Scientists Discover Lecanemab’s Mechanism: Fc Fragment Activates Microglia to Clear Amyloid Plaques

Scientists at the Vlaams Instituut voor Biotechnologie (VIB) and KU Leuven have identified how lecanemab, the monoclonal antibody marketed as Leqembi, combats Alzheimer’s disease. This discovery clarifies the drug’s therapeutic function and provides insights for developing improved treatments. Approved by the FDA in 2023, lecanemab targets amyloid-beta plaques, yet its precise mode of action remained unclear until this study. Researchers found that the drug’s effectiveness relies on its Fc fragment, a component of the antibody that activates microglia—brain immune cells—to remove toxic amyloid deposits. This finding addresses uncertainties about the drug’s benefits and limitations, such as side effects like amyloid-related imaging abnormalities (ARIA).

“When lecanemab binds to amyloid-beta plaques, the Fc fragment interacts with microglia, prompting these cells to engulf and break down the plaques.”

The study, led by Dr. Giulia Albertini and Prof. Bart De Strooper, demonstrated that the Fc fragment acts as a molecular activator. When lecanemab binds to amyloid-beta plaques, the Fc fragment interacts with microglia, prompting these cells to engulf and break down the plaques. This process, termed microglial activation, is critical because microglia typically fail to clear plaques effectively. The researchers showed that the Fc fragment is essential for this activation, as microglia remained inactive without it. This discovery aligns with earlier findings from Rockefeller University, which indicated that lecanemab binds to soluble amyloid-beta protofibrils—highly toxic intermediates in plaque formation—preventing their aggregation into plaques. By targeting these protofibrils, lecanemab disrupts plaque formation and facilitates their clearance through immune mechanisms.

Microglia, the brain’s immune cells, play a dual role in Alzheimer’s disease. While they can detect amyloid-beta plaques, their ability to clear these deposits is often impaired, contributing to chronic inflammation and neuronal damage. The VIB-KU Leuven study provides insights into how lecanemab enhances microglial function. Using advanced techniques like single-cell and spatial transcriptomics, the team identified a gene expression pattern in microglia linked to effective plaque removal. This pattern included heightened activity of the SPP1 gene, which encodes a protein involved in immune response and tissue repair. The study also highlighted the importance of the NOVA-ST method, a novel analytical tool developed by the Stein Aerts lab, which enabled precise mapping of microglial activity in the brain. These findings emphasize the complexity of microglial activation and the potential of targeting these cells to combat Alzheimer’s.

The clinical impact of lecanemab was assessed in the phase 3 Clarity AD trial, which included 1,795 patients with early-stage Alzheimer’s. Results showed that lecanemab slowed cognitive decline by 27%, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, compared to a 20% slowdown in the placebo group. The drug also reduced amyloid-beta burden in the brain, as evidenced by positron emission tomography (PET) scans. Patients reported improved quality of life metrics, including reduced anxiety and depression, with up to 49-56% fewer instances of these symptoms over 18 months. These outcomes align with preclinical studies showing that lecanemab lowers amyloid levels in the brain, blood, and cerebrospinal fluid (CSF).

However, the drug’s benefits are offset by side effects, particularly ARIA, a condition marked by brain swelling and microhemorrhages. ARIA occurs in approximately 15-20% of patients, with severe cases requiring hospitalization. The study’s authors noted that lecanemab’s mechanism—targeting protofibrils and activating microglia—may explain its lower ARIA rates compared to aducanumab, another amyloid-targeting drug. While the exact relationship between the Fc fragment and ARIA remains under investigation, the findings suggest that optimizing the Fc fragment’s properties could mitigate these risks. Balancing efficacy and safety remains a key challenge in Alzheimer’s drug development.

“The Fc fragment acts as a molecular activator, essential for microglial activation, as microglia remained inactive without it.”

The VIB-KU Leuven study has significant implications for Alzheimer’s research. By defining the microglial program responsible for plaque clearance, the findings open avenues for therapies that directly activate microglia without antibodies. This approach could reduce side effects and enhance treatment efficacy. Researchers are exploring small molecules that mimic the Fc fragment’s function to enable targeted microglial activation. Additionally, the study’s emphasis on protofibril targeting highlights the importance of early intervention, as these toxic intermediates are more harmful than mature plaques. This insight could guide the development of drugs that intercept amyloid-beta pathology at its earliest stages.

“The VIB-KU Leuven study provides insights into how lecanemab enhances microglial function, and this pattern included heightened activity of the SPP1 gene.”

The study also underscores the value of interdisciplinary collaboration in neuroscience. The integration of techniques like NOVA-ST and single-cell transcriptomics has provided unprecedented resolution into microglial activity, demonstrating how advanced technologies can unravel complex biological processes. As the global Alzheimer’s population grows, such breakthroughs are essential for addressing the disease’s multifaceted nature. The next steps involve translating these findings into clinical applications, including personalized therapies tailored to individual patient profiles.