Researchers at Stanford University have identified a mutation in the PLCG2 gene that may lower the risk of Alzheimer’s disease. The team argues that this genetic change influences how immune cells in the brain function, supporting the view that Alzheimer’s may involve the brain’s immune system. The study appears in Immunity.
Alzheimer’s disease is a neurodegenerative condition primarily affecting older adults, characterized by the accumulation of beta-amyloid plaques. Newer work indicates that dementia is linked to chronic brain inflammation. The researchers propose that changes in immune cells could be connected to how the disease develops.
To explore this idea, scientists examined several PLCG2 variants in mouse models. The gene is active in microglia, the brain’s immune cells that detect and eliminate germs and damaged cells. When the gene was removed from mice, the animals showed a higher tendency to develop Alzheimer’s-like pathology because microglia lost their normal response to amyloid deposits.
Different PLCG2 mutations had distinct effects on dementia risk. The M28L variant appears to hinder microglial responses to amyloid plaques, increasing disease susceptibility. In contrast, the P522R variant seemed to enhance microglial function in a way that improved a memory-related measure in mice used as a model for Alzheimer’s disease.
Although the M28L variant is observed in humans, there is currently no evidence that it provides protection in people. The new findings align with recent ideas that Alzheimer’s may be driven by immune processes and that amyloid plaques might not be the sole trigger of symptoms.
The researchers suggest that therapies aimed at stimulating microglia to tackle amyloid deposits could help slow disease progression. Earlier work shows that modulating immune cells can affect disease outcomes in other conditions, illustrating the potential for immune-targeted strategies in brain disorders. This line of research emphasizes a shift away from viewing plaques as the only culprits and toward understanding how immune cell function shapes neuronal health. Further studies will clarify how PLCG2 variants influence human risk and whether microglial activity can be leveraged for protection in people.