Heparan sulfate (HS), along with serum amyloid P component, has been identified in all types of amyloid investigated so far, regardless of the type of amyloid protein deposited. To assess whether unique or specific HS proteoglycans (HSPGs) may be involved in the formation of these lesions, we have investigated the accumulation of several distinct HSPG epitopes in the cerebra of patients with different forms of neurodegenerative disease. A panel composed of several antibodies revealed distinctive patterns of HSPG accumulation. In patients with dementia of the Lewy body type, the burned-out-type plaques and preamyloid-type plaques were strongly stained by both the anti-HS 'chain' and anti-HS 'stub' antibodies, but by none of the available anti-core protein antibodies. In Alzheimer's disease, the preamyloid-type plaques, dense-cored-type plaques, neuritic-type plaques and the neurofibrillary tangles were stained by the anti-'stub' antibody. The anti-'chain' and the anti-core protein antibodies, in contrast, failed to stain the preamyloid-type plaques and burned-out-type plaques, but stained the neuritic-type plaques in these patients. These data suggest differences in the types of HS and HSPG (fragments) that accumulate in amyloid lesions that may hallmark neurodegenerative disorders of different etiologies.