What Are Tau Proteins?
Tau is an axonal protein that stabilizes microtubules in neurons and regulates cytoskeleton reorganization, but when abnormally modified—particularly through hyperphosphorylation—it detaches from microtubules, forms pathological aggregates, and drives neurodegeneration in Alzheimer's disease and other tauopathies. 1
Normal Physiological Function
Tau proteins are microtubule-associated proteins highly enriched in neurons that bind to and stabilize the microtubule cytoskeleton, which is essential for maintaining neuronal structure and function 2, 3
Tau regulates microtubule dynamic stability through its interactions with dynein and kinesin motor proteins, thereby influencing axonal transport of cellular cargo 1
Beyond microtubule binding, tau participates in synaptic structure and function, neuronal signaling pathways, and cell viability regulation 2, 3
Six isoforms of tau are produced in adult human brain from a single gene on chromosome 17q21 through alternative splicing, with heterogeneous species created by multiple post-translational modifications including phosphorylation, methylation, and glycation 1, 3
Pathological Role in Neurodegenerative Disease
Alzheimer's Disease
The National Institute on Aging and Alzheimer's Association define AD pathology as requiring both beta-amyloid plaques AND tau neurofibrillary tangles for definitive diagnosis, with tau pathology correlating more strongly with clinical symptoms and neurodegeneration than amyloid alone 4
Hyperphosphorylated tau (p-tau) loses its binding affinity for microtubules, destabilizes the cytoskeleton, impairs axonal transport, and aggregates into neurofibrillary tangles that are toxic to neurons 1, 5
Beta-amyloid deposition precedes tau pathology by 25-30 years, but tau accumulation drives the clinical manifestations of dementia 4
Plasma p-tau217 is highly specific for AD pathology (elevated 250-600% in AD versus other neurodegenerative diseases) and is not significantly elevated in other tauopathies, making it essentially pathognomonic when using validated assays 6
Other Tauopathies
Frontotemporal lobar degeneration (FTLD) includes tau-positive variants such as Pick's disease with Pick bodies (specific tau inclusions), progressive supranuclear palsy, and corticobasal degeneration 4, 7
Chronic traumatic encephalopathy (CTE) is definitively a tauopathy characterized by a unique pattern of phosphorylated tau deposition following repetitive mild traumatic brain injury, with extensive p-tau pathology observed throughout the brain in late-stage disease 1, 4
Tau elevation in CSF is not specific to AD—it occurs in prion diseases, CTE, and some FTLD variants, requiring integration with amyloid biomarkers for accurate diagnosis 4
Clinical Diagnostic Implications for Geriatric Patients
Biomarker Interpretation Algorithm
If both p-tau217 AND amyloid-beta are elevated: High likelihood of AD pathology; consider anti-amyloid therapies like donanemab or aducanumab 1, 8
If p-tau217 is normal but cognitive impairment exists: Actively pursue alternative diagnoses including frontotemporal dementia, corticobasal degeneration, or vascular dementia 6
If total tau is elevated but p-tau217 is normal and amyloid-beta is normal: Favor FTLD over AD, as the p-tau/total tau ratio differs between these conditions 4
Family History Considerations
Mutations in the MAPT gene (encoding tau) cause frontotemporal dementia with parkinsonism-17 (FTDP-17), establishing that dysfunctional tau alone can cause neurodegeneration independent of amyloid pathology 7
Mixed pathology is the rule rather than exception in elderly patients—the presence of one proteinopathy doesn't exclude others, with alpha-synuclein pathology frequently co-existing with AD tau pathology 4
Critical Pitfalls
Not all p-tau assays perform equally—clinicians must use validated high-performing platforms (Simoa, Elecsys, Lumipulse, IP-MS) to ensure accurate results, as lower-performing assays produce misleading results 1, 6
Cerebrovascular disease, cardiovascular disease, age, and creatinine levels are biological confounders that may influence p-tau217 measurements and require careful interpretation 6
Serial p-tau217 measurements can monitor disease progression and treatment response, with longitudinal increases correlating with worsening cognition and brain atrophy 8