Rutgers neuroscientist Peng Jiang and his neuroscience colleague Mengmeng Jin have made a discovery they say could reshape how scientists think about Alzheimer’s treatment.
Their study, published in Nature Neuroscience, identifies a rare gene mutation that appears to protect the brain’s immune cells from the damage typically caused by the disease.
“We believe it’s a major advance in the field,” Jiang said. “Rather than looking at mutations that increase risk, we’re searching for mutations that can confer resilience.”
The work reflects a shift in Alzheimer’s disease research, Jiang said. Instead of focusing only on removing toxic proteins, scientists may be able to strengthen the brain’s own defense system to keep it resilient and healthy longer.
For Jiang, the science is inseparable from the human impact.
How a rare mutation offers protection
“We’re trying to learn from nature to harness a naturally occurring mutation for therapeutic purposes,” he said.
Individuals with Down syndrome, who carry three copies of chromosome 21, almost universally develop early-onset Alzheimer’s disease due to the accelerated accumulation of toxic proteins in the brain. Yet a small subset of people with Down syndrome shows remarkable resilience—they never develop dementia despite having the same pathological buildup.
This observation motivated the Rutgers team to investigate the biological effects of a rare mutation, CSF2RB A455D, identified in the immune cells of a small number of individuals with Down syndrome. Their research reveals previously unknown functions of this mutation and provides new insights into mechanisms that may influence the risk of neurodegeneration.
Testing the mutation in mouse models
They focused on microglia, the brain’s immune cells that act as housekeepers, clearing away waste and protecting neurons. Using stem cell technology, the researchers created human microglia with the mutation and placed them into the brains of mice to develop a chimeric mouse brain model, allowing them to observe how these human cells function in a living brain environment. These mice were then exposed to Alzheimer’s-related proteins.
The results surprised researchers. The microglia with the mutation stayed young and avoided long-term inflammation that usually damages brain cells. The cells were better at cleaning up harmful proteins and protecting nearby neurons.
When researchers placed both mutated and unmutated microglia together in brain environments containing Alzheimer’s-related proteins, the mutated microglia slowly took over.
The unmutated microglia became weaker over time, while the mutated ones stayed strong, effectively refreshing the brain’s immune system. This effect showed up not only in cells from people with Down syndrome but in cells from the general population.
“We transplant the cells, then inject pathological proteins,” said Jin, a postdoctoral research fellow. “We observe how the human microglia react.”
Potential for new Alzheimer’s therapies
The discovery opens the door to new therapeutic strategies, the scientists said. One approach involves transplanting microglia engineered with the protective mutation into patients’ brains.
Another could involve using gene therapy to introduce the mutation directly into existing microglia, potentially restoring their ability to defend against Alzheimer’s damage.
More information:
Mengmeng Jin et al, A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease, Nature Neuroscience (2025). DOI: 10.1038/s41593-025-02117-8
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