Recent molecular insights and biosensor-based diagnostic technologies for hyperphosphorylated Tau in Alzheimer's disease.

Tau pathology is a defining feature of Alzheimer's disease (AD), with hyperphosphorylated Tau (p‑Tau) emerging as a central biomarker for early diagnosis and disease monitoring. Various p‑Tau epitopes have demonstrated superior diagnostic precision and now form the molecular basis of updated AD diagnostic frameworks. Classical immunoassays such as enzyme-linked immunosorbent assay (ELISA), chemiluminescent enzyme immunoassay (CLEIA), and single molecule array (SIMOA) remain central to fluid based detection, offering high sensitivity and clinical validation. Recent advances in tau biology, especially in post-translational modifications, have driven the development of next generation biosensors. Electrochemical, optical, and nanostructured platforms now enable real-time, label-free, and attomolar level detection of p‑Tau in biofluids and live cell models. These systems are increasingly portable and suitable for point of care or in vivo applications. This review highlights the evolution of p‑Tau detection technologies, from benchmark immunoassays to cutting edge biosensors. Special attention is given to advanced affinity reagents, including aptamers, synthetic peptides, and antibody mimetics, which enhance biosensor specificity, stability, and translational potential. Together, these innovations are redefining AD diagnostics, enabling early intervention and more effective disease monitoring.