An assay method is disclosed which isolates and detects the presence of a disease related conformation of a protein (e.g., PrP.sup.Sc) present in a sample also containing the non-disease related conformation of the protein (e.g., PrP.sup.C). The sample is treated (e.g., contacted with protease) in a manner which hydrolyzes the disease related conformation and not the non-disease related conformation. The treated sample is contacted with a binding partner (e.g., a labeled antibody which binds PrP.sup.Sc) and the occurrence of binding provides and indication that PrP.sup.Sc is present. Alternatively the PrP.sup.Sc of the treated sample is denatured (e.g., contacted with guanadine) or unfolded. The unfolded PrP.sup.Sc is contacted with a binding partner and the occurrence of binding indicates the presence of PrP.sup.Sc in the sample. In another embodiment, PrP.sup.Sc and PrP.sup.C are reacted with a labeled antibody that binds both conformations and a conformation that binds only the disease related conformation, and the presence of the disease related conformation is determined by comparing the two.