AbstractPolymerization of monomeric amyloid-β peptides (Aβ) into soluble oligomers and insoluble fibrils is one of the majorpathways triggering the pathogenesis of Alzheimer’s disease (AD). Using small molecules to prevent the polymerizationof Aβ peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigated the effects ofmono- and bi-flavonoids on Aβ42 toxicity and fibrillogenesis and found that the bi-flavonoid, taiwaniaflavone (TF)effectively and specifically inhibits Aβ toxicity and fibrillogenesis. Compared to TF, the mono-flavonoid apigenin (AP)is less effective and less specific. Our data showed that differential effects of the mono- and bi-flavonoids on Aβfibrillogenesis correlate with their varying cytoprotective efficacies. We also found that other bi-flavonoids, namely 2',8''-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit Aβ toxicity and fibrillogenesis, implying thatthe participation of two mono-flavonoids in a single bi-flavonoid molecule enhanced their activity. Bi-flavonoids, whilestrongly inhibited Aβ fibrillogenesis, accumulated nontoxic Aβ oligomeric structures, suggesting that these are off-pathway-oligomers. Moreover, TF abrogated the toxicity of preformed Aβ oligomers and fibrils, indicating that TF andother bi-flavonoids may also reduce the toxicity of toxic Aβ species. Altogether, our data clearly show that bi-flavonoids,possibly due to the possession of two Aβ binders separated by an appropriate size linker, are likely to be promisingtherapeutics to suppress Aβ toxicity.Keywords: Amyloid-β, Taiwaniaflavone, Aapigenin, Flavonoid, Fibrillogenesis, Toxicity