Using a series of recombinant tau and FAC1 mutant proteins, this study demonstrates by Western and dot blot analysis that 1) shared epitopes between tau and FAC1 are responsible for Alz‐50 binding; 2) Alz‐50 reactivity is dependent on two discontinuous portions of the tau molecule; 3) Alz‐50 reactivity is most likely the result of a conformational alteration of tau monomers in Alzheimer's disease; and 4) the epitope for MC‐1, a novel monoclonal antibody, maps to similar regions of tau but does not react with FAC1. These data raise questions regarding previous studies which have suggested that tau lacks a specific conformation and illustrate the utility of the Alz‐50 and MC‐1 antibodies in recognizing a distinct pathological conformation of the tau molecule in Alzheimer's disease. J. Neurosci. Res. 48:128–132, 1997. © 1997 Wiley‐Liss, Inc.