Alzheimer's disease (AD), the most common cause of dementia in the elderly, is the sixth leading cause of death in the United States. We hypothesize that the impaired clearance of Aβ42 from the brain is partly responsible for the onset of sporadic AD. In this work, we evaluated the activity of insulin-degrading enzyme (IDE) toward Aβ42 in the presence of resveratrol, a polyphenol found in red wine and grape juice. By liquid chromatography/mass spectrometry, we identified initial cleavage sites in the absence and presence of resveratrol that carry biological relevance connected to the amyloidogenic properties of Aβ42. Incubation with resveratrol results in a substantial increase in Aβ42 fragmentation compared to the control, signifying that the polyphenol sustains IDE-dependent degradation of Aβ42 and its fragments. Our findings suggest that therapeutic and/or preventative approaches combining resveratrol and IDE may hold promise for sporadic AD.