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

People 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 dramatic, reflected in an exponential rise in peer-reviewed publications on DSAD over the past decade (Figure 1). The field has matured from a niche interest to a globally connected research network producing high-quality, high-impact science. The consistency of amyloid overproduction in DS and the predictable onset of pathology make DSAD uniquely suited to testing preventive and disease-modifying therapies. This special issue of Alzheimer's & Dementia showcases the breadth and maturity of this field, from molecular mechanisms to clinical and societal perspectives, and highlights the essential role of inclusion and partnership. One particularly important contribution comes from a self-advocate with Down syndrome, who reminds us that meaningful progress requires inclusive research with and not just about people with DS. Context and public health Etiology and biological basis Mechanisms Genetics Neuropathology Clinical expression Clinical aspects Cognition Biomarkers Blood-based biomarkers Neuroimaging Methods MRI PET Prevention and modifiable factors Lifestyle Future directions The implications of DSAD research now extend well beyond the boundaries of the syndrome itself. Insights gained from DSAD cohorts are informing biomarker validation, clarifying the interplay between amyloid and tau, and guiding therapeutic strategies for all forms of AD. As anti-amyloid and anti-tau treatments enter clinical practice, the inclusion of individuals with DS in clinical trials is both an ethical imperative and a scientific necessity, one that promises to improve care for all. The study of AD in DS is no longer tangential, it is central to the global effort to understand and defeat dementia. The convergence of large-scale collaboration, advanced biomarkers, and sustained funding has positioned the field at the threshold of transformative discovery. As we move forward, the lessons learned from DS will continue to illuminate the biology of AD in the general population, ultimately advancing the shared goal of extending healthy brain aging for all. The authors are grateful to all the people with Down syndrome and their families who have participated in research studies described in this special issue. The co-editors are also appreciative of the researchers who published papers in this special issue. EH and AC are supported by NIH/NIA U19AG068054. E.H. is also supported by NIH/NIA P30AG066519 and RF1AG079519. J.F. is funded by grants from the Fondo de Investigaciones Sanitario, Carlos III Health Institute (INT21/00073, PI20/01473, and PI23/01786), and the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Program 1, jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, una manera de hacer Europa. J.F. is also supported by NIH/NIA (R01AG056850, R21AG056974, R01AG061566, 1R01AG081394, and R61AG066543), the Department de Salut de la Generalitat de Catalunya (SLT006/17/00119), the Fundación Tatiana Pérez de Guzmán el Bueno (IIBSP-DOW-2020-151), and the Horizon 2020–Research and Innovation Framework Programme from the European Union (H2020-SC1-BHC-2018-2020). E.M.G. is supported by Alzheimer Association HPE-ADRD 24HPE1284307. Elizabeth Head has served as a consultant for Alzheon and CycloTherapeutics and is a section editor for Alzheimer's & Dementia. Juan Fortea reported serving on the advisory boards, adjudication committees, or speaker honoraria from AC Immune, Adamed, Alzheon, Biogen, Eisai, Esteve, Fujirebio, Ionis, Laboratorios Carnot, Life Molecular Imaging, Lilly, Novo Nordisk, Perha, Roche, and Zambón. Juan Fortea reports holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to ADx, WO2019175379). Ann Cohen and Eimear McGlinchey have no conflicts to report. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.