Plasma p-tau217 best captures early longitudinal cognitive changes in subjective cognitive decline compared with p-tau181 and NfL

Background Blood-based biomarkers are increasingly used to support the biological diagnosis of Alzheimer’s disease (AD), but their prognostic value in subjective cognitive decline (SCD) remains incompletely understood. We investigated whether plasma p-tau217, p-tau181, and neurofilament light chain (NfL) are associated with domain-specific longitudinal cognitive changes in SCD. Methods 76 SCD patients underwent plasma biomarker assessment and extensive neuropsychological evaluation at baseline and after two years. Participants were classified according to plasma biomarker status: p-tau217-negative, gray-zone, or positive; p-tau181-negative or positive; and NfL-negative or positive. Linear mixed effects models with random intercepts were used to assess the effects of time, biomarker status, and their interaction on cognitive outcomes. Results Plasma p-tau217 showed the most consistent association with longitudinal cognitive trajectories. p-Tau217-positive participants declined in short story delayed recall and visual search, while gray-zone participants showed an intermediate memory trajectory. For category fluency, p-tau217-negative participants improved over time. Plasma p-tau181 showed weaker and less consistent associations, mainly involving memory measures and emerging primarily in post hoc analysis. NfL was associated with a more heterogeneous profile, without a clear pattern of longitudinal cognitive decline. Discussion Plasma p-tau217 was associated with early domain-specific cognitive vulnerability in SCD, involving episodic memory and attentional functioning. These findings suggest that plasma p-tau217 showed more consistent associations with early domain-specific cognitive changes than p-tau181 and NfL, supporting its role in cognitive stratification of individuals within the earliest stages of the AD continuum.