Since 2019, the Fisher Center for Alzheimer’s Research Foundation has supported a groundbreaking project at the Imagine Institute (Institut Imagine) of the Hôpital Necker-Enfants malades AP-HP in Paris, France, focusing on the role of mast cells in the pathology and treatment of Alzheimer’s disease.

Genome-wide association studies (a type of research that looks for links between specific gene variants and disease risk) have recently shed light on the contribution of immune system cells to Alzheimer’s disease. But while most researchers in the field have focused on the role of microglia—immune cells that act as the brain’s cleanup crew—Dr. Hermine and his team have turned their attention to a different and largely overlooked type of cell that also resides in the brain: mast cells.

Mast cells are immune system cells present in tissues throughout the human body. They are typically associated with allergic reactions and histamine release, and might also act as first responders to the toxic buildup of amyloid beta (Aβ) that damages the neurons of Alzheimer’s patients, leading to the symptoms of cognitive dysfunction and memory loss typical of the disease.

Patients affected by mastocytosis—a rare disorder characterized by the abnormal accumulation of mast cells in the body—frequently exhibit neurological symptoms similar to those of Alzheimer’s patients, such as anxiety, depression, and memory loss. Building on the clinical observation of these patients, Dr. Hermine and his team have obtained results that provide strong evidence of the involvement of mast cells in the development of Alzheimer’s disease.

Dr. Hermine and his team have identified two main areas of overlap between mast cells and Alzheimer’s disease.

The first arises from the discovery of a gene that exhibits strong links to Alzheimer’s, but that has not yet been associated with any known function. Upon further study, this gene turned out to be highly active in mast cells, and researcher Mirjana Weimershaus, PhD, has shown that its removal in cell culture models leads to mast cells no longer being able to move properly. This finding suggests that faulty versions of the gene might disrupt how mast cells travel in the brain, possibly interfering with their role in responding to Alzheimer’s.

The second connection that Dr. Hermine and his team have identified is that the activation of mast cells may negatively impact the ability of neurons to connect to one another. Specifically, they have determined that activated mast cells (and not resting ones) seem to interfere with the structure of synapses—the junctions where two neurons communicate with each other—and that this interference may contribute to early synapse loss, another hallmark of Alzheimer’s disease. Future research will explore when and how mast cells get involved in this process, and how exactly they might influence the chain of events that leads to cognitive decline.

Alongside their research on the role of mast cells in Alzheimer’s pathology, Dr. Hermine and his team have been testing masitinib, a new drug co-developed in his lab that targets both mast cells and microglia and has already shown promise in Phase IIb/III clinical trials, helping to slow memory loss.

Although these results are encouraging, scientists do not yet fully understand how masitinib works. Dr. Hermine’s team has begun to uncover the details of its mode of action by identifying the specific signaling proteins that mast cells release and how masitinib blocks them. This could help pinpoint exactly how the drug interrupts disease progression, and thus pave the way toward more targeted treatments in the future.