Novel insights into Alzheimer's disease through the study of individuals with Down syndrome

Novel insights into Alzheimer's disease through the study of individuals with Down syndromePeople with Down syndrome (DS) represent the largest genetically defined population at risk for Alzheimer's disease (AD). 1 Virtually all adults with DS develop AD neuropathology by midlife due to triplication of the amyloid precursor protein (APP) gene on chromosome 21.As medical advances and social integration have extended life expectancy into the 60s, AD has emerged as the major determinant of cognitive decline, morbidity, and mortality in this DS population. 2 What was once viewed as an inevitable consequence of aging in DS is now recognized as a unique scientific opportunity to uncover the earliest events that drive AD.The predictable and accelerated course of DS-associated AD (DSAD) provides an unparalleled window into the molecular and cellular origins of amyloid and tau pathology, neuroinflammation, cerebrovascular pathology, and neurodegeneration.It allows us to study, with precision, the sequence of pathological changes long before symptoms emerge.This is knowledge that benefits not only individuals with DS but also the broader AD community seeking to prevent disease before it begins.The past decade has witnessed a transformation in DSAD research, driven by unprecedented collaboration, infrastructure, and investment.Large-scale international initiatives such as the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS), 3,4 the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI), 5 the Horizon 21 Consortium (https://horizon-21.org/) 6 and the Trial Ready Cohort-Down Syndrome (TRC-DS) (https://www.trcds.org/)are reshaping our understanding of the natural history of AD in DS.Together, these cohorts provide longitudinal, multimodal data encompassing clinical, cognitive, fluid, imaging, and genetic measures, allowing harmonized comparisons across continents and with sporadic and autosomal dominant forms of AD.Equally important has been the extraordinary increase in research investment, particularly through the National Institutes of Health (NIH) and its National Institute on Aging (NIA), catalyzed by the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project (https://www.nih.gov/ include-project).This strategic funding initiative has enabled infrastructure for multi-site studies, data sharing, and advanced biomarker development, while also fostering the training and expansion of a new generation of DSAD investigators.The impact has been dra-