What is the significance of phosphorylated tau protein?

From the Guidelines

Phosphorylated tau is a key biomarker for Alzheimer's disease, and its measurement in plasma, particularly p-tau217, has been shown to accurately separate AD dementia from other neurodegenerative diseases with high diagnostic accuracy, as evidenced by a recent study published in 2022 1.

Key Findings

• Phosphorylated tau (p-tau) assays have been developed for use as blood biomarkers for AD, including assays for tau phosphorylated at amino acid 181 (p-tau181), 217 (p-tau217), or 231 (p-tau231) 1.
• Plasma p-tau levels are related to both the density of Aβ plaques and tau tangles, and levels of different plasma p-tau variants can differentiate between cases with significant AD brain pathology from those without 1.
• Increased plasma levels of p-tau variants have specifically been observed in AD and not in other tauopathies, including primary age-related tauopathy, progressive supranuclear palsy, corticobasal degeneration, or Pick’s disease 1.

Diagnostic Accuracy

• Plasma p-tau217 has been shown to have similar diagnostic performance to CSF biomarkers and tau-PET imaging in the memory clinic setting 1.
• The diagnostic accuracy of plasma p-tau217 is high, with increased levels observed in AD dementia compared to non-AD neurodegenerative disease, making it a valuable tool for diagnosis and monitoring disease progression 1.

Clinical Implications

• The use of plasma p-tau as a biomarker has the potential to improve the diagnosis and management of AD, particularly in the early stages of the disease 1.
• Further research is needed to fully understand the clinical implications of plasma p-tau and its potential as a therapeutic target 1.

From the Research

Phosphorylated Tau Overview

• Phosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer's disease (AD) patient brains 2
• Increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation 2, 3
• Hyperphosphorylated tau forms the neurofibrillary tangles (NFTs) that correlate well with the progression of cognitive impairments 3, 4

Role of Phosphorylated Tau in Alzheimer's Disease

• Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction, and formation of neurofibrillary tangles 5
• The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins 5
• Phosphorylated tau interactome is enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation 5

Therapeutic Targets and Biomarkers

• New assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression 2
• Multiple therapies targeting phosphorylated tau are in various stages of clinical trials, including kinase inhibitors, phosphatase activators, and tau immunotherapy 2
• Phosphorylated tau may serve as a disease-specific biomarker for Alzheimer's disease and other tauopathies 2, 4

Phosphorylated Tau in Other Tauopathies

• Tauopathies, including Pick's disease, frontotemporal dementia, corticobasal degeneration, Alzheimer's disease, argyrophilic grain disease, progressive supranuclear palsy, and Huntington's disease, are the result of misprocessing and accumulation of tau within the neuronal and glial cells 4
• Phosphorylated tau plays a key role in the pathology of these diseases, leading to synaptic impairment and degeneration of neurons 4