Immunocytochemistry, using antibodies specific for different carboxy termini of beta-amyloid. A beta 40 and A beta 42(43), was used to compare beta-amyloid deposits in aged animal models to nondemented and demented Alzheimer's disease human cases. Aged beagle dogs exhibit diffuse plaques in the absence of neurofibrillary pathology and the aged polar bear brains contain diffuse plaques and PHF-1-positive neurofibrillary tangles. The brains of nondemented human subjects displayed abundant diffuse plaques, whereas the AD cases had both diffuse and mature (cored) neuritic plaques. Diffuse plaques were positively immunostained with an antibody against A beta 42(43) in all examined species, whereas A beta 40 immunopositive mature plaques were observed only in the human brain. Anti-A beta 40 strongly immunolabeled cerebrovascular beta-amyloid deposits in each of the species examined, although some deposits in the polar bear brain were preferentially labeled with anti-A beta 42(43). beta-amyloid deposition was evident in the outer molecular layer of the dentate gyrus in the aged dog, polar bear, and human. Within this layer, A beta 42 was present as diffuse deposits, although these deposits were morphologically distinct in each of the examined animal models. In dogs, A beta 42 was cloud-like in nature; the polar bear demonstrated a more aggregated type of deposition, and the nondemented human displayed well-defined deposits. Alzheimer's disease cases were most frequently marked by neuritic plaques in this region. Taken together, the data indicate that beta-amyloid deposition in aged mammals is similar to the earliest stages observed in human brain. In each species, A beta 42(43) is the initially deposited isoform in diffuse plaques.