- Tau pathology is a hallmark of several neurodegenerative disorders collectively known as tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and chronic traumatic encephalopathy (CTE). To detect and monitor these conditions, a number of protein biomarkers have been developed, particularly those that reflect abnormal tau metabolism, aggregation, and associated neuronal damage.
- One of the most widely studied and clinically relevant biomarkers is phosphorylated tau (p-Tau). Specific phosphorylation sites, such as p-Tau181, p-Tau217, and p-Tau231, are elevated in the cerebrospinal fluid (CSF) and plasma of individuals with AD. Among these, p-Tau217 has shown particularly high sensitivity and specificity for distinguishing AD from other forms of dementia and even from preclinical stages of the disease. These phosphorylated forms of tau correlate closely with the presence of amyloid plaques and neurofibrillary tangles, the two key pathological features of AD. Notably, p-Tau biomarkers tend to rise before overt symptoms appear, making them valuable for early diagnosis.
- Total tau (t-Tau), another commonly measured biomarker, reflects the overall release of tau protein into CSF due to neuronal damage. However, t-Tau is not specific to tauopathies and can also be elevated in other conditions such as stroke, traumatic brain injury, and encephalitis. Therefore, while it is a useful marker for neuronal injury, it lacks the disease specificity provided by phosphorylated tau forms.
- In addition to phosphorylated and total tau, research has identified truncated tau fragments generated by proteolytic cleavage. These truncated forms are thought to contribute to tau aggregation and the seeding of pathological tau species in the brain. Although less commonly used in routine diagnostics, truncated tau is gaining attention as a potential marker of disease progression.
- Emerging methods, such as real-time quaking-induced conversion (RT-QuIC) and other tau seeding assays, aim to detect misfolded or oligomeric tau species. These assays capitalize on tau’s prion-like properties to identify its pathological forms in biological fluids. Additionally, positron emission tomography (PET) imaging using tau-specific tracers such as [¹⁸F]Flortaucipir can visualize tau aggregates in the brain, offering a non-invasive in vivo assessment of tau pathology, although this is not a fluid biomarker.
- Beyond tau itself, several ancillary biomarkers provide indirect insights into tau-mediated neurodegeneration. Neurofilament light chain (NfL) is a marker of axonal damage that is elevated in many neurodegenerative conditions, including those involving tau pathology. While not tau-specific, its levels often correlate with disease severity and progression. Glial fibrillary acidic protein (GFAP), an astrocytic marker, is also elevated in tauopathies and reflects astrocyte activation associated with neuroinflammation. YKL-40 (chitinase-3-like protein 1) is another glial biomarker linked to inflammation and tau accumulation.
- Together, these biomarkers form a robust framework for understanding and monitoring tau-related neurodegenerative diseases. Their continued refinement and integration into diagnostic algorithms hold promise for earlier detection, improved differential diagnosis, and more personalized treatment approaches in clinical practice.
