The extracellular deposition of amyloid beta (Aβ) in senile plaques constitutes one of the defining hallmarks of Alzheimer's disease. Aβ peptides can aggregate spontaneously to highly insoluble amyloid fibrils, but several components are likely to influence the kinetics of fibrillogenesis in vivo. We report here that high density lipoprotein (HDL), the predominant lipoprotein in the human brain, reduces amyloid formation in vitro as determined by thioflavin T fluorescence and high speed sedimentation assays. The inhibition occurred in a dose dependent manner, and with concentrations of HDL above 1% resulting in more than 70% inhibition. We also examined the combined effect of apolipoprotein E (apoE) and HDL on Aβ fibrillogenesis. We found that HDL particles enriched with any of the three apoE isoforms inhibited Aβ fibrillogenesis as their native counterparts. Taken together, these findings suggest that HDL-like particles in the brain may prevent the formation of Aβ fibrils. © 2000 Academic Press.