Scientists Pinpoint How Lecanemab Clears Alzheimer's Plaques
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- VIB and KU Leuven researchers demonstrated that lecanemab's Fc fragment acts as an anchor that reprograms microglia to clear amyloid plaques, and removing the fragment completely abolished the antibody's effect in a mouse model carrying human microglial cells.
- Dr. Giulia Albertini and Magdalena Zielonka, co-first authors, said the study is the first to provide direct proof linking microglial activity to lecanemab's plaque-clearing efficacy, resolving a long-standing debate over whether the Fc fragment was needed.
- Prof. Bart De Strooper's team used single-cell and spatial transcriptomics to identify a specific microglial gene-activity pattern — including strong SPP1 expression — that is triggered only when the Fc fragment is intact, pointing to the cellular program responsible for plaque removal.
- The study, published in Nature Neuroscience, tested the same antibodies given to patients, allowing researchers to observe human-specific immune responses at unprecedented resolution according to Zielonka.
- Lecanemab (marketed as Leqembi) is already FDA-approved and shown to slow cognitive decline, but side effects have limited its overall benefit — a gap the new findings could help close by guiding safer, next-generation antibody designs.
- De Strooper said the Fc-fragment mechanism opens the door to future Alzheimer's therapies that activate microglia directly, without relying on antibodies at all, potentially reshaping treatment strategies for the more than 55 million people living with the disease worldwide.
Why it matters: For the 55 million people living with Alzheimer's, this is the first clear mechanistic answer to why lecanemab works — and where it falls short. The Fc-frament finding gives drug designers a precise target: engineer antibodies that better recruit microglia, or skip antibodies entirely and activate the brain's immune cleanup crew directly.
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