Plasma biomarker strategies to reduce diagnostic uncertainty in p-tau217-based assessment of CSF amyloid positivity in secondary-care patients with MCI.

Introduction: Plasma p-tau217 accurately reflects amyloid pathology, but dual-cutoff strategies leave a non-negligible grey zone requiring confirmatory testing. We evaluated whether integrating plasma Aβ measurements could reduce diagnostic uncertainty in patients with mild cognitive impairment (MCI). Methods: Plasma p-tau217 was measured using the Lumipulse platform, and plasma Aβ40 and Aβ42 were quantified by liquid chromatography-mass spectrometry (ABtest-MS) in 186 secondary-care MCI patients. CSF Aβ42/Aβ40 defined amyloid status. Logistic regression models were compared, and dual-cutoff strategies targeting 95% predictive values were applied. Results: p-tau217 was the strongest individual biomarker. Models incorporating plasma Aβ measures improved AUC, model fit, and reduced the grey zone from 27.4% with p-tau217 alone to 12.3%. A sequential two-step strategy restricted additional Aβ testing to p-tau217-indeterminate cases and reduced the final grey zone to 13.4%. Discussion: Plasma Aβ measurements complement p-tau217 by reducing the indeterminate results, with the potential to improve diagnostic efficiency and streamline diagnostic workflows.