The tau biomarker cascade is condensed in Down syndrome compared with sporadic Alzheimer’s disease

Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium-Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analysed on the Lilly Meso Scale Delivery Platform were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modelling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help to identify optimal treatment windows for these individuals.