The prognostic value of blood-based p-tau217 levels on progression to clinical impairment.

Plasma p-tau217 closely tracks amyloid-β (Aβ) pathology, yet its ability to predict long-term clinical progression in cognitively unimpaired (CU) adults remains uncertain. We analyzed harmonized data from 2,705 CU participants (Agemean=69.8±7years; Female=63%) across six longitudinal cohorts with up to 13.5 years of follow-up. Cox models evaluated associations between p-tau217 and progression to a clinical diagnosis of cognitive impairment, while natural cubic spline models assessed associations with longitudinal decline on a cognitive composite. Higher p-tau217 was associated with increased risk of progression (hazard-ratio[HR]=1.38; 95%CI:1.31-1.44), independent of demographics and APOEε4, and in models with Aβ-PET (HR=1.30; 95%CI:1.23-1.38). Very high p-tau217 levels (>2.5SD) were associated with 61%[95%CI:53-68%] absolute risk of progression over 10 years. Elevated p-tau217 associated with accelerated cognitive decline, both independent of, and synergistic with, greater Aβ-PET. These findings establish plasma p-tau217 as a robust prognostic marker in preclinical AD and support its value in future individualized risk prediction.