Beta-amyloid (Abeta) peptides are thought to play a major role in the pathogenesis of Alzheimer's disease. Compounds that disrupt the kinetic pathways of Abeta aggregation may be useful in elucidating the role of oligomeric, protofibrillar and fibrillar Abeta in the etiology of the disease. We have previously reported that scyllo-inositol inhibits Abeta(42) fibril formation but the mechanism(s) by which this occurs has not been investigated in detail. Using a series of scyllo-inositol derivatives in which one or two hydroxyl groups were replaced with hydrogen, chlorine or methoxy substituents, we examined the role of hydrogen bonding and hydrophobicity in the structure-function relationship of scyllo-inositol-Abeta binding. We report here that all scyllo-inositol derivatives demonstrated reduced effectiveness in preventing Abeta(42) fibrillization compared with scyllo-inositol, suggesting that scyllo-inositol interacts with Abeta(42) via key hydrogen bonds that are formed by all hydroxyl groups. Increasing the hydrophobicity of scyllo-inositol by the addition of two methoxy groups (1,4-di-O-methyl-scyllo-inositol) produced a derivative that stabilized Abeta(42) protofibrils in vitro. Prophylactic administration of 1,4-di-O-methyl-scyllo-inositol to TgCRND8 mice attenuated spatial memory impairments and significantly decreased cerebral amyloid pathology. These results suggest that Abeta aggregation can be targeted at multiple points along the kinetic pathway for the improvement of Alzheimer's disease-like pathology.