Two clinical trials of a potential Alzheimer's drug were halted this week, highlighting circulating skepticism about the hypothesis that amyloid beta plaque is a major factor in the disease's genesis.

The pulled drug, semagacestat (made by pharmaceutical firm Eli Lilly & Co.), was being tested in trials that enrolled more than 2,600 Alzheimer's patients with mild or moderate symptoms across 31 countries. In preliminary analyses, researchers found that patients taking the drug seemed to be suffering from more cognitive troubles than those taking the placebo. Although a complete cure was not expected, researchers noted that they had hoped the compound would at least slow the progression of the degenerative brain disease.

Autopsies and imaging have revealed that Alzheimer's patients tend to have extra amyloid beta plaque built up in their brains. And new spinal fluid tests seem to be able to predict increased risk of the disease based on higher levels of amyloid. These patterns have led researchers on a hunt to find compounds that might stop or limit plaque growth, thereby possibly slowing the disease.

But, as the causes—and a cure—for the disease remain unknown, some researchers suspect that "our current views may be too simplistic," P. Murali Doraiswamy, head of Biological Psychiatry at Duke University, told The New York Times. And with 115.4 million people estimated to have the disease worldwide by 2050, the urgency to find an effective treatment continues to grow.

The Lilly drug under tests in the Phase III clinical trials was a gamma secretase inhibitor, which had been shown to decrease the amount of amyloid in sampled cerebral spinal fluid, Reuters reported.

But because this purported plaque-limiter seemed to exacerbate cognitive problems—and increase the incidence of skin cancer in those taking it—the company recommended stopping both trials, which had been underway since 2008.

Some suspect that in knocking down gamma secretase "with a sledgehammer," the drug might have been altering too many different proteins in an enzyme that "has a lot of different functions," Rudolph Tanzi, a neurology professor at Harvard Medical School told Bloomberg.

But that does not mean that other attacks on plaque are necessarily doomed to failure. "Having the drug fail doesn't say the hypothesis is wrong that amyloid causes the disease," Steven DeKosky, dean of University of Virginia's School of Medicine and occasional consultant for Lilly, told the Times, noting that "it's too soon to say" whether stopping the plaque growth some other way will be more effective. It remains unknown whether the compound under test—or the entire approach—is flawed.

"When one like this fails, it's discouraging to the field," Ronald Peterson, director of the Alzheimer's Disease Research Center at the Mayo Clinic, told the Times about the drug. "But it's not the end of the day…We have other targets out there and other ways to attack the same target."

Lilly has another Alzheimer's drug in Phase III trials—solanezumab, a monoclonal antibody that seems to work as a neuroprotector.

Pulling the plug on the Lilly trials does not "disprove the amyloid beta hypothesis and it does not change our commitment to our development programs," Ellen Rose, a Johnson & Johnson spokesperson, told Bloomberg. Bristol-Myers Squibb has plans to move forward with its own Phase II gamma secretase inhibitor trails, and other companies, including Pfizer and Elan, have potential compounds in testing, Bloomberg reported.

Image courtesy of Wikimedia Commons/National Institute on Aging