Alzheimer's disease (AD) is a primary neurological disease with no effective cure. A hallmark of AD is the presence of intracellular tangles and extracellular plaques derived from the aberrant aggregation of tau- and beta-amyloid (A beta). A beta presents in the brain as well as in cerebrospinal fluid and the circulation, and A beta toxicity has been attributed to amyloidosis and inflammation, among other causes. In this study, the effects of the plasma protein corona have been investigated with regard to the blood cell association and cytokine secretion of oligomeric (A beta o) and fibrillar A beta(1-42)(A beta(f)), two major forms of the peptide aggregates. A beta o displayed little change in membrane association in whole blood or washed blood (i.e., cells in the absence of plasma proteins) at 37 degrees C, while A beta(f) showed a clear preference for binding with all cell types sans plasma proteins. Immune cells exposed to A beta o, but not to A beta(f), resulted in significant expression of cytokines IL-6 and TNF measured in real-time by a localized surface plasmon resonance sensor. These observations indicate greater immune cell association and cytokine stimulation of A beta o than A beta(f) and shed new light on the contrasting toxicities of A beta o and A beta(f) resulting from their differential capacities in acquiring a plasma protein corona. These results further implicate a close connection between A beta amyloidosis and immunopathology in AD.