A protein’s ebb and flow

A menacing substance builds up in the brains of people with Alzheimer’s disease not because they make too much of it, but rather because they can’t get rid of it, a study appearing online December 9 in Science suggests.

Understanding how the substance, called amyloid-beta, lodges in the brain is likely to yield clues about how Alzheimer’s disease inflicts its devastating damage.

There’s no clear consensus on the ultimate cause of Alzheimer’s, but many scientists think A-beta is at the heart of the disease. The protein is thought to interfere with cells in the brain, scrambling its normal operations.

In some rare forms of Alzheimer’s disease, genetic mutations ramp up the production of A-beta, creating an imbalance that floods the brain with the protein. But the cause of the accumulation is murkier for the most common form of Alzheimer’s disease.

Although the new study is preliminary and has limitations, it suggests that A-beta clearance is the problem. The research “takes a long-held hypothesis and finally supports it with data,” says psychiatrist Bill Klunk of the University of Pittsburgh School of Medicine.

In the study, researchers led by Randall Bateman of the Washington University School of Medicine in St. Louis designed a method to track the flux of A-beta in people living with the disease. The amino acid leucine was labeled with carbon-13, which is scarce in the body, and infused into 12 healthy volunteers and 12 volunteers with Alzheimer’s disease.

As cells made proteins over the next several hours, including A-beta, they occasionally grabbed a labeled leucine. Chemical tests on the participants’ spinal fluid, which served as an indicator of conditions in the brain, revealed the levels of labeled A-beta.

“The whole point is to get access to a compartment — in other words, the brain — that we don’t normally have access to in people,” Bateman says. “It allows us to probe the underlying turnover rate of these proteins as they’re made in the brain and also as they’re cleared away.”

Checks of the spinal fluid showed that initially, the labeled A-beta increased, then decreased as the body cleared it. Both groups of volunteers produced amyloid-beta at about the same rate. Yet people with Alzheimer’s cleared A-beta at a rate about 30 percent slower than that of the healthy controls, the team found.

“We see there’s a very clear imbalance, but it doesn’t appear to be driven by production at all,” Bateman says. “It appears to be driven by clearance.”

This imbalance could result in a net accumulation of the protein, which many researchers believe precedes or causes brain damage and dementia in Alzheimer’s, Bateman says.

The study hasn’t nailed down the cause of the imbalance, though. “While I believe these data are important, a lot remains to be explained,” says Alzheimer’s researcher and internist Paul Aisen of the University of California, San Diego. “The interpretation of the data is quite challenging.”

In particular, A-beta levels in the spinal fluid are not a clear indicator of levels in the brain, he says. The relationship between the two is complex and poorly understood, making it problematic to make claims about the protein in the brain, Aisen says. Further complicating the picture is the fact that A-beta levels are known to be lower in the spinal fluid of Alzheimer’s patients, compared with healthy people.

The researchers plan to focus next on trying to establish exactly how A-beta is cleared from the brain.