"Our study is the first to clearly demonstrate how this anti-amyloid antibody therapy works in Alzheimer's disease. We show that the therapy's efficacy relies on the antibody's Fc fragment, which activates microglia to effectively clear amyloid plaques," says Dr. Giulia Albertini, co-first author of the study. "The Fc fragment works as an anchor that microglia latch onto when they are near plaques, as a consequence of which these cells are reprogrammed to clear plaques more efficiently."

Alzheimer's Disease and the Role of Microglia

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

Antibody Therapy and the Fc Fragment

Lecanemab is one of the therapies designed to target amyloid-beta plaques and slow disease progression, and it has already received FDA approval. However, side effects have limited its overall benefit, and until now, 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. The team led by Prof. Bart De Strooper demonstrated that this fragment is essential, as microglia only responded when it was intact and functional.

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.

The research conducted at the VIB-KU Leuven Center for Brain & Disease Research was supported by the European Research Council (ERC), Alzheimer's Association USA, Research Foundation Flanders (FWO), Queen Elisabeth Medical Foundation for Neurosciences, Stichting Alzheimer Onderzoek -- Fondation Recherche Alzheimer (STOPALZHEIMER.BE), KU Leuven, VIB, and UK Dementia Research Institute University College London.