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Alzheimer's Disease Treatment Lecanemab Blocks Plasma Contact System, Study Finds

Rockefeller University researchers have unraveled a molecular mechanism through which Leqembi (lecanemab), an anti-amyloid drug developed by Biogen and Eisai, might have its therapeutic effect in Alzheimer's disease (AD). Leqembi, which has a list price of $26,500 a year, first received an accelerated approval, since  converted to a full approval, from the US Food and Drug Administration based on the surrogate endpoint that it clears amyloid plaques. In a new study in the Proceedings of the National Academy of Sciences, the Rockefeller researchers write that toxic beta-amyloid (Aβ) protofibrils, thought to be a major driver of AD, activate a molecular cascade called the plasma contact system, potentially leading to the vascular and inflammatory abnormalities associated with AD. Using western blotting, chromogenic assays, and other approaches, the authors found that Aβ protofibrils are more effective activators of the human plasma contact system than other Aβ forms, such as monomers, intermediate-length oligomers, and fibrils. The authors further found that Aβ protofibrils accelerate activation of the plasma contact system by binding to coagulation factor XII (FXII) and high-molecular-weight kininogen (HK). Lecanemab, they note, works by blocking the binding of FXII and HK to Aβ and prevents Aβ protofibril-mediated acceleration of blood clotting in normal human plasma. Moreover, lecanemab's effective blocking of the contact system could reduce bradykinin production and, therefore, reduce the occurrence of amyloid-related imaging abnormalities in AD patients, the researchers say.


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