Research from the Wu Tsai Neurosciences Institute at Stanford University has uncovered a critical mechanism by which Alzheimer’s disease may erase memories. The study, published in the Proceedings of the National Academy of Sciences on January 26, 2026, suggests that the disease hijacks neurons, prompting them to eliminate their own synaptic connections.
Alzheimer’s is notorious for its devastating impact on memory, primarily through the destruction of neurons and their connections. Researchers have long investigated the role of amyloid beta, a protein fragment that accumulates in the brain, but they have also recognized a wider array of contributing factors, including tau proteins and chronic inflammation.
A new study led by Carla Shatz, a professor at Stanford and an affiliate of the Wu Tsai Neurosciences Institute, proposes a connection between amyloid beta and inflammation that may elucidate the initial stages of memory loss. The research indicates that both amyloid beta and inflammatory processes converge on a receptor known as LilrB2, which signals neurons to prune synapses.
Linking Amyloid Beta and Inflammation
Shatz’s previous research highlighted the role of LilrB2 in synaptic pruning—an essential process in brain development and learning. In 2013, her team discovered that amyloid beta binds to LilrB2, triggering the removal of synapses. This latest study expands on that foundation by exploring the relationship between inflammation and synapse loss.
A significant part of the research involved the complement cascade, an immune system process that helps eliminate damaged cells. Although beneficial under healthy conditions, chronic inflammation is a recognized risk factor for Alzheimer’s. The researchers hypothesized that molecules in the complement cascade might interact with LilrB2 in a similar way to amyloid beta.
To test this hypothesis, the team screened molecules in the complement cascade and identified C4d as a potential candidate. When injected into the brains of healthy mice, C4d caused significant synapse loss, indicating its active role in synaptic pruning.
Implications for Alzheimer’s Treatment
This finding suggests that both amyloid beta and inflammatory processes could drive synapse loss through a shared pathway, prompting a reevaluation of Alzheimer’s treatment strategies. Shatz emphasized that current FDA-approved treatments primarily focus on breaking apart amyloid plaques, which have shown limited efficacy and carry substantial side effects.
“Current approaches like busting up amyloid plaques haven’t worked that well,” Shatz stated. “Even if they did, they only address part of the problem.” She advocates for developing therapies that target receptors like LilrB2 to better protect synapses and, consequently, preserve memory.
The study involved contributions from multiple researchers, including first author Barbara Brott and colleagues from Stanford’s departments of biology and neurobiology. Funding for the research was provided by various organizations, including the National Institutes of Health and the Sapp Family Foundation, among others.
These insights not only advance understanding of Alzheimer’s pathology but could also pave the way for innovative therapeutic approaches aimed at safeguarding memory in individuals affected by this debilitating disease.
