Consequently, the distinctly misfolded conformers of highly potent four-repeat (4R) tau seeds we found recently in rpAD patients [3,27] raise a series of critical mechanistic questions regarding the role of pathogenic conformers of tau in distinct phenotypes of AD and which specific structural domains (epitopes) of misfolded tau drive the propagation, toxicity, and apparent diversity of pathological and clinical features in AD. This evidence concerns the gene MAPT and Alzheimer disease.