This study evaluated current methods for demonstrating and categorizing cortical plaques, with the aim of establishing objective methodology for future diagnostic evaluation. Analysis of four methods of tissue processing revealed that the highest numbers of plaques were identified in formalin-fixed, paraffin-embedded tissue regardless of the stain used. Analysis of three silver stains and four immunohistochemical dilutions of an antibody to beta A4 protein revealed that the recent silver method published by Garvey et al. [(1990) J Histotechnol 14: 39-42] was equivalent to beta A4 immunohistochemistry in demonstrating the highest number of plaques. Plaque differentiation was easier and more reliable in silver compared to beta A4-stained sections, although the number of identifiable small compact plaques was significantly reduced in silver-stained sections. These studies show that plaque differentiation may be compromised by tissue processing and staining protocols. The establishment of superior methods may provide better diagnostic resolution for patients with Alzheimer's disease.