Association of Plasma Phosphorylated Tau 217 With Clinical Deterioration Across Alzheimer Disease Stages.

Background and objectives: Phosphorylated tau at threonine 217 (p-tau217) is a highly sensitive blood-based biomarker for Alzheimer disease (AD) pathology, showing high diagnostic accuracy. However, its prognostic value across different clinical stages of AD remains unclear. The aim of this study was to assess the prognostic utility of plasma p-tau217, measured using a commercially available immunoassay, regarding clinical and functional decline across the clinical stages of AD in a cohort with up to 10 years of follow-up.

Methods: We conducted a retrospective longitudinal cohort study using data from the Sant Pau Initiative on Neurodegeneration, a research project performed at the Sant Pau Memory Unit between 2011 and 2022. Participants were classified into clinical stages 1-6 based on AD pathology status in CSF, determined by the p-tau181/Aβ1-42 ratio. The primary outcomes were cognitive decline, measured by changes in the Mini-Mental State Examination (MMSE), and progression to dementia. Plasma p-tau217 and CSF p-tau181 levels were assessed, and statistical analysis was performed using linear mixed-effects models for longitudinal changes in MMSE scores and Cox proportional hazard regression was used to examine progression to dementia.

Results: A total of 731 participants (mean age 71.5 ± 10.1 years; 60% female) were included. Plasma p-tau217 levels showed a significant increase across advancing AD stages, with all between-group comparisons remaining significant after false discovery rate adjustment (p < 0.05). Longitudinal analysis showed a significant increase in plasma p-tau217 (β = 7.7, 95% CI 3.0-12.5, p = 0.002) and CSF p-tau181 (β = 3.2, 95% CI 1.4-5.0, p = 0.001). Baseline plasma p-tau217 levels were associated with faster MMSE decline (β = -0.08, 95% CI -0.11 to -0.05, p < 0.001) and progression to dementia (hazard ratio 1.03, 95% CI 1.01-1.05, p < 0.001), independent of clinical stage.

Discussion: Plasma p-tau217 was significantly associated with cognitive and functional decline in AD. These findings support the potential use of plasma p-tau217 as a prognostic marker for monitoring AD progression in clinical practice. Future studies should validate these results across diverse cohorts and explore their utility in early-stage detection and monitoring.