INTRODUCTION: People with Down syndrome (DS) often develop Alzheimer disease (AD). Here we asked whether ultrasensitive plasma immunoassays for a tau N-terminal fragment (NT1-tau) and Aβ isoforms predict cognitive impairment. METHODS: Plasma NT1-tau, Aβ (37) , Aβ (40) , and Aβ (42) levels were measured in a longitudinal discovery cohort (N = 85 participants, 220 samples) and a cross-sectional validation cohort (N = 239). We developed linear models and predicted values in the validation cohort. RESULTS: Linear mixed models for NT1-tau, Aβ (42,) and Aβ (37:42) were significant for age, there was no main effect of time in the discovery cohort. In cross-sectional models, NT1-tau and Aβ (42) increased with age. NT1-tau predicted DLD scores. The discovery cohort linear model for NT1-tau predicted NT1-tau levels in the validation cohort. DISCUSSION: NT1-tau correlates with age and worse cognition in DS. Further validation of NT1-tau and other plasma biomarkers of AD neuropathology in DS cohorts is important for clinical utility.