Active amyloid beta (A beta) vaccination has been shown to be effective in clearing cerebral A beta and improving cognitive function in mouse models of Alzheimer's disease. However, an A beta vaccine clinical trial was suspended after meningoencephalitis was detected in a subset of subjects. Passive immunization has been suggested to be a safer alternative to active A beta immunization but there are reports of increased risk of microhemorrhages associated with its administration in aged beta-amyloid precursor protein transgenic mice bearing abundant vascular amyloid deposition. In addition, the cost may be prohibitive for large-scale clinical use. Therefore, we are designing novel A beta immunogens that encompass the B cell epitope of A beta but lack the T cell-reactive sites. These immunogens induced the production of A beta-specific antibodies in the absence of an A beta-specific cellular immune response in wild-type mice and are being tested in beta-amyloid precursor protein transgenic mice. These data together with published reports from several other groups suggest that a safe, active A beta vaccine is a tenable goal.