Senile plaques (SPs), one of two defining lesions of Alzheimer's disease (AD), are composed of a mixture of full-length Abeta1-40/42, and N- or C-terminally truncated Abeta peptides, including Abeta11-40/42. Sequential proteolysis of amyloid precursor protein (APP) by beta- and gamma-secretases produces Abeta1-40/42, but beta-site APP-cleaving enzyme 1 (BACE1), the major beta-secretase, also generates Abeta11-40/42, and BACE1 overexpression in cultured cells results primarily in secretion of Abeta11-40/42. The ratio of Abeta11-40/42 to Abeta1-40/42 depends on the ratio of BACE1 to APP, and Abeta11-40/42 can be generated from both full-length APP and its carboxy-terminal fragment (C99). Here, we investigated the role of Abeta11-40/42 in the pathogenesis of AD and Down's syndrome (DS) brains. We demonstrated significant amount of Abeta11-42 in DS brains by Western blots. While pyroAbeta11-42-modified Abeta species existed predominantly in mature SP cores in AD brain sections, both unmodified free Abeta11-40 and pyro-modified Abeta11-40 are detected in vascular amyloid deposits by immunohistochemistry. Using novel ELISAs for quantifying free Abeta11-40/42 and pyroAbeta11-40/42, we showed that insoluble Abeta11-42 predominated in extracts of AD and DS brains. This is the first systematic study of Abeta11-40/42 in neurodegenerative Abeta amyloidosis implicating Abeta11-40/42 in SP formation of AD and DS brains. The detection of Abeta11-42 in young DS brain suggests an early role for this N-terminally truncated Abeta peptide in the pathogenesis of SPs in AD and DS.