A New Treatment for Alzheimer's?

Neurologists urge caution upon reports of a successful therapy.

A puzzling disease: Alzheimer's patients given an anti-inflammatory drug show rapid improvement, according to a report from physicians in California. These doctors believe that the treatment improves the connections in the brain. Credit: Technology Review

A drug commonly used to treat arthritis caused a dramatic and rapid improvement in patients with Alzheimer's disease, according to physicians in California. However, scientists and others not involved in the work worry that the report, which was based on trials in a few patients and hasn't been independently confirmed, may offer little more than false hope for Alzheimer's sufferers and their families.

Alzheimer's patients injected with the anti-inflammatory drug etanercept--marketed as Enbrel--showed dramatic improvements in their functioning within minutes, according to Edward Tobinick, director of the Institute for Neurological Research, a private medical facility in Los Angeles where the patients were treated, and an assistant clinical professor of medicine at the University of California, Los Angeles.

"The patients improve literally before your eyes," says Tobinick, who began using etanercept in Alzheimer's patients three years ago. He uses an unconventional method to administer the drug; he injects it near patients' spines. In 2006, he reported success with weekly treatments given to 15 people over the course of six months. In a case study in the latest issue of the Journal of Neuroinflammation, Tobinick and Hyman Gross, who practices in Santa Monica, describe how a patient improved within 10 minutes of treatment, and how cognitive tests performed two hours after the treatment showed a marked improvement over tests given before the injection. Tobinick says that the rapid improvement is typical in patients he has injected with etanercept. He treats them weekly, or, in some cases, less often.

"In each case, the person was more alert, calm, attentive, and they stayed on track," says Sue Griffin, director of research at the Donald W. Reynolds Institute on Aging at the University of Arkansas for Medical Sciences, who watched Tobinick treat several patients. Griffin says that she was skeptical when she first heard about Tobinick's approach, but having witnessed the effect firsthand, she says, "It was just completely amazing, like nothing I'd ever seen for an Alzheimer's person."

Minutes before the treatment, the patient in the case study couldn't recall the year or which state he was in. Ten minutes after the injection, he answered these questions correctly. As part of a cognitive assessment performed the day before the treatment, the patient was asked to draw a clock face showing a certain time. He sketched a square. Two hours after the injection, he drew a round face with two hands in approximately the correct positions.

The case report on this patient's rapid improvement is "interesting," says William Thies, vice president of medical and scientific relations for the Alzheimer's Association, but he adds that "we're going to need more information before it's something that people should get wildly excited about."

"There are some kernels of good science here," says David Standaert, director of the Center for Neurodegeneration and Experimental Therapeutics at the University of Alabama at Birmingham, but he cautions that "this is not enough evidence that we would start treating people outside of a trial." Standaert was not involved in the work.

Etanercept has been used since 1998, primarily to treat rheumatoid arthritis. It's usually injected into the thigh, stomach, or upper arm, but Tobinick says that by injecting it into the neck, near the spine, the drug can reach the brain. It's a method that requires considerable skill. "It would be incorrect for anyone to think that they could just take Enbrel if they have Alzheimer's, and they'll get better," he says.

For decades, scientists have been trying to figure out how Alzheimer's disease does its damage so that they can determine how it might be treated. A hallmark of the disease is the globs of protein that form in the brain. There's mounting evidence that "part of what damages the brain is the body's own immune responses to these abnormal proteins," Standaert says. Various anti-inflammatory drugs have been trialed in Alzheimer's patients, but with disappointing results.

Etanercept reduces inflammation by blocking a protein called tumor necrosis factor (TNF), which plays an important role in immune responses. TNF occurs naturally in the brain, but studies have found elevated levels in people suffering from Alzheimer's disease.

Recent evidence suggests that TNF regulates the activity of synapses, which connect brain cells and enable electrical signals to travel around the brain. In Alzheimer's patients, an excess of TNF may wreck havoc on those connections, Tobinick says. "Even though the neurons may be working, the connections between the neurons and between the different lobes of the brain may not be working properly."

By using etanercept to reduce levels of TNF in the brains of Alzheimer's patients, Tobinick thinks he may have normalized those connections, leading to an immediate improvement in cognitive functioning. He says that he's working with academic partners to design larger-scale trials of the treatment. However, Sonia Fiorenza, a spokeswoman for Amgen, which markets Enbrel, says that the company won't be sponsoring trials because it doesn't believe there's enough evidence that it may be useful in Alzheimer's disease.

Some researchers want to see independent studies carried out, in part because Tobinick has disclosed that he has stock in Amgen and holds patents on the use of the drug and other anti-TNF agents to treat Alzheimer's disease.

It's not unusual for researchers to have a financial interest in something they're studying, Thies says, and "it doesn't stop them from doing good science." However, "you're going to have to have some independent confirmation in the hands of others."

"You have to do these [studies] double blind, placebo controlled, by people who don't have a financial interest," says J. Wesson Ashford, a senior research scientist at the Stanford University/VA Aging Clinical Research Center. (He was not involved in Tobinick's work.) "I'd really like to believe it, but I've seen it so many times, when people say something and it doesn't turn out to be anything."

"This is something that's got to be looked at," Griffin says. "I hope that scientists will pay attention to this, and the funding agencies will pay attention to this."

"This is not a cure," she adds, but if there's a person who can't dress or feed himself, is arrogant, mean, and up all night, "and you can take them to the point where they can feed themselves, they're calmer, attentive, conversational--in other words, you can stand them--that's great."

http://www.technologyreview.com/Biotech/20066/