Putative Alzheimer disease (AD)-specific proteins (A68) were purified to homogeneity and shown to be major subunits of one form of paired helical filaments (PHFs). The amino acid sequence and immunological data indicate that the backbone of A68 is indistinguishable from that of the protein tau (τ), but A68 could be distinguished from normal human τ by the degree to which A68 was phosphorylated and by the specific residues in A68 that served as phosphate acceptors. The larger apparent relative molecular mass (M_r) of A68, compared to normal human τ, was attributed to abnormal phosphorylation of A68 because enzymatic dephosphorylation of A68 reduced its M_r to close to that of normal τ. Moreover, the LysSerProVal motif in normal human τ appeared to be an abnormal phosphorylation site in A68 because the Ser in this motif was a phosphate acceptor site in A68, but not in normal human τ. Thus, the major subunits of a class of PHFs are A68 proteins and the excessive or inappropriate phosphorylation of normal τ may change its apparent M_r, thus transforming τ into A68.