- In Alzheimer’s disease (AD), tau pathology is one of the defining molecular hallmarks, alongside amyloid-β (Aβ) accumulation.
- Tau, a microtubule-associated protein, becomes abnormally phosphorylated and aggregates into neurofibrillary tangles (NFTs) within neurons. These tangles disrupt neuronal function and are closely associated with the progression of cognitive decline. As such, tau-related protein biomarkers play a central role in the diagnosis, staging, and monitoring of AD.
- Among the most important biomarkers is phosphorylated tau at threonine 181 (p-Tau181), which is consistently elevated in the cerebrospinal fluid (CSF) and, more recently, in plasma of individuals with Alzheimer’s disease. p-Tau181 levels correlate with disease severity and are considered highly specific to AD when compared to other neurodegenerative diseases. More recently, p-Tau217 has emerged as an even more sensitive and specific marker, showing a stronger correlation with both amyloid deposition and tau pathology across the Alzheimer’s disease continuum. It can distinguish AD from other tauopathies, such as frontotemporal dementia or progressive supranuclear palsy, with high accuracy. p-Tau231 is another early biomarker that rises before overt clinical symptoms and may be particularly useful in detecting preclinical AD.
- Total tau (t-Tau) is also elevated in AD, reflecting general neuronal injury and degeneration. However, because it lacks specificity to Alzheimer’s and can also be increased in other conditions involving acute or chronic neuronal damage (e.g., stroke, trauma), it is typically interpreted alongside other markers like p-Tau and Aβ42. The ratio of p-Tau to Aβ42 or t-Tau to Aβ42 is commonly used in clinical assessments to improve diagnostic accuracy.
- Non-tau biomarkers such as neurofilament light chain (NfL), GFAP (glial fibrillary acidic protein), and YKL-40 are also increasingly studied in AD. While NfL is a general marker of axonal injury and is not specific to AD, it reflects disease progression and severity. GFAP, an astrocyte marker, is elevated in plasma and CSF early in the disease process and may complement tau measurements by indicating neuroinflammatory responses. YKL-40, a marker of glial activation and inflammation, also rises in the CSF of AD patients and correlates with tau pathology and disease progression.
- Together, these biomarkers—particularly p-Tau181, p-Tau217, t-Tau, and supporting markers like NfL and GFAP—are transforming how Alzheimer’s disease is diagnosed and monitored. They are increasingly used in clinical trials to stratify patients, track therapeutic efficacy, and define early or preclinical stages of disease, moving the field closer to personalized and preemptive care.
