That the topography, severity, and progression of beta-amyloid deposition in the brain of Alzheimer's disease (AD) and Down's syndrome (DS) cases is not uniform is well documented. We have addressed at present, the issue of whether the structural composition of beta-peptide (A beta) within the early amyloid deposits might contribute to this phenomenon. The cerebral cortex, the caudate/putamen, and the cerebellum from 10 AD and 8 DS cases were immunostained with antibodies that recognize the 1-17; 17-24 amino acid residues of A beta, and the COOH-terminus of A beta 42 variant, thus to the epitopes of A beta located amino- and carboxy-terminally to the site of the putative alpha-secretase cleavage. We demonstrate that numerous diffuse, early plaques in AD and especially in DS cases show predominance of the carboxy-terminally located epitopes of A beta; the most prominent in the cerebellum, less pronounced in the cerebral cortex, and only marginal, or absent in the striatum, except for some DS cases. These data suggest that the deposition of the carboxy-terminal fragment of A beta truncated at the position of alpha-secretase cleavage or close to it in diffuse plaques may be brain-region-specific, reflecting either dissimilar processing of amyloid precursor protein or the resolution of early A beta deposits, and may substantially contribute to different progression of beta-amyloidosis in various brain regions.