An immunohistochemical study was carried out on the brains of 20 cases with Alzheimer's disease and the same number of non-Alzheimer's controls using a monoclonal antibody to amyloid beta protein. The morphology and distribution of immunoreactive plaque-like lesions and the sensitivity of immunostaining were assessed both with and without formic acid pretreatment of the sections, and these results were compared with those obtained from conventional Congo red and silver impregnation staining methods. The brains of 8 cases with Down's syndrome (ages 18 to 62) were also studied using similar staining techniques. In the cases with Alzheimer's disease Congo red and immunostaining without formic acid pretreatment mainly stained the core deposits of amyloid in compact plaques, whereas the silver stain could also detect numerous diffuse plaques. Immunostaining with formic acid pretreatment was the most sensitive technique, and this showed many additional immunoreactive lesions of faint granular staining with little evidence of amyloid deposition or degenerating neurites. Similar ill-defined, faintly immunoreactive areas were the only neocortical lesions observed in the two cases aged 31 and 38 years respectively, and in addition to these lesions, older cases of Down's syndrome revealed extensive and numerous discrete senile plaques with amyloid deposition. Far fewer immunoreactive lesions were observed in the non-Alzheimer's controls. The ill-defined, beta protein immunoreactive regions mentioned above, therefore, are presumed to be very early stages in senile plaque development, and it is concluded that an extensive appearance of beta protein immunoreactive plaque lesions throughout the cortex and subcortical gray matter structures is typical of Alzheimer's disease.