain and elucidate shared mechanisms underlying BFCN vulnerability in several neurodegenerative diseases. Results may provide novel targets for therapeutics impactful for many neurodegenerative diseases. The results from this project will meet the goals of the NIH INCLUDE project by establishing scientific data to improve the health and neurodevelopment of individuals with Down syndrome and have a broader impact on the health of individuals at risk for other neurodegenerative diseases characterized by the loss of BFCNs, including DS-AD, AD, PD, and DLB.