Electrochemical profiling of plasma pTau-181 levels associated with mild cognitive impairment and Alzheimer's disease using an MXene-gold nanorod interface.

Early diagnosis of Alzheimer's disease (AD) remains a major clinical challenge, particularly during the mild cognitive impairment (MCI) stage, where subtle cognitive changes overlap with normal ageing and reliable diagnostic indicators are limited. Plasma phosphorylated tau at threonine-181 (pTau-181) has emerged as a disease-specific biomarker associated with tau pathology and early neurodegenerative progression, with increasing evidence supporting its relevance for identifying individuals at risk of AD during the prodromal phase. However, accurate quantification of plasma pTau-181 is hindered by its extremely low concentration and the complex biochemical environment of blood. In this study, a label-free electrochemical impedance biosensor was developed for sensitive detection of plasma pTau-181 using a self-assembled two-dimensional MXene-gold nanorod (MXene-GNR) hybrid interface. Modification of a glassy carbon electrode with the MXene-GNR nanocomposite enhanced interfacial charge-transfer behaviour and increased the electroactive surface area by approximately 37%, enabling improved anti-pTau-181 immobilization and signal transduction. The biosensor exhibited a concentration-dependent impedance response toward pTau-181 over a wide dynamic range and achieved an ultrasensitive limit of detection of 12.561 fg mL-1 in 10% plasma spiked samples while maintaining high analytical selectivity. Clinical plasma analysis demonstrated statistically significant differentiation of AD and MCI groups from healthy controls (p < 0.001), supporting the relevance of plasma pTau-181 measurement for assessing disease-associated cognitive impairment. These findings demonstrate the potential of the MXene-GNR electrochemical platform as a minimally invasive approach for plasma biomarker evaluation toward early AD diagnosis and monitoring.