Alzheimer's disease (AD) is characterized by pathological lesions such as amyloid-beta (A beta) plaques and cerebral amyloid angiopathy. Both these lesions consist mainly of aggregated A beta protein and this aggregation is affected by macromolecules such as heparan sulfate (HS) proteoglycans. Previous studies demonstrated that HS enhances fibrillogenesis of A beta and that this enhancement is dependent on the degree of sulfation of HS. In addition, it has been reported that these sulfation epitopes do not occur randomly but have a defined tissue distribution. Until now, the distribution of sulfation epitopes of HS has not yet been studied in human brain. We investigated whether a specific HS epitope is associated with A beta plaques by performing immunohistochemistry on occipital neocortical and hippocampal tissue sections from AD patients using five HS epitope-specific phage display antibodies. Antibodies recognizing highly N-sulfated HS demonstrated the highest level of staining in both fibrillar A beta plaques and non-fibrillar A beta plaques, whereas antibodies recognizing HS regions with a lower degree of N-sulfate modifications were only immunoreactive with fibrillar A beta plaques. Thus, our results suggest that a larger variety of HS epitopes is associated with fibrillar A beta plaques, but the HS epitopes associated with non-fibrillar A beta plaques seem to be more restricted, selectively consisting of highly N-sulfated epitopes.