We previously identified a novel amyloid beta-protein (A beta), that binds to GM1 ganglioside, in brains exhibiting the early pathological changes of AD. In this study, we raised monoclonal antibodies, using membrane fractions containing abundant GM1 ganglioside-bound A beta as antigens. Monoclonal antibody 4396, produced in this study, immunoprecipitates A beta42 in the membrane fractions of brains with diffuse plaques, but does not react with soluble A beta42 or GM1 ganglioside. Furthermore, this antibody recognizes the A beta bound to lipid vesicles containing GM1 ganglioside, and unexpectedly, phosphatidylinositol. In contrast, a control anti-A beta monoclonal antibody does not recognize the A beta bound to these lipid vesicles. These results indicate that A beta associated with lipids has an immunoreactivity distinct from that of soluble A.