Alzheimer’s disease may mislead the brain into eliminating its own memories, according to groundbreaking research from the Wu Tsai Neurosciences Institute at Stanford University. A study published on January 26, 2026, reveals that a single molecular switch may trigger neurons to prune their own synaptic connections, shedding light on the mechanisms behind this devastating condition.
Traditionally, Alzheimer’s has been associated with the accumulation of amyloid beta, a protein fragment believed to damage neurons. However, the complexity of Alzheimer’s involves various factors, including tau proteins, chronic inflammation, and immune responses. This study offers insights into how inflammation and amyloid beta might work together in a shared biological pathway contributing to memory loss.
Linking Amyloid Beta and Inflammation
The research, led by Carla Shatz, a prominent professor at Stanford, aims to connect two major theories about Alzheimer’s progression. The findings suggest that both amyloid beta and inflammatory responses converge on a specific receptor that signals neurons to eliminate synapses—the critical points of communication between brain cells. The study’s first author, Barbara Brott, along with Shatz, emphasizes the significance of this receptor, known as LilrB2.
Earlier research by Shatz established that LilrB2 plays a vital role in synaptic pruning during brain development and learning. In 2013, her team demonstrated that amyloid beta binds to LilrB2, prompting neurons to remove synapses. Importantly, mice genetically modified to lack this receptor showed protection against memory loss linked to Alzheimer’s.
Inflammation’s Role in Synapse Loss
The study also examined the complement cascade, an immune process involved in clearing pathogens and damaged cells. While inflammation is a recognized risk factor for Alzheimer’s, its exact role in synaptic pruning had not been thoroughly explored. Shatz’s team hypothesized that molecules from the complement cascade might interact with LilrB2 similarly to amyloid beta.
To investigate, the researchers screened various complement cascade molecules and identified one, the protein fragment C4d, that bound effectively to LilrB2. Subsequent experiments in live animals revealed that injecting C4d into the brains of healthy mice resulted in the removal of synapses, a surprising outcome given that C4d was previously thought to lack significant function.
The cumulative evidence indicates that both amyloid beta and inflammatory processes may drive synaptic loss through a common mechanism, prompting a reevaluation of how Alzheimer’s affects memory.
Neurons as Active Participants
This study challenges the prevailing notion that glial cells are the primary culprits in synapse removal during Alzheimer’s progression. Shatz asserts that neurons are not passive victims; they actively participate in the process of synaptic loss. “Neurons aren’t innocent bystanders,” she stated, highlighting their critical role in memory degradation.
These findings may have profound implications for future treatments for Alzheimer’s. Currently, available FDA-approved therapies primarily target amyloid plaques in the brain. Shatz notes that these treatments have shown limited efficacy and significant side effects, including headaches and potential brain bleeding.
A more promising approach may involve targeting receptors like LilrB2, which directly regulate synapse removal. By protecting synapses, researchers and clinicians may find a way to preserve memory and improve outcomes for individuals affected by Alzheimer’s disease.
The study was supported by the National Institutes of Health and various foundations, including the Sapp Family Foundation and the Phil and Penny Knight Initiative for Brain Resilience. The collaboration included contributions from multiple departments at Stanford and the California Institute of Technology.
As Alzheimer’s research continues to evolve, understanding the intricate mechanisms involved in memory loss will be crucial in developing more effective treatments, potentially transforming the landscape of care for those living with this challenging condition.
