Brigham, Children’s Hospital researchers find increased mutations in Alzheimer’s patient brain cells

Exterior of Brigham and Women’s Health Care Center pictured here.Barry Chin/Globe Staff

Alzheimer’s disease patients had a greater number of mutations in their brain cells than people who were normally aging, a new study by researchers at Brigham and Women’s Hospital and Boston Children’s Hospital found.

“We know these mutations increase with age. Now we’ve found that with Alzheimer’s disease, there’s even more of them,” said one of the lead authors, Dr. Michael B. Miller of the Department of Pathology at the Brigham. The study was published Wednesday in the journal Nature.

Miller said neurons in the brain die in Alzheimer’s disease and the new findings “help us better understand ways in which the cells might be dying.”

“Our analysis reveals that excitatory neurons in the brains of individuals with [Alzheimer’s disease] accumulate genomic damage—and likely permanent mutations—beyond the levels that occur as a result of ageing alone,” the study said.

Researchers used single-cell whole genome sequencing of neurons of patients with and without Alzheimer’s. “It gives us information about what’s happening in the cell, what’s going wrong in the cell,” Miller said.

On top of the mutations expected from normal aging, he said, there was an “extra group of mutations of different types.”

He said researchers would like to delve further into what causes the mutations and cell deaths and ultimately “develop tests and treatments that target those pathways.”

Dr. Andrew Budson, a professor of neurology at the Boston University School of Medicine, said the study was “a very nice piece of work.”

“What the paper has firmly shown through the research is that there are all these DNA mutations that occur in these Alzheimer’s brain cells far and above the normal mutations that sometimes happen to brain cells in just normal aging,” he said.

“That damage may be one of the reasons brain cells are dying,” he said.

Alzheimer’s is a mysterious, heartbreaking disease that affects millions of older people. There is no cure, though some drugs have been approved for it. There are multiple hypotheses about what causes it.

One long-held theory, Budson said, is that there is a buildup of beta-amyloid plaques in the brain “and then it causes these tau tangles to occur inside the cells and then the cells die.” The new study illuminates a possible mechanism, he said, raising the possibility that the tau tangles create free radicals that react with the brain cells’ DNA, causing harmful mutations that kill them.

Alzheimer’s disease destroys memory and thinking skills as the brain shrinks and brain cells die. Eventually, the disorder wipes out the ability to carry out even the simplest tasks.

As of 2020, an estimated 5.8 million Americans were living with the disease. For most, symptoms appear in their mid-60s. Some people can get it earlier.

Miller’s co-lead author was August Yue Huang, a research fellow at Boston Children’s Hospital and Harvard Medical School. The senior authors were Michael A. Lodato, Eunjung Alice Lee, and Christopher A. Walsh of Boston Children’s Hospital.