Leqembi’s Alzheimer’s Action: How Antibody Activates Brain’s Immune Cells

The Alzheimer’s drug lecanemab, marketed as Leqembi, has shown promise in slowing cognitive decline, but until recently, the precise mechanism behind its action remained a mystery. Now, scientists at VIB and KU Leuven have pinpointed a crucial element: the ‘Fc fragment’ of the antibody, which activates the brain’s immune cells, called microglia, to clear the toxic amyloid plaques characteristic of Alzheimer’s disease. This discovery, published in Nature, offers the first clear explanation of how this type of antibody therapy functions and could pave the way for developing even more effective Alzheimer’s treatments.

Understanding Alzheimer’s and the Role of Microglia

More than 55 million people globally are living with Alzheimer’s disease, a devastating neurodegenerative condition driven by the accumulation of amyloid plaques in the brain. These plaques, formed from misfolded proteins, disrupt communication between neurons and ultimately lead to cognitive impairment and dementia. Whereas the brain’s resident immune cells, microglia, naturally gather around these plaques, they often lack the ability to effectively remove them. Researchers have been focused on finding ways to restore this crucial immune function, and lecanemab represents one approach.

How Lecanemab Works: The Key Role of the Fc Fragment

Lecanemab is a monoclonal antibody designed to target and bind to amyloid-beta plaques, with the goal of slowing disease progression. It received FDA approval, but its benefits have been tempered by potential side effects. The new research clarifies how the drug achieves its therapeutic effect.

Antibodies consist of two primary parts: a region that binds to the target (in this case, amyloid plaques) and the Fc fragment, which signals the immune system. Previous studies hinted at microglia’s involvement in plaque clearance, but direct evidence linking their activity to lecanemab’s effectiveness was lacking. Some scientists even suggested that plaque removal might occur independently of the Fc fragment. The team, led by Professor Bart De Strooper, definitively demonstrated that the Fc fragment is essential for activating microglia.

To investigate this, researchers utilized a specialized Alzheimer’s mouse model engineered to include human microglial cells. This allowed them to observe, with unprecedented detail, how lecanemab interacts with human immune cells and promotes plaque clearance. Crucially, when the Fc fragment was removed, the antibody lost its ability to stimulate plaque removal.

Human Microglia: A Critical Component of the Research

“Our study is the first to clearly demonstrate how this anti-amyloid antibody therapy works in Alzheimer’s disease,” explains Dr. Giulia Albertini, co-first author of the study. “We show that the therapy’s efficacy relies on the antibody’s Fc fragment, which activates microglia to effectively clear amyloid plaques.” Magdalena Zielonka, also a co-first author, emphasizes the importance of using human microglia in the study. “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.”

Unpacking the Plaque-Clearing Process

The researchers delved deeper into the mechanisms by which activated microglia remove amyloid plaques. They identified key cellular processes, including phagocytosis (engulfing and removing debris) and lysosomal activity (breaking down cellular waste), that were only triggered when the Fc fragment was present. Without it, the microglia remained largely inactive.

Using advanced techniques like single-cell and spatial transcriptomics, the team also identified a specific gene activity pattern in microglia associated with effective plaque removal. This pattern involved strong expression of the gene SPP1, uncovered using NOVA-ST, a method developed at VIB-KU Leuven. This gene signature could potentially serve as a biomarker to assess the effectiveness of therapies aimed at activating microglia.

Implications for Future Alzheimer’s Treatments

This research doesn’t just explain how lecanemab works; it opens up new avenues for developing even more targeted and effective Alzheimer’s treatments. By defining the specific microglial program responsible for clearing plaques, scientists can now explore strategies to directly activate microglia, potentially bypassing the need for antibodies altogether. News-Medical reports that Professor De Strooper believes this understanding is crucial for designing the next generation of Alzheimer’s drugs.

“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,” he concludes.

What Comes Next: Refining Therapies and Identifying Biomarkers

The research team’s findings will likely spur further investigation into the specific mechanisms driving microglial activation and plaque clearance. Future studies will focus on identifying compounds that can directly stimulate the SPP1 gene expression and other key components of the microglial program. Clinical trials may also be designed to assess the effectiveness of therapies that target microglia directly, potentially offering a more potent and less side-effect-prone approach to treating Alzheimer’s disease. Researchers will also be looking for ways to identify individuals who are most likely to benefit from lecanemab or similar therapies, based on their individual microglial profiles.