Combination of Resveratrol and Curcumin with Anti-Amyloid Monoclonal Antibodies Aducanumab and Lecanemab Leads to Greater Inhibition of Amyloid-Beta Aggregation

This study evaluated the antiamyloidogenic effects of the monoclonal antibodies aducanumab and lecanemab in combination with the small molecules resveratrol and curcumin. The Aβ42 aggregation kinetics study revealed that both antibodies alone demonstrated 50-71% inhibition of Aβ42 fibrillogenesis, whereas their combination with resveratrol or curcumin resulted in markedly enhanced suppression of Aβ42 fibrillogenesis (89-97% inhibition), indicating a strong additive effect. Electron microscopy studies confirmed a substantial reduction in fibril load following combination treatment with monoclonal antibodies and small molecules. In the cellular assays, antibody-small molecule combinations were nontoxic to mouse hippocampal HT22 neurons and significantly mitigated Aβ42-induced cytotoxicity, outperforming antibody monotherapy treatment. Computational modeling suggested complementary binding modes, with antibodies targeting the N-terminal surface of Aβ42 assemblies and resveratrol or curcumin binding to internal regions. Together, these findings provide proof-of-concept data to develop novel antiamyloid monoclonal antibody and small molecule combination strategies for treating Alzheimer's disease.