Tauopathy

Tau is a microtubule-associated protein encoded by the MAPT gene on chromosome 17, which undergoes alternative splicing to produce six isoforms in the adult human brain. In tauopathies, tau becomes hyperphosphorylated, detaches from microtubules, and aggregates into paired helical filaments or straight filaments that form neurofibrillary tangles. This aggregation is thought to be toxic to neurons, disrupting axonal transport and synaptic function. The distribution of tau pathology often correlates with clinical symptoms; for example, in Alzheimer's disease, tau tangles spread along a stereotypical path from the entorhinal cortex to the hippocampus and neocortex, mirroring cognitive decline. In contrast, primary tauopathies like progressive supranuclear palsy show tau inclusions in basal ganglia and brainstem, leading to movement abnormalities.

Tauopathies are broadly divided into primary tauopathies, where tau is the predominant pathology, and secondary tauopathies, where tau accumulation occurs alongside other proteins, as in Alzheimer's disease. Primary tauopathies include frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, and Pick's disease. Each has distinct clinical features: FTDP-17 often presents with behavioral changes and executive dysfunction; PSP is characterized by vertical gaze palsy and postural instability; CBD manifests as asymmetric apraxia and rigidity. Secondary tauopathies also include chronic traumatic encephalopathy, which arises from repeated head trauma and features perivascular tau deposits. The classification is evolving with advances in neuroimaging and biomarkers, allowing more precise antemortem diagnosis.

Mutations in the MAPT gene cause familial forms of tauopathy, with over 50 pathogenic variants identified, many affecting splicing or the microtubule-binding domain. These mutations lead to altered tau isoform ratios or increased aggregation propensity. The H1 haplotype of MAPT is a common risk factor for PSP and CBD, while the H2 haplotype is protective. In Alzheimer's disease, tau pathology is influenced by the APOE ε4 allele, which also increases amyloid deposition. Age is the strongest risk factor for sporadic tauopathies, and traumatic brain injury is a major environmental trigger for chronic traumatic encephalopathy. Genome-wide association studies have implicated additional loci, such as STX6 and MOBP, in PSP susceptibility, highlighting the complex genetic architecture.

Beyond the well-known tauopathies, several rare and atypical forms exist. For instance, globular glial tauopathy is characterized by tau inclusions in oligodendrocytes and astrocytes, presenting with frontotemporal dementia or motor neuron disease. Another rare entity is primary age-related tauopathy (PART), which is often found incidentally in elderly brains and may represent a distinct condition from Alzheimer's disease. Tau pathology also occurs in some prion diseases, such as Gerstmann-Sträussler-Scheinker syndrome, and in certain lysosomal storage disorders. In the realm of research, tau imaging with PET tracers like flortaucipir has enabled in vivo detection of tau deposits, and immunotherapies targeting tau are in clinical trials. A notable historical fact: the first description of neurofibrillary tangles by Alois Alzheimer in 1907 predates the identification of tau as their component by nearly 80 years.

Neurofibrillary tangle

Intraneuronal aggregates of hyperphosphorylated tau protein, a hallmark of tauopathies.

MAPT

Microtubule-associated protein tau gene, located on chromosome 17q21, encoding tau protein.

Primary tauopathy

A tauopathy in which tau pathology is the primary or sole neuropathological feature.

Secondary tauopathy

A tauopathy in which tau accumulation occurs secondary to another pathological process, such as amyloid deposition in Alzheimer's disease.

FTDP-17

Frontotemporal dementia with parkinsonism linked to chromosome 17, caused by MAPT mutations.