Plasma p-tau181 as a Marker of Conversion to Alzheimer's Disease Dementia and Worsening in Cognitive Functions in Subjective Cognitive Decline and Mild Cognitive Impairment: A Longitudinal Study

Background: Plasma p-tau181 has proven to be a promising diagnostic and prognostic tool in the earliest phases of Alzheimer's disease (AD). We aimed to evaluate the prognostic role of p-tau181 in predicting conversion to AD dementia and worsening in cognition in mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Methods: We consecutively enrolled 163 patients (50 SCD, 70 MCI, and 43 AD-demented (AD-d)), who underwent plasma p-tau181 analysis with the Simoa assay. Patients were classified according to the Revised Criteria of the Alzheimer's Association Workgroup as Core1+ or Core1− (based on amyloid-PET, CSF Aβ42/Aβ40, CSF p-tau181/Aβ42). Results: Plasma p-tau181 levels were significantly influenced by Core1 status (B = 1.41, p < 0.001) and clinical diagnosis (B = 0.63, p < 0.001). Plasma p-tau181 was highly accurate in discriminating between Core1+ and Core1− patients (AUC = 0.88 [95% CI 83.00–94.00]) with a cut-off value of 2.25 pg/mL presenting good accuracy (85.90%), specificity (74.58%), and excellent sensitivity (92.78%). Classifying patients according to p-tau181 cut-off, we found that p-tau181+ patients showed an increased risk of converting to AD dementia (HR = 11.65, p = 0.018). Moreover, SCD p-tau181+ worsened over time in tasks assessing long-term verbal (p = 0.012) and spatial memory (p = 0.009). Conclusions: Plasma p-tau181 is not only a good diagnostic marker for AD pathology, but it also plays a role as a predictor of both conversion to AD dementia and of worsening of cognitive performance since the earliest phase of AD. © 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.