Amyloid beta (Aβ) is a naturally occurring peptide which is known to aggregate and deposit as senile plaques in the brains of Alzheimer's disease (AD) patients. Early hypotheses suggested that the high molecular weight Aβ fibrils found in plaques were more cytotoxic but more recent data indicate that smaller Aβ aggregation intermediates may in fact be more deleterious to cells. We have explored two cell lines in order to determine what form of Aβ is most disruptive to cells. Human THP-1 monocytes will undergo differentiation to macrophages in response to many stimuli including Aβ. We observed that slower aggregating Aβ(1-42) solutions were able to differentiate the non-adherent monocytes to adherent macrophages. The transformation was measured by an XTT cell proliferation/viablility assay, which detected the Aβ(1-42)-induced loss of suspended cells from the medium and direct cell counting of adherent cells. Continued aggregation of Aβ(1-42) diminished its ability to differentiate the cells and faster-aggregating Aβ(1-42) solutions had little effect on cell differentiation raising the possibility that an aggregation intermediate was mediating the transformation. Bacterial lipopolysaccharide (LPS), a potent stimulator of THP-1 cells, had a much lesser effect on differentiation compared to Aβ(1-42). Separate studies using human aortic vascular smooth muscle cells (HA-VSMCs) indicated the intermediate Aβ(1-42) species was cytotoxic as measured by XTT. Our data demonstrates that an intermediate Aβ(1-42) aggregation species differentiates monocytes and reduces cell viability in HA-VSMCs. These results support the hypothesis that a smaller Aβ assembly species may be the most biologically active and important form in AD.