Researchers at Boston Children's Hospital have discovered that immune cells in the brains of Alzheimer's patients carry the same mutations that drive blood cancers like lymphoma and leukemia, a finding that could reshape how doctors approach diagnosis and treatment of the neurodegenerative disease.
The study, published in Cell, analyzed cancer-related genetic mutations in brain tissue from nearly 200 Alzheimer's patients and compared them to healthy brains. Scientists found that microglia, the brain's immune cells, had accumulated mutations in specific cancer-driving genes at much higher rates in diseased brains than in controls.
The discovery was unexpected and has profound implications. "We find that to some extent, Alzheimer's disease is a little like cancer, driven by the same mutations that drive blood cancers," said Christopher Walsh, chief of the Division of Genetics and Genomics at Boston Children's Hospital and an investigator with the Howard Hughes Medical Institute. "This is helpful because we have a lot of drugs to fight cancer and some of them might be useful therapeutically for Alzheimer's disease."
What made the finding especially striking was that the same mutations appeared not just in brain tissue but in blood samples taken from the same Alzheimer's patients. Microglia were long thought to remain confined to the brain and unable to cross the blood-brain barrier.
"It was actually a really unexpected finding that suggests a totally new mechanism for Alzheimer's disease pathogenesis," said August Yue Huang, a co-author from the Division of Genetics and Genomics. "The findings mean that the blood's immune cells with cancer mutations are likely getting into the brain and contributing to disease."
The researchers propose a mechanism by which aging or injury weakens the blood-brain barrier, allowing mutant immune cells to cross from the bloodstream into the brain. Once there, these cells transform into microglia-like structures and may proliferate in response to protein clumps that accumulate in Alzheimer's brains. Because mutated cells have a biological advantage, they expand preferentially, creating a more inflammatory environment that damages nearby neurons.
The discovery opens a path to practical applications. Blood tests could potentially identify people carrying these mutations and flag them as having elevated Alzheimer's risk, since accessing brain tissue in living patients is difficult or impossible. A follow-up preprint study found that these cancer driver mutations in blood independently increased Alzheimer's disease risk, separate from APOE4, the well-established genetic risk factor.
The research involved collaborators from Harvard Medical School, the Broad Institute of MIT and Harvard, and the Icahn School of Medicine at Mount Sinai. Funding came from the Howard Hughes Medical Institute, the National Institute on Aging, and the NIH Common Fund.
Author Jessica Williams: "This is the kind of cross-disciplinary insight that could open an entirely new drug pipeline for Alzheimer's, borrowing weapons already proven against cancer."
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