The amyloid hypothesis suggests that the process of amyloid-␤ protein (A␤) fibrillogenesis is responsible for triggering a cascade of physiological events that contribute directly to the initiation and progression of Alzheimer's disease. Consequently, preventing this process might provide a viable therapeutic strategy for slowing and/or preventing the progression of this devastating disease. A promising strategy to achieve prevention of this disease is to discover compounds that inhibit A␤ polymerization and deposition. Herein, we describe a new class of small molecules that inhibit A␤ aggregation, which is based on the chemical structure of apomorphine. These molecules were found to interfere with A␤1-40 fibrillization as determined by transmission electron microscopy, Thioflavin T fluorescence and velocity sedimentation analytical ultracentrifugation studies. Using electron microscopy, time-dependent studies demonstrate that apomorphine and its derivatives promote the oligomerization of A␤ but inhibit its fibrillization. Preliminary structural activity studies demonstrate that the 10,11-dihydroxy substitutions of the D-ring of apomorphine are required for the inhibitory effectiveness of these aporphines, and methylation of these hydroxyl groups reduces their inhibitory potency. The ability of these small molecules to inhibit A␤ amyloid fibril formation appears to be linked to their tendency to undergo rapid autoxidation, suggesting that autoxidation product(s) acts directly or indirectly on A␤ and inhibits its fibrillization. The inhibitory properties of the compounds presented suggest a new class of small molecules that could serve as a scaffold for the design of more efficient inhibitors of A␤ amyloidogenesis in vivo. Alzheimer's disease (AD)1 is a progressive neurodegenerative disease that is characterized by the presence of extracellular amyloid plaques and intraneuronal neurofibrillary tangles in the brains of AD patients (1-3). Biochemical analysis of amyloid plaques revealed that the main constituent of amyloid plaques is fibrillar aggregates of a 39 -42-residue peptide referred to as the amyloid-␤ (A␤) protein (4). Several lines of evidence point toward a central role for the process of A␤ amyloid fibril formation in the etiology of AD. Transgenic animals overexpressing mutant forms of the amyloid precursor protein develop amyloid plaques, one of the major histopathologic hallmarks of AD (5). Several pathogenic AD mutations have been shown to effect the processing of amyloid precursor protein, resulting in increased A␤ levels, in particular the more amyloidogenic A␤42 (6). These data implicate the process of amyloid formation as the cause of neurodegeneration and disease progression in AD. Thus, a small molecule that reduces A␤ production or slows and/or inhibits A␤ aggregation would be considered a useful therapeutic strategy for slowing and/or preventing the progression of AD (7-10).Although a causal link between amyloid fibril formation and AD is supported by genetic, neuropathologic, and biochemica...