Lecanemab, sold as Leqembi, is a monoclonal antibody treatment for Alzheimer’s disease that targets and eliminates harmful amyloid plaques while slowing cognitive decline. Scientists from VIB and the University of Leuven have figured out exactly how it works. Their research shows that specific parts of antibodies, known as “Fc fragments,” are important in activating the brain’s immune cells, microglia, which then begin to clear these toxic deposits. This study provides the first clear explanation of how this type of therapy works, answers long-standing questions, and provides guidance for developing safer and more effective treatments for Alzheimer’s disease. The results of this study were published in Nature Neuroscience.
“Our study is the first to clearly demonstrate how this anti-amyloid antibody therapy works in Alzheimer’s disease. We show that the efficacy of this therapy relies on the Fc fragment of the antibody, which activates microglia to effectively clear amyloid plaques,” said Julia Albertini, Ph.D., co-first author of the study. “The Fc fragment acts as an anchor to anchor microglia when they are in the vicinity of plaques, and as a result these cells are reprogrammed to clear plaques more efficiently.”
Alzheimer’s disease and the role of microglia
More than 55 million people worldwide are affected by Alzheimer’s disease. Alzheimer’s disease is caused by the accumulation of amyloid plaques in the brain. These toxic protein clusters damage neurons and eventually cause dementia. Microglia naturally gather around these plaques, but are usually unable to effectively remove them. In response, researchers have developed treatments aimed at restoring this essential immune function.
Antibody therapy and Fc fragments
Lecanemab, one of the treatments aimed at targeting amyloid-beta plaques and slowing disease progression, is already FDA-approved. However, its overall benefits have been limited by side effects, and until now its exact mechanism of action has remained unclear.
Antibodies are made up of two main parts. One part binds to a specific target, such as amyloid plaques, and the other part, the Fc fragment, sends a signal to the immune system. Previous studies suggested that microglia play a role in plaque clearance, but direct evidence linking microglial activity and lecanemab efficacy was lacking. Some scientists had proposed that plaque removal is possible without the involvement of Fc fragments. The team, led by Professor Bart de Strooper, demonstrated that this fragment is essential because microglia respond only when they are intact and functioning.
To investigate this, the researchers used a specially designed Alzheimer’s disease mouse model containing human microglial cells. This allowed us to take a closer look at how lecanemab interacts with human immune cells and promotes plaque clearance. Once 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,” added co-first author Magdalena Jeronka.
Inside the brain plaque removal process
The team then investigated how activated microglia actually clear amyloid plaques in this hybrid model. They identified key cellular processes involved in this clearance, including phagocytosis and lysosomal activity. These processes were triggered only when the Fc fragment was present. Without it, microglia remain inactive.
Using advanced techniques such as single-cell and spatial transcriptomics, the researchers also identified specific gene activity patterns in microglia associated with effective plaque clearance. This pattern includes strong expression of the gene SPP1 and was revealed using NOVA-ST, a method developed by the Stein Aerts lab (VIB-KU Leuven).
Aiming for safer and more effective Alzheimer’s disease treatment
By precisely defining the microglial program involved in plaque clearance, the findings suggest new therapeutic strategies for Alzheimer’s disease. Future treatments may be able to directly activate microglia without relying on antibodies.
“This opens the door to future treatments that may activate microglia without the need for antibodies. Understanding the importance of the Fc fragment will help guide the design of the next generation of Alzheimer’s drugs,” concluded Professor Bart de Strooper.
The research carried out at the VIB-KU Leuven Brain and Disease Research Center was supported by the European Research Council (ERC), Alzheimer’s Society of the United States, Flanders Research Foundation (FWO), Queen Elizabeth Neuroscience Medical Foundation, Stichting Alzheimer Onderzouk — Alzheimer Research Foundation (STOPALZHEIMER.BE), KU Leuven, VIB, and Dementia Research Institute University College UK. London.
