During the past several years, evidence has been accumulated to support the thesis that immunological factors may play some role in Alzheimer's disease (AD). We have characterized the reactive antigens detected by certain monoclonal antibodies secreted by Epstein-Barr virus (EBV)-transformed B cell lines from the peripheral blood of AD patients and controls. Autoantibodies against beta-amyloid protein beta-amyloid protein (beta-A) in amyloid plaques and blood vessels and in enzyme-linked immunosorbent assays (ELISA) have been reported in four cell lines derived from an AD patient. In this study, over 3300 EBV-transformed B cell lines from thirteen individuals were tested in ELISAs for antibodies against beta-A peptides. Significantly more autoantibodies against beta-A (1-40) were found in the AD group, 2.26 +/- 0.62% (39/1794 cell lines) than in the control group, 0.28 +/- 0.36% (5/1552 cell lines) with P < 0.005. These new antibodies did not react with plaques or amyloid deposits in blood vessels. In contrast to the four plaque-reactive autoantibodies which reacted better with beta-A (1-40) than with beta-A (1-28), 70% of these anti-beta-A (1-40) antibodies reacted as well or better with beta-A (1-28). Many of them were also reactive with beta-A (1-16). Tested against a panel of cytoskeletal proteins and Hela cells, many of these anti-beta-A (1-40) antibodies appear to be polyreactive. The higher incidence of anti-beta-A antibody secreting B cells in AD patients provides further evidence that autoimmunity may play a role in AD.