Pharmaceutical companies have called off one of the largest drug studies in Alzheimer’s disease, a setback that shrinks the chances of finding a treatment for the condition anytime soon.  

On Monday, Pfizer and Johnson & Johnson said that their Alzheimer’s drug, bapineuzumab, had failed to improve the memory or thinking ability in 1,300 volunteers with mild to moderate forms of Alzheimer’s.

That followed an announcement two weeks ago that the drug didn’t appear to help patients that carry a genetic risk factor for the disease (see “Pfizer ‘Disappointed’ with First Results for Alzheimer’s Drug Candidate”). As a result of the setbacks, the companies said they would cancel two other large studies of the drug.

The clinical trials of bapineuzumab, involving a total of 4,500 volunteers in four related studies, was the largest of three major efforts underway to use antibodies to clear or block the formation of brain plaques that are a hallmark of the disease, and may also be its cause.

The plaques are formed by buildup of amyloid-beta, a bit of protein that recent scientific research has fingered as the main culprit in Alzheimer’s disease. Based on that theory, pharmaceutical companies have concentrated their efforts on finding antibodies that can stick to amyloid-beta, with the idea that this could help people’s own immune systems dissolve plaques or prevent them from forming.

Results of another large antibody study, of Eli Lilly’s drug solanezumab, will be released by the end of next month, according to an Eli Lilly spokesperson.

Why are these drugs failing? One reason may be that by the time people develop symptoms, their brains are already too damaged to rescue. Recent studies have confirmed that patients suffer brain changes long before they experience confusion or forgetfulness (see “An Alzheimer’s Warning 25 Years Before Symptoms Show”). As a result, even good drugs won’t work if they are given too late.

“Timing may be absolutely critical when you intervene,” says Laurie Ryan, who oversees more than 30 smaller Alzheimer’s studies at the National Institute of Aging. “There seems to be a cascade of events.”

That makes Genentech’s upcoming study of creneuzumab, another anti-amyloid antibody, particularly interesting, Ryan says. The trial will test the drug on about 300 people with a genetic mutation that nearly guarantees they will develop Alzheimer’s. Participants will receive the drug while they are still healthy, making the study the first large-scale effort to learn if antibodies can actually prevent the disease.

Despite drugmakers’ costly bets on blocking amyloid-beta, there’s continued debate over what really causes Alzheimer’s. The disease involves many other changes to the brain’s white matter—such as tangles of another protein, called tau—and without a clearer understanding of the root cause of Alzheimer’s, some say it’s no surprise drugs are failing.

“There is a disconnect between our understanding of amyloid biology and Alzheimer’s disease,” says Craig Atwood, an endocrinologist and gerontologist at the University of Wisconsin-Madison. “You can clear amyloid from the brain of somebody, but they can still be completely demented,” he says. Instead, Atwood and a small contingent of Alzheimer’s researchers argue that the disease is due to hormonal changes associated with aging that affect brain cells. 

Not every drug being tested is tied to the amyloid plaque theory. A small study of another potential treatment—a mixture of antibodies known as IVIG—recently suggested it might slow the mental decline of patients (see “Study Suggests Alzheimer’s Disease Can Be Stabilized”). Although the biological action of the therapy isn’t known, the results were the first hint that a drug might be able to pause the progressive disease.

Ryan thinks the complexity of Alzheimer’s means we may need many drugs, not just one, as well as studies of whether exercise and diet can help. “Depending on where people are on the spectrum of the disease, you might want to use different therapies to hit different targets,” she says. “Clearly it’s best if you can prevent or slow the onset of an illness like Alzheimer’s, but at the same time, there are numerous people who have the disease and who will be getting the disease before we have treatments. We need to have therapies that work across the spectrum.”