The amyloid beta protein (A beta) deposited in the Alzheimer's disease (AD) brain is heterogeneous at both its amino and carboxyl termini. Recent studies of the genetic forms of AD indicate that the aggregation and deposition of A beta 42 may be a common initiating event in all forms of AD. Here, we analyzed the amino termini of the A beta species deposited in the AD brain, focusing specifically on species with amino-terminal pyroglutamate at position 3 (A beta 3(pE)). Immunocytochemical analysis of AD brains with an antibody specific for A beta 3(pE) confirmed that these species deposit in blood vessels and senile plaques. Using specific sandwich ELISAs, we determined the amounts of A beta 3(pE)-40 and A beta 3(pE)-42(43) in AD brain compared with other forms. This analysis showed that A beta 3(pE)-40 is closely correlated with the extent of A beta deposition in blood vessels, whereas A beta 3(pE)-42(43) is not. In addition, A beta 3(pE)-42(43) is an important component of the A beta deposited in senile plaques of the AD brain, constituting approximately 25% of the total A beta 42(43). In vitro comparison of A beta 1-42 and A beta 3(pE)-42 showed that A beta 3(pE)-42 is highly prone to oligomerization. These findings suggest that A beta 3(pE)-42 may be particularly important in AD pathogenesis.