When August Yue Huang analyzed blood samples from patients with Alzheimer's disease, he expected to find nothing unusual. Instead, his team at Boston Children's Hospital discovered something that would upend decades of assumptions about the disease: the same cancer-driving mutations they had found in the brain's immune cells were also circulating in the blood. "It was actually a really unexpected finding," Huang said, "that suggests a totally new mechanism for Alzheimer disease pathogenesis."
The discovery, published in Cell, emerged from an ambitious study that sequenced 149 cancer-driving genes from brain tissue donated by 190 people with Alzheimer's disease and 121 healthy individuals. The Alzheimer's brains showed more single-letter DNA changes than healthy tissue, with the most mutations clustering in five specific cancer driver genes—mutations commonly seen in blood cancers like lymphoma and leukemia. The cells accumulating these changes were microglia, the brain's resident immune cells that act as garbage collectors, clearing debris and dying cells.
"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. Working with colleagues Alice Eunjung Lee and August Yue Huang—both professors at Harvard Medical School and associate members of the Broad Institute—the team realized this connection could open an unexpected door. "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."
The researchers theorize that as the blood-brain barrier weakens with age or injury, immune cells from the bloodstream slip into the brain and convert into microglia-like cells. When protein clumps like tau or amyloid trigger inflammation, these mutant cells gain a selective advantage and proliferate—but their survival comes at a cost. The mutations make the cellular environment more inflammatory and hostile, causing innocent neurons to wither and die.
In a follow-up preprint on bioRxiv, Huang and Lee showed that these cancer mutations in blood samples increased Alzheimer's risk independently of APOE4, a well-established genetic risk factor. "Because it's hard to access brain tissue in a living patient, genetic screens using blood samples could be developed to test whether a person carries these mutations, and has an increased risk of developing Alzheimer's disease," Lee said. The findings suggest that a simple blood test might someday identify people who could benefit from treatments originally designed for cancer—transforming how the disease is detected and managed.