Researchers at the Wu Tsai Neurosciences Institute at Stanford University have unveiled a potential mechanism behind the memory loss associated with Alzheimer’s disease. Published on January 26, 2026, in the journal Proceedings of the National Academy of Sciences, their study suggests that Alzheimer’s may manipulate the brain into erasing its own memories by activating a specific molecular switch.
The research focuses on the roles of amyloid beta, a protein fragment known to accumulate in the brains of Alzheimer’s patients, and chronic inflammation, both of which appear to converge on the same receptor that signals neurons to eliminate synapses. This groundbreaking insight provides a new perspective on how Alzheimer’s progresses, highlighting that neurons actively respond to these signals rather than being mere victims of the disease.
Connecting Amyloid Beta and Inflammation
Led by Carla Shatz, the Sapp Family Provostial Professor, and research scientist Barbara Brott, the study identifies a receptor named LilrB2 as a crucial player in this process. Shatz has explored the functions of LilrB2 for nearly two decades and previously found that it facilitates normal synaptic pruning during brain development and learning.
In 2013, her team established that when amyloid beta binds to LilrB2, neurons are prompted to remove synapses. Further research indicated that genetically removing this receptor protected mice from memory loss in models of Alzheimer’s disease. This pivotal discovery sheds light on the intricate relationship between amyloid beta and synapse loss.
The team also investigated the complement cascade, a process involved in immune responses. While it typically helps eliminate pathogens, recent findings have linked excessive activation of this cascade to synaptic pruning in neurological disorders, leading researchers to explore if molecules from this cascade could interact with LilrB2 similarly to amyloid beta.
Surprising Findings and Implications
During their experiments, researchers identified a protein fragment called C4d that effectively binds to LilrB2, raising concerns about its role in synapse loss. In tests conducted on healthy mice, injections of C4d resulted in the stripping of synapses from neurons, revealing unexpected functions for a molecule previously thought to lack significance.
The combined evidence suggests that both amyloid beta and inflammatory factors may trigger synapse loss through a shared pathway. Shatz noted that this insight could prompt a reevaluation of the mechanisms underlying Alzheimer’s disease. She stated, “There’s an entire set of molecules and pathways that lead from inflammation to synapse loss that may not have received the attention they deserve.”
Furthermore, the findings challenge the prevailing notion that glial cells are primarily responsible for synapse removal during Alzheimer’s progression. Instead, the research indicates that neurons themselves actively participate in this process, as Shatz remarked, “Neurons aren’t innocent bystanders. They are active participants.”
The implications of this research extend to future treatment strategies. Current FDA-approved drugs primarily focus on disrupting amyloid plaques but have shown limited effectiveness and potential side effects, including headaches and brain bleeding. Shatz advocates for exploring therapies that target receptors like LilrB2, which could help protect synapses and, in turn, preserve memory.
The study involved collaboration among researchers from various departments at Stanford University, including the Departments of Biology and Neurobiology, as well as contributions from the California Institute of Technology. Funding came from multiple organizations, including the National Institutes of Health and the Champalimaud Foundation.
In summary, this research not only advances the understanding of Alzheimer’s disease but also opens up new avenues for potential treatments that could better address memory loss associated with this devastating condition.
