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.