Decoding Alzheimer's disease through down syndrome: insights from a genetically defined population

This review explores Alzheimer's disease (AD) in individuals with Down syndrome (DS), a genetically defined population with near-universal development of AD neuropathology by age 40. We examine the genetic basis of DS-AD, epidemiology, biomarker trajectories, and clinical trial innovations, highlighting how insights from DS research inform broader AD pathogenesis, early detection, and therapeutic strategies.

Advances in biomarker research, including longitudinal studies such as ABC-DS, have mapped predictable trajectories of amyloid, tau, and neurodegeneration in DS-AD, aligning closely with clinical staging. Plasma and CSF biomarkers (Aβ42, p-tau, NfL, GFAP) and neuroimaging modalities (amyloid/tau PET, MRI) demonstrate early and sequential changes decades before dementia onset. Revised AD diagnostic criteria now classify DS individuals as Stage 0 from birth, acknowledging genetic determinism and enabling earlier intervention. Comparative analyses between DS-AD, autosomal-dominant AD, and sporadic AD reveal shared pathological features but distinct timing and distribution of amyloid and tau. Clinical trials targeting amyloid and APP pathways in DS are underway, leveraging predictable disease progression to accelerate therapeutic development.

Studying AD in DS provides a unique lens into the natural history of Alzheimer's disease, offering critical insights into genetic drivers, biomarker evolution, and therapeutic opportunities. The genetically defined and biologically concordant nature of DS-AD enables precise staging and early intervention strategies that can be translated to sporadic and familial AD. Continued investment in DS research will advance biomarker validation, refine clinical trial design, and inform personalized treatment approaches for the broader AD population.