Tauopathy is a neurodegenerative disease characterized by the accumulation of tau protein in tangles in the human brain. These tangles result from hyperphosphorylation of a microtubule protein known as tau, which causes the protein to dissociate from microtubules and form insoluble aggregates. The mechanism of tangle formation is not yet well understood, and whether tangles are a primary cause of Alzheimer's disease or play an important role is unknown. Neurofibrillary tangles were first described by Alois Alzheimer in one of his patients with Alzheimer's disease. Tangles are considered a secondary neuropathy. AD is also classified as amyloidosis because of the presence of senile plaques. When tau becomes hyperphosphorylated, the protein dissociates from microtubules in axons. Tau then disperses and the protein begins to aggregate, eventually forming the neurofibrillary tangles seen in Alzheimer's patients. Microtubules are also disrupted when tau dissociates. The combination of neurofibrillary tangles and unstable microtubules leads to disruption of processes such as axonal transport and neuronal communication. The degree of NFT involvement in AD is determined by Braak stages. Braak stages I and II are used when NFT involvement is confined primarily to the transientis cortices of the brain, stages III and IV when there is also involvement of limbic regions such as the hippocampus, and V and VI when there is widespread involvement of the cerebral cortex. This should not be confused with the degree of involvement of the senile plaque, which progresses differently. In both Pick's disease and cortical degeneration, tau proteins are deposited as inclusion bodies within swollen or "swollen" neurons. Retrograde grain disease, another type of dementia, is characterized by an abundance of agglutinin-like grains and coiled bodies on microscopic examination of brain tissue. Some consider it a variant of Alzheimer's disease. It may coexist with other diseases such as progressive supranuclear palsy and cortical degeneration, as well as Pick's disease. Tauopathies often overlap with synucleinopathies, possibly because of the interaction between synuclein and tau proteins. Non-Alzheimer's disease synucleinopathies are sometimes grouped together as a "Pick complex" because of their association with frontotemporal dementia, or frontal lobar degeneration.