How does abnormal tau protein form neurofibrillary tangles?

In the context of Alzheimer disease, neurofibrillary tangles are composed of tau, a protein that is normally present in neurons to support cellular structure.1

In a healthy state, tau functions normally; however, in the pathology of Alzheimer disease, these tau molecules are incorrectly processed. This abnormal processing causes the molecules to clump together, eventually forming the twisted protein fibers known as neurofibrillary tangles. These structures, which consist of paired helical filaments, accumulate within the cytoplasm of neurons, particularly in the cerebral cortex and hippocampus. While these tangles are a hallmark used to diagnose the disease during autopsy, it remains unclear whether they are a primary cause of the condition or a consequence of the underlying disease process.12