As shown in TEM images, shorter and thinner fibrils were generated in the samples of metal-free Ab40 with 4-6. For Cu(II)-Ab40, 5 formed chopped filamentous Cu(II)-Ab40 aggregates, and 3, 4, and 6 produced both amorphous and fibrillary aggregates. These morphological changes were similar to those of Zn(II)-Ab40 incubated with 3-5, and 6 generated a bunch of fibrillary species with chopped filamentous aggregates. Moreover, the disaggregation experiments exhibited the effects of 1-6 on preformed Ab42 and Ab40 aggregates in the absence and presence of Cu(II) and Zn(II), as summarized in Figs. and and S5b. Compounds 4-6 could disassemble preformed metal-free Ab and metal-Ab aggregates and modulate their further aggregation. In the case of 3, the reactivity was only shown in the presence of metal ions. Compounds 1 and 2 showed a less noticeable impact on preformed metal-free and metal-treated Ab aggregates. Collectively, our gel/Western blot and TEM studies demonstrate that 4-6 can modulate the fibrillization of Ab in the absence and presence of metal ions as well as disassemble preformed metal-free Ab and metal-Ab aggregates. In contrast, among the flavonoids (1-3) containing two hydroxyl groups on the A ring, 3 exhibits the corresponding reactivities only towards metal-mediated Ab aggregation pathways. These indications describe the significance of three hydroxyl groups on the A ring in the flavonoid structure to impact the aggregation of metal-free Ab and metal-Ab.