Alzheimer’s Drug Leqembi’s Mechanism of Action Revealed

A key Alzheimer’s drug, lecanemab (marketed as Leqembi), has finally revealed its secret. Scientists have discovered that the drug works by activating the brain’s immune cells – microglia – to clear harmful amyloid plaques, but only through a specific part of the antibody called the Fc fragment. This finding could reshape how future Alzheimer’s therapies are designed.

Alzheimer’s Disease and the Role of Microglia

More than 55 million people worldwide live with Alzheimer’s disease, a condition driven by the buildup of amyloid plaques in the brain. These toxic protein clusters damage neurons and eventually lead to dementia. While microglia naturally gather around these plaques, they are typically unable to remove them effectively. Researchers have been developing treatments aimed at restoring this essential immune function.

Antibody Therapy and the Fc Fragment

Lecanemab is a therapy designed to target amyloid-beta plaques and gradual disease progression and it has already received FDA approval. However, side effects have limited its overall benefit, and until recently, its exact mode of action remained unclear.

Antibodies are made up of two main parts. One part binds to a specific target, such as amyloid plaques, while the other part, the Fc fragment, signals the immune system. Earlier research suggested that microglia play a role in clearing plaques, but direct proof linking their activity to lecanemab’s effectiveness was missing. Some scientists had also proposed that plaque removal could occur without involvement of the Fc fragment. Researchers from VIB and KU Leuven demonstrated that the fragment is essential, as microglia only responded when it was intact, and functional.

How the Fc Fragment Activates Microglia

To investigate this, researchers used a specially designed Alzheimer’s mouse model that included human microglial cells. This allowed them to closely observe how lecanemab interacts with human immune cells and promotes plaque clearance. When the Fc fragment was removed, the antibody no longer had any effect.

“The fact that we used human microglia within a controlled experimental model was a major strength of our study. This allowed us to test the very antibodies used in patients and observe human-specific responses with unprecedented resolution,” adds Magdalena Zielonka, co-first author.

Inside the Brain’s Plaque-Clearing Process

The team then examined how activated microglia actually remove amyloid plaques in this hybrid model. They identified key cellular processes involved in this cleanup, including phagocytosis and lysosomal activity. These processes were only triggered when the Fc fragment was present. Without it, the microglia remained inactive.

Using advanced techniques such as single-cell and spatial transcriptomics, the researchers also identified a specific gene activity pattern in microglia associated with effective plaque removal. This pattern included strong expression of the gene SPP1 and was uncovered using NOVA-ST, a method developed by the Stein Aerts lab (VIB-KU Leuven).

Toward Safer and More Effective Alzheimer’s Treatments

By defining the exact microglial program responsible for clearing plaques, the findings point toward new strategies for treating Alzheimer’s disease. Future therapies may be able to activate microglia directly, without relying on antibodies.

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