Dangerous blood condition may guard against Alzheimer’s disease | Science

Medicine so far has nothing to offer that clearly prevents Alzheimer’s disease, although keeping your weight down, exercising regularly, and inheriting certain protective genes can lower your risk. Now, a study has identified another, unexpected source of protection: clonal hematopoiesis, a blood cell imbalance best known as a risk factor for cancer and heart disease.

“Clonal hematopoiesis has been associated with so many bad outcomes that it is surprising that it is protective in this situation,” says cardiovascular biologist Kenneth Walsh of the University of Virginia, who wasn’t connected to the study, reported on 12 December at the American Society of Hematology meeting in Atlanta. But Walsh says the work is convincing and “will have to be reckoned with and explained.”

He and other researchers caution that the discovery doesn’t offer any immediate opportunities for treating or preventing Alzheimer’s disease. Given the negative health effects of clonal hematopoiesis, inducing it in healthy people is a nonstarter. Still, the finding has a provocative implication: that cells from the bloodstream are restocking the brain’s immune cells, perhaps bolstering its ability to clear out toxic debris.

Charles Darwin probably never imagined that natural selection unfolds in our bone marrow. But clonal hematopoiesis results from competition among the 50,000 to 200,000 stem cells that dwell there and divide to produce all our red and white blood cells. Over the years these stem cells accrue mutations, some of which result in a “fitter” cell whose progeny, known collectively as a clone, can soon outnumber their counterparts. In some people with clonal hematopoiesis, the offspring of a single mutated stem cell account for more than half of the blood cells in the body.

This blood cell imbalance is rare in young people, but becomes more common with age, occurring in up to 30% of people over age 70. Clonal hematopoiesis is not cancer—people with the condition have a normal number of blood cells—but it can be a prelude to blood cancers such as leukemia and lymphoma. People with the condition are also twice as likely to develop cardiovascular disease, and researchers have linked it to stroke, osteoporosis, type 2 diabetes, heart failure, and chronic obstructive pulmonary disorder. Overall, scientists have found, people with clonal hematopoiesis are up to 50% more likely to die by various ages.

Pathologist Siddhartha Jaiswal of the Stanford University School of Medicine and colleagues wondered whether the skewed populations of immune cells in clonal hematopoiesis might also increase the risk of Alzheimer’s disease. Other investigators, after all, had shown the brain’s own immune cells, the microglia, may drive Alzheimer’s disease. But any connection seemed a long shot. Cells from the blood clones might have to infiltrate the brain to have an effect—and most investigators think the microglia typically settle down in the brain early in life and are not born in the bone marrow.

When the scientists analyzed DNA from the blood cells of more than 5700 people and compared the data with Alzheimer’s incidence, they were stunned to see that clonal hematopoiesis has a substantial effect on developing the disease. But rather than increasing its risk, it appeared to make people 30% to 40% less likely to suffer from the illness. That’s a larger protective effect than any other factor identified so far, Jaiswal says.

More evidence of the protective effect came from postmortem brain samples of people in the DNA sequencing study who didn’t have Alzheimer’s disease when they died. Two molecular hallmarks of the illness—plaques of the protein beta amyloid and snarls of the protein tau—were less abundant in the brains of people with clonal hematopoiesis than in those without it, lead author Hind Bouzid, also at Stanford, reported at the meeting. She, Jaiswal, and their colleagues also revealed their findings in a preprint posted on medRxiv.

Jaiswal’s team implicated microglia in the protective effect. They analyzed brain tissue samples from eight people with clonal hematopoiesis and in six found that unidentified cells carried the same mutations as the blood cell clones. In two other people with clonal hematopoiesis, they detected the blood mutations in the microglia themselves, finding the telltale changes in between 40% and 80% of the cells. The researchers inferred that altered blood cells produced in the bone marrow had slipped into the subjects’ brains. There, the cells may have morphed into microglia.

Immunologist Cameron McAlpine of the Icahn School of Medicine at Mount Sinai says the portion of the study linking clonal hematopoiesis to Alzheimer’s disease is “beautiful.” But he isn’t convinced that bone marrow–derived blood cells regularly enter the brain. “They show it can occur, but I wonder to what degree it does occur.”

If the work is confirmed, pinning down the protective mechanism is the next step in transforming the curious observation into something physicians might exploit. It’s possible, for example, that mutant microglia are better at clearing away the beta-amyloid plaques and tau tangles that build up in Alzheimer’s disease. But for now, Jaiswal says, how clonal hematopoiesis safeguards the brain remains a “million-dollar question.”