Apolipoprotein E4 (ApoE4) increases the risk of late-onset Alzheimer's disease (AD). It binds tightly to beta-amyloid protein (A beta), which is known to activate the classical complement pathway in vitro. Since complement activation is a possible mechanism for promoting inflammation in AD, we tested, utilizing ELISA techniques, whether the various isoforms of ApoE could influence A beta complement activation, or could themselves activate the pathway. A beta applied alone to ELISA plate wells at concentrations of 100-500 ng showed a linear increase in ability to activate serum complement, but all the ApoE isoproteins were inactive. When 200 or 430 ng of A beta were plated and then exposed to solutions of 100-200 ng of ApoE2, ApoE3, ApoE4 or bovine serum albumin (BSA), only ApoE4 significantly enhanced the activation. This ApoE4-specific enhancement of complement activation by A beta may relate to its role in increasing the risk of late-onset AD.