MAPT and Alzheimer disease: However, several challenges have emerged: 1) lack of specificity and variable affinities to the multiple conformations of tau fibrils (e.g., 4R straight chain filaments in PSP vs. 3/4R paired helical filaments in AD), 2) non-negligible off-target binding to neuromelanin and monoamine oxidase A/B, and 3) the role of primary age-related tauopathy, which is not considered pathogenic and may require careful interpretation of PET data.