As people age, cells steadily acquire new genetic mutations. Research at Boston Children’s Hospital celland in the process an unexpected development was revealed. Researchers have discovered that microglia, immune cells found in the brain, accumulate mutations in certain cancer-causing genes. However, rather than causing cancer, these mutations may contribute to the development of Alzheimer’s disease.
The study was led by Christopher Walsh, M.D., chief of the Genetics and Genomics Division at Boston Children’s Hospital and a Howard Hughes Medical Institute investigator. Collaborators included Dr. Alice Eun-Jung Lee and Dr. August Yue Huang, also from the Department of Genetics and Genomics. All three are professors at Harvard Medical School and associate members of a wide range of research institutes at MIT and Harvard.
The research team says the discovery could point to new ways to diagnose and treat Alzheimer’s disease.
“We now know that Alzheimer’s disease is in some ways similar to cancer; it is caused by the same mutations that cause blood cancers such as lymphoma and leukemia,” Professor Walsh said. “This is helpful because there are many cancer-fighting drugs, some of which may help treat Alzheimer’s disease.”
Cancer driver mutations found in Alzheimer’s disease brains
For the study, researchers analyzed 149 cancer-promoting genes in brain tissue samples from 190 people with Alzheimer’s disease and compared them with brain samples from 121 healthy people.
Alzheimer’s disease samples contained more single-letter DNA changes than healthy tissue. Many of these changes appeared repeatedly in the same five cancer driver genes, suggesting that microglia accumulate mutations in specific sets of genes.
Microglia act as the brain’s cleaners. These cells remove debris and help remove infected, damaged, or dying cells. Scientists have long believed that microglia, unlike many other immune cells circulating in the bloodstream, are confined to the brain and do not cross the blood-brain barrier.
An unexpected connection between blood cells and the brain
Mutations identified in microglia are commonly associated with blood cancers. This observation led researchers to look for the same mutations in blood samples from Alzheimer’s patients.
They didn’t expect to find them.
Instead, blood cells from the same Alzheimer’s patients had the same cancer-associated mutations.
“This was actually a really unexpected finding that suggests a completely new mechanism for the development of Alzheimer’s disease,” Professor Huang said. “This finding means that immune cells in the blood that carry cancer mutations may be able to enter the brain and cause disease.”
How mutant immune cells drive Alzheimer’s disease
Researchers propose that age and injury weaken the blood-brain barrier, allowing immune cells from the bloodstream to invade the brain. Once there, these cells can transform into microglia-like cells.
At the same time, the protein clumps that accumulate in the brain cause microglia to proliferate and respond. Cells with biological advantages, such as microglial-like cells with cancer-associated mutations, are more likely to proliferate.
According to the researchers, these mutant cells can create a more inflammatory and harmful environment than healthy microglia. As a result, nearby neurons become damaged and die, which can contribute to the progression of Alzheimer’s disease.
Possibility of testing and treatment for new Alzheimer’s disease
This discovery could ultimately lead to new approaches to detecting Alzheimer’s disease risk.
“Because it is difficult to access brain tissue from living patients, we may be able to develop genetic screens using blood samples to test whether a person has these mutations and is at increased risk of developing Alzheimer’s disease,” Lee said.
In a follow-up study posted as a preprint on bioRxiv, Huang and Lee found additional evidence supporting this association. Their analysis showed that cancer driver mutations detected in blood samples increased the risk of Alzheimer’s disease, independent of APOE4, which is an established genetic risk factor for Alzheimer’s disease.
The study 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 Xu Jingpei Foundation (SUHF).
