Figure 1.

“Two-hit” model for pathologic conversion of tau.

The neuritic plaque is required, but insufficient for the pathological conversion of tau in Alzheimer's disease (AD). Similarly, traumatic brain injury in chronic traumatic encephalopathy (CTE) is necessary but insufficient to cause tau tangle formation. A second-risk determinant involving a variety of risk alleles/factors including loss of nuclear TAR DNA-binding protein 43 (TDP-43) function, is necessary to facilitate the pathological conversion of the wild-type tau that will eventually lead to neuronal loss and cognitive dysfunction.