As people grow older, their cells steadily pick up new genetic mutations. A study from Boston Children’s Hospital, published in Cell, has uncovered an unexpected twist in that process. Researchers found that microglia, the immune cells that reside in the brain, accumulate mutations in specific cancer-driving genes. Rather than causing cancer, however, these mutations may contribute to the development of Alzheimer’s disease.
The research was led by Christopher Walsh, MD, PhD, Chief of the Division of Genetics and Genomics at Boston Children’s Hospital and an Investigator of the Howard Hughes Medical Institute. Collaborators included Alice Eunjung Lee, PhD, and August Yue Huang, PhD, also of the Division of Genetics and Genomics. All three are Professors at Harvard Medical School and Associate Members of the Broad Institute of MIT and Harvard.
The team says the findings could point to new ways to diagnose and treat Alzheimer’s disease.
“We find that to some extent, Alzheimer’s disease is a little like cancer — driven by the same mutations that drive blood cancers like lymphoma and leukemia,” said Walsh. “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.”
Cancer Driver Mutations Found in Alzheimer’s Brains
To investigate, researchers analyzed 149 cancer-driving genes in brain tissue samples from 190 people with Alzheimer’s disease and compared them with samples from 121 healthy brains.
The Alzheimer’s samples contained more single-letter DNA changes than the healthy tissue. Many of these alterations repeatedly appeared in the same five cancer driver genes, suggesting that microglia were accumulating mutations in a specific set of genes.
Microglia serve as the brain’s cleanup crew. These cells remove debris and help eliminate infected, damaged, or dying cells. Scientists had long believed that microglia remain confined to the brain and do not cross the blood brain barrier, unlike many other immune cells that circulate through the bloodstream.
Unexpected Link Between Blood Cells and the Brain
The mutations identified in microglia are commonly associated with blood cancers. That observation prompted the researchers to look for the same mutations in blood samples from people with Alzheimer’s disease.
They did not expect to find them.
Instead, the blood cells from the same Alzheimer’s patients carried the identical cancer-associated mutations.
“It was actually a really unexpected finding that suggests a totally new mechanism for Alzheimer’s disease pathogenesis,” said Huang. “The findings mean that the blood’s immune cells with cancer mutations are likely getting into the brain and contributing to disease.”
How Mutant Immune Cells May Fuel Alzheimer’s
The researchers propose that aging or injury can weaken the blood-brain barrier, allowing immune cells from the bloodstream to enter the brain. Once there, these cells may transform into microglia-like cells.
At the same time, protein clumps that build up in the brain trigger microglia to multiply and respond. Cells that possess a biological advantage are more likely to expand, including the microglia-like cells carrying cancer-related mutations.
According to the researchers, these mutated cells may create a more inflammatory and damaging environment than healthy microglia. As a result, nearby neurons can be harmed and die, contributing to the progression of Alzheimer’s disease.
Potential for New Alzheimer’s Tests and Treatments
The discovery could eventually lead to new approaches for detecting Alzheimer’s risk.
“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,” said Lee.
In a follow-up study posted as a preprint on bioRxiv, Huang and Lee found additional evidence supporting the connection. Their analysis showed that cancer driver mutations detected in blood samples increased Alzheimer’s disease risk independently of APOE4, a well-established genetic risk factor for the disease.
The research was conducted in collaboration with the Icahn School of Medicine at Mount Sinai. Funding was provided by the Howard Hughes Medical Institute, the National Institute on Aging, the NIH Common Fund through the Somatic Mosaicism Across Human Tissues (SMaHT) consortium, and the Suh Kyungbae Foundation (SUHF).