Phosphorylated Tau Biomarkers in Alzheimer's Disease: From Early Detection to Clinical Potential-A Comprehensive Review

Alzheimer's disease (AD) is characterized by the pathological accumulation of neurofibrillary tangles (NFTs) and amyloid plaques, with hyperphosphorylated tau protein playing a central role in the formation of NFTs. Among the various phosphorylation sites on tau, p-tau181, p-tau231, and p-tau217 have emerged as promising biomarkers for AD. In addition, given the complexity of tau modifications across multiple sites, recent studies have explored tau forms phosphorylated at several sites simultaneously, hypothesizing that multi-site phosphorylation may offer greater diagnostic value than single-site modifications. These biomarkers can be measured in plasma and cerebrospinal fluid (CSF) using immunoassays, and their levels can be correlated with neuroimaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). This review article comprehensively compares these three phosphorylation sites to evaluate their roles as biomarkers in AD, focusing on their diagnostic accuracy, utility in early detection, and potential for monitoring disease progression. Each biomarker offers unique advantages and disadvantages, which influence its applicability in both clinical and research settings. Further, the review also highlights the evolving nature of this field, emphasizing the need for standardized approaches and further research to validate these biomarkers across diverse populations and integrate them into routine clinical practice. By synthesizing current evidence, including recent validation of fully automated platforms for plasma p-tau, this article provides insights into the transformative potential of tau biomarkers for improving AD diagnosis and management. The FDA's clearance of a plasma p-tau217-based blood test in May 2025 represents a pivotal step toward accessible, non-invasive AD diagnostics. This development highlights the valuable role of tau as a potential biomarker for the disease.