Tauopathies

Tauopathies are a group of neurodegenerative disorders characterized by abnormal aggregation of the microtubule-associated protein tau in the brain. In healthy neurons, tau helps stabilize microtubules; in disease, tau becomes hyperphosphorylated, misfolds, and forms intraneuronal neurofibrillary tangles and other inclusions in neurons and glial cells, contributing to neuronal dysfunction and death.

Tau exists in several isoforms, produced by alternative splicing of the MAPT gene. Some tauopathies predominantly accumulate 3-repeat tau (3R), others predominantly accumulate 4-repeat tau (4R), and some show both. This isoform composition aids in classifying diseases and understanding their pathology. Tau pathology can be the principal feature of primary tauopathies or occur alongside other disease processes in secondary tauopathies, as seen in Alzheimer’s disease where tau tangles accompany amyloid plaques.

Clinical manifestations vary widely. Primary tauopathies include progressive supranuclear palsy and corticobasal degeneration, which often present with movement disorders and parkinsonism, as well as behavioral or language changes in forms of frontotemporal degeneration. Pick disease represents another classic 3R tauopathy with prominent cortical atrophy and dementia. Alzheimer's disease also involves tau pathology, though it is typically accompanied by amyloid pathology. The regional distribution of tau aggregates influences the clinical picture, including motor, cognitive, and behavioral symptoms.

Diagnosis relies on clinical assessment supported by imaging and biomarkers. MRI may reveal characteristic atrophy patterns; tau PET imaging and cerebrospinal fluid measures of tau can aid in identifying tau pathology. Genetic testing for MAPT mutations helps in familial tauopathies.

There are currently no disease-modifying cures for tauopathies. Management focuses on symptomatic care and support, with ongoing research exploring tau-targeted therapies and immunotherapies aimed at reducing tau aggregation and spread.