The Secret Behind Lecanemab: How This Alzheimer's Drug Destroys Brain Plaque

For some time, Lecanemab (Leqembi), an Alzheimer’s drug, has been widely recognised for its ability to slow cognitive decline. However, the precise mechanism of how this drug works within the brain has remained a mystery until now.

A research team from VIB and KU Leuven has just unveiled this “secret key”. In a study published in the journal Nature Neuroscience, scientists discovered that Lecanemab’s effectiveness depends entirely on a specific part of the antibody called the Fc fragment. This part acts as a trigger for microglia, the brain’s protective immune cells, to begin moving and clearing accumulations of toxic protein.

Alzheimer’s disease affects more than 55 million people worldwide, triggered by the accumulation of amyloid plaques that damage neurons. Although microglia naturally gather around these plaques, they often fail to clear them effectively.

This is where Lecanemab comes in. This monoclonal antibody has two main functions: one part binds to amyloid plaques, whilst another part, the Fc fragment, signals to the immune system.

“Our study is the first to clearly demonstrate how this anti-amyloid antibody therapy works in Alzheimer’s disease. We showed that the efficacy of the therapy depends on the Fc fragment of the antibody, which activates microglia to clear amyloid plaques more effectively,” said Dr. Giulia Albertini, one of the lead authors of the study.

“The Fc fragment functions as an anchor where microglia can take a foothold when near the plaques. As a result, these cells are reprogrammed to clear the plaques more efficiently.”

To prove this theory, researchers used special mouse models containing human microglial cells. This allowed the team to observe human-specific immune responses with high resolution. The results were striking: when the Fc fragment was removed, the antibody lost all its power and produced no effect whatsoever.

Magdalena Zielonka, another researcher in the study, emphasised the importance of using this model. “The fact that we used human microglia in the controlled experimental model is the main strength of this study. It allowed us to test antibodies that are actually used in patients and observe human-specific responses,” she explained.

Using advanced techniques, the team identified that this clearing process involved the activity of certain genes, including strong expression of the SPP1 gene. Without the presence of the Fc fragment, microglia remain passive and powerless against the plaques.

This discovery not only solved a scientific puzzle but also opened the way for the development of next-generation Alzheimer’s drugs. By understanding that microglial activation is the key, researchers hope to create safer and more effective therapies in the future.

“This opens the door to future therapies that may be able to activate microglia without requiring antibodies. Understanding the importance of the Fc fragment helps guide the design of next-generation Alzheimer’s drugs,” concluded Prof. Bart De Strooper, the research team leader.

This step is hoped to minimise the side effects that have limited Lecanemab use, whilst offering new hope to millions of patients worldwide.