Tau (neurofibrillary tangles)

Tau is a microtubule-associated protein that under normal conditions stabilises the axonal cytoskeleton by binding to tubulin; in Alzheimer's disease and other tauopathies it becomes hyperphosphorylated, detaches from microtubules, and aggregates into paired helical filaments that form insoluble neurofibrillary tangles (NFTs) inside neurons. The Braak staging system (stages I–VI) tracks the hierarchical spread of NFTs from the entorhinal cortex through the hippocampus to association neocortex, and this progression correlates more tightly with cognitive severity than amyloid plaque burden does. Tau accumulation is thought to disrupt axonal transport, impair synaptic function, and ultimately trigger neurodegeneration, making tau the primary candidate for the neurotoxic effector of Alzheimer's pathology in current models that position amyloid upstream and tau downstream. Tau biomarkers — particularly phospho-tau 181 and 217 in CSF and plasma — have become key diagnostic targets in the AT(N) biomarker framework.