Researchers from VIB and KU Leuven have uncovered, for the first time, the precise mechanism through which the Alzheimer’s drug lecanemab (Leqembi) clears toxic amyloid plaques and slows cognitive decline. Their findings, published in Nature Neuroscience, provide the first direct mechanistic explanation for how monoclonal antibody therapies work in Alzheimer’s disease and offer a framework for developing safer, next-generation treatments.
Fc Fragment Found Essential for Activating Microglia
As reported by medicalxpress, the team demonstrated that the antibody’s Fc fragment plays a crucial role in engaging microglia—the brain’s immune cells—and triggering the cellular machinery required to remove amyloid plaques.
“Our study is the first to clearly show how this anti-amyloid antibody therapy works,” said Dr. Giulia Albertini, co-first author. “The Fc fragment acts as an anchor that microglia latch onto near plaques, reprogramming the cells to clear amyloid more efficiently.”
This discovery resolves longstanding uncertainties in the field and confirms that microglial activation is central to the drug’s therapeutic efficacy.
Amyloid Plaques and Microglial Dysfunction
Alzheimer’s disease affects more than 55 million people globally and is marked by the accumulation of amyloid plaques—protein aggregates that damage neurons and drive dementia. Although microglia naturally cluster around these plaques, they fail to eliminate them in the diseased brain.
In recent years, therapies like lecanemab have aimed to restore this lost microglial function. However, until now, researchers lacked direct evidence linking microglial activity to plaque removal by these antibodies.
Lecanemab’s Fc Fragment Drives Microglial Response
Lecanemab, already approved by the U.S. FDA, targets amyloid-beta plaques and slows disease progression. Yet its mechanism remained unclear, and side effects raised concerns about its safety.
Antibodies contain one region that binds to the target (the amyloid plaques) and another—the Fc fragment—that signals the immune system.
Several studies hinted that the Fc region activates microglia. However, some theories suggested the antibody could act without Fc signaling.
The new study led by Prof. Bart De Strooper decisively shows that microglia respond only when the Fc fragment is fully functional. Antibodies lacking the Fc component showed no effect in plaque clearance.
Human Microglia Model Enables High-Resolution Insights
To produce these insights, researchers used a unique Alzheimer’s mouse model engrafted with human microglial cells. This allows them to test clinically relevant antibodies in a controlled system.
“This approach let us observe human-specific immune responses with unprecedented clarity,” said Magdalena Zielonka, co-first author.
How Microglia Clear Plaques After Activation
The team then mapped the full cellular process by which microglia eliminate amyloid plaques when activated by lecanemab. They identified two essential mechanisms:
- Phagocytosis – engulfing and removing plaque material
- Lysosomal activity – breaking down the ingested debris
Neither process occurred when the Fc fragment was absent.
Using single-cell and spatial transcriptomics—including NOVA-ST, a technique developed at VIB-KU Leuven—the researchers uncovered a distinct microglial gene program marked by strong expression of SPP1. This signature appears to drive efficient plaque clearance.
Blueprint for Next-Generation Alzheimer’s Therapies
These findings offer a clearer direction for future drug development.
“This opens doors to therapies that may activate microglia without relying on antibodies,” said Prof. De Strooper. “Recognizing the importance of the Fc fragment helps guide the design of next-generation Alzheimer’s drugs.”
The study not only clarifies how current therapies work but also lays the foundation for more targeted and safer strategies to treat Alzheimer’s disease.