Longitudinal plasma p-tau217 as a marker for tracking progression and predicting cognitive decline in Alzheimer’s disease

Plasma phosphorylated tau217 (p-tau217) is a promising biomarker for Alzheimer’s disease (AD) with strong cross-sectional concordance with beta-amyloid (Aβ) and tau pathology. However, its longitudinal behavior across disease stages and assay platforms, and its prognostic value for cognitive decline according to Aβ status, remain insufficiently characterized. This study aimed to evaluate stage- and assay-specific longitudinal changes in plasma p-tau217 and to determine their utility for predicting cognitive decline. We analyzed longitudinal data from 393 participants in the NA-ADNI, including cognitively unimpaired (CU) and cognitively impaired (CI) individuals. Plasma p-tau217 was measured using five assay platforms. Linear mixed-effects models were used to assess longitudinal biomarker trajectories, with time as the primary predictor and random intercepts and slopes. Aβ status and time-by-Aβ interactions were included to examine differential trajectories. Annualized biomarker changes were derived and related to longitudinal cognitive outcomes using models of Clinical Dementia Rating-Sum of boxes (CDR-SB) scores. Marginal R2 values quantified the variance explained. Plasma p-tau217 levels increased significantly over time across all assay platforms in both CU and CI groups (all q < 0.05). The largest standardized time effects were observed for the ALZpath-Simoa assay (βstd = 0.112 in CU; βstd = 0.100 in CI). Aβ + individuals showed steeper longitudinal increases than Aβ- individuals, with interaction effects ranging from βint = 0.102 to 0.164 in CU and from βint = 0.070 to 0.113 in CI. Annualized changes in p-tau217 were associated with cognitive decline in a stage- and assay-dependent manner. In CU, change in %p-tau217 measured by C2N-MS showed the strongest association with CDR-SB progression (β = 0.075, q < 0.001). In CI, absolute p-tau217 change measured by C2N-MS showed the strongest association (β = 0.238, q < 0.001), particularly among Aβ + individuals. Adding annualized change of other plasma biomarkers provided modest and stage-dependent improvements, with GFAP yielding the greatest incremental value in CI. Longitudinal plasma p-tau217 is a robust marker of AD progression, but its optimal prognostic application depends on cognitive stage, Aβ status, and assay platform. These findings support stage-specific strategies for using serial plasma biomarkers in clinical monitoring and therapeutic trials.