Although Alzheimer's disease (AD) is characterized by the extracellular deposition of fibrillar aggregates of beta-amyloid (A beta), transient oligomeric species of A beta are increasingly implicated in the pathogenesis of AD. Natively unfolded monomeric A beta can misfold and progressively assemble into fibrillar aggregates, following a well-established "on pathway" seeded-nucleation mechanism. Here, we show that three simple saccharides, mannose, sucrose, and raffinose, alter A beta aggregation kinetics and morphology. The saccharides inhibit formation of A beta fibrils but promote formation of various oligomeric aggregate species through different "off pathway" aggregation mechanisms at 37 degrees C hut not at 60 degrees C. The various oligomeric A beta aggregates formed when coincubated with the different saccharides are morphologically distinct but all are toxic toward SH-SY5Y human neuroblastoma cells, increasing the level of toxicity and greatly prolonging toxicity compared with A beta alone. As a wide variety of anti-A beta aggregation strategies are being actively pursued as potential therapeutics for AD, these studies suggest that care must be taken to ensure that the therapeutic agents also block toxic oligomeric A beta assembly as well as inhibit fibril formation. (C) 2010 American Institute of Chemical Engineers Biotechnol. Prog., 26: 1172-1179, 2010