Prognostic Value of Blood-Based P-Tau217 Levels for Progression to Cognitive Impairment

Importance: Blood-based biomarkers for Alzheimer disease, particularly plasma phosphorylated tau 217 (p-tau217), accurately reflect early Alzheimer disease brain pathology in cognitively unimpaired individuals, but estimates of absolute risk of progression to cognitive impairment across multiple cohorts are needed. Objective: To estimate absolute risk of progression to cognitive impairment and rates of cognitive decline based on plasma p-tau217 across cognitively unimpaired older adults. Design, Setting, and Participants: Longitudinal cohort study using harmonized data from 2684 cognitively unimpaired older adults (defined within cohort) across 6 observational and clinical trial cohorts based in North America, Japan, and Australia. The earliest enrollment was in 2004, with most recent follow-up in 2025. Exposure: Baseline plasma p-tau217. Main Outcomes and Measures: The primary outcome was time to progression to cognitive impairment (mild cognitive impairment, dementia, or 2 consecutive global Clinical Dementia Rating scores ≥0.5). The secondary outcome was longitudinal change on the latent Preclinical Alzheimer Cognitive Composite (PACC; higher values indicate better performance). Results: Among the 2684 participants (median [IQR] age, 69.6 [66.2-74.2] years; 1697 [63%] female), there were 478 events of progression to cognitive impairment over a median follow-up of 5.4 years (maximum follow-up of 13.5 years). Each 1-SD increase in baseline p-tau217 level was associated with an increased risk of progression to cognitive impairment (hazard ratio, 1.38 [95% CI, 1.30-1.46]), and the association remained significant after adjustment, including β-amyloid positron emission tomography scan Centiloids (hazard ratio, 1.32 [95% CI, 1.24-1.41]). Participants with high (1.1-2.4 SD) and very high (>2.5 SD) baseline p-tau217 had 24% (95% CI, 20%-28%) and 38% (95% CI, 33%-43%) absolute risk of progression over 5 years, respectively, and risk was markedly higher over 10 years, although longer-term estimates were constrained by limited data. Elevated p-tau217 was also associated with faster cognitive decline based on change in latent PACC score. Among the overall sample, baseline latent PACC scores ranged from -0.8 to 2.7. The 5-year annualized decline for the very high p-tau217 group was -0.07 latent PACC units/y (95% CI, -0.10 to -0.05), relative to 0.03 units/y (95% CI, 0.02-0.04) in the low p-tau217 group. Conclusions and Relevance: In a pooled sample of multiple selected cohorts of cognitively unimpaired older adults, higher plasma p-tau217 levels were consistently associated with increased risk of clinical progression and accelerated cognitive decline. By providing time-specific absolute risk estimates, these findings support the potential of p-tau217 for prognostic model development, with direct implications for future trial design. Further validation in unselected populations is needed to inform individual prognosis and clinical decision-making in cognitively unimpaired individuals.