Lecanemab, also known by its brand name Leqembi, is a treatment for Alzheimer’s disease that helps remove toxic plaques from the brain and slows memory decline.
While this treatment has already been approved for use, scientists until now did not fully understand how it worked. A new study led by researchers from VIB and KU Leuven has uncovered the exact process that makes this drug effective.
Published in the journal Nature Neuroscience, the study shows that Leqembi’s success depends on a special part of the antibody called the “Fc fragment.”
This part of the drug activates the brain’s immune cells—called microglia—so they can begin removing the harmful plaques made of amyloid-beta, a protein that builds up in the brains of people with Alzheimer’s.
Dr. Giulia Albertini, one of the lead authors, explained that the Fc fragment acts like a handle for microglia. When the microglia grab onto this handle near a plaque, they become reprogrammed to clean it up more effectively.
This is the first direct explanation of how this type of antibody therapy works, and it could help scientists design better treatments with fewer side effects.
Alzheimer’s disease affects more than 55 million people around the world. It is caused in part by the buildup of sticky amyloid plaques in the brain.
These plaques damage brain cells and eventually lead to memory loss and dementia. Microglia, the brain’s natural immune cells, are supposed to help clear these plaques. But in Alzheimer’s, they become less effective.
Leqembi is a monoclonal antibody therapy that binds directly to amyloid plaques. Until now, it wasn’t clear whether its effect came only from this binding or from other immune processes.
Some scientists had proposed that the plaque might be cleared in other ways, without involving the Fc fragment. This study proves that the Fc fragment is crucial—without it, microglia do not react, and the plaques are not removed.
To study this, researchers used a special mouse model of Alzheimer’s that had been implanted with human microglia cells. This gave them a controlled way to test how the human immune system responds to the antibody.
When they gave the mice Leqembi with the Fc fragment, they saw the microglia become active and clear the plaques. But when they used a version of the antibody without the Fc fragment, there was no effect.
They also used advanced tools to explore what was happening inside the microglia. They found that two key processes—phagocytosis (cellular “eating”) and lysosomal activity (breaking down waste)—were triggered only when the Fc fragment was present.
The team also identified a gene called SPP1 that was strongly turned on in active microglia. This gene may be part of the cleaning process and could be useful for developing future treatments.
The researchers believe that this discovery opens the door to new types of Alzheimer’s therapies. If scientists can design drugs that turn on microglia in the same way—without needing antibodies—they might avoid some of the side effects seen with current treatments.
Prof. Bart De Strooper, senior author of the study, says that understanding how Leqembi works gives researchers a clear roadmap for designing next-generation Alzheimer’s treatments. These new drugs could be safer and more effective by focusing on the exact cellular machinery needed to clean up the brain.
This breakthrough could change how we treat Alzheimer’s disease and bring hope to millions of people living with memory loss and dementia.
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The study is published in Nature Neuroscience.
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