Are We Taking the Wrong Approach to Curing Alzheimer’s?

Like virtually every other expert on Alzheimer's disease, Sam Gandy was skeptical when he first heard about a Russian antihistamine that not only stopped the cognitive decline of Alzheimer's but also reversed it, with benefits lasting at least 12 months (compared with the six to nine months of current drugs). "My first reaction was 'This is too good to be true,' " he says. But he quickly became convinced that there was something to what he calls the "remarkable efficacy data," and began studying the drug, called dimebolin, himself. That produced perhaps the biggest surprise yet: in studies unveiled today at the International Conference on Alzheimer's Disease, which is going on in Vienna this week, dimebolin increased the amount of the very molecule that all the conventional wisdom about Alzheimer's holds is responsible for the disease.

That molecule is called beta amyloid. Although a growing number of scientists have been questioning the belief that it causes Alzheimer's and that getting rid of it is our best hope of treating the disease, as I have described before (including here, here and here), it remains the reigning dogma. As a result, drug companies as far as the eye can see are focusing their research on ways to prevent or destroy beta amyloid and the plaques it forms (it's the sticky plaques that are thought to gum up the brain, but that, too, is open to serious question). But when Gandy, of Mount Sinai School of Medicine in New York, and colleagues conducted a series of experiments in cells and in Alzheimer's mouse models to gauge the effect of dimebolin on beta amyloid, they found that dimebolin caused a sharp increase in beta amyloid, Gandy told the ICAD attendees.

"I would say that conventional wisdom in the field . . . is that an amyloid benefit would mean amyloid-lowering," Gandy told me by e-mail from Vienna. "Certainly, up until now, no one has been looking (intentionally) to treat Alzheimer's by raising amyloid levels. [So] it was startling to observe that a compound with an apparently beneficial clinical effect on cognition caused acute elevation of amyloid beta levels in 3 out of 3 systems, in 2 labs."

That has so many implications I hardly know where to start. Obviously it means that amyloid-busting compounds that companies hope to turn into drugs might be a seriously misguided approach. And plaque-clearing drugs may be not only useless against Alzheimer's, but possibly dangerous. One emerging idea gaining a lot of credibility is that the plaques are like toxic-waste sites, binding up bad-for-the-brain molecules. Open the toxic-waste dump, and you release the brain-poisoning molecules. That makes you wonder just how bad an idea vaccines against amyloid are (and not only because in one high-profile clinical trial they caused brain inflammation in some volunteers, forcing the trial to end early). If vaccines "work," in the sense of stimulating the immune system to destroy plaques, it might be the brain equivalent of releasing all the poisons in an encased Superfund site.

"I certainly think that plaques per se are largely inert," says Gandy. "Long story short: [Alzheimer's mouse models] developed aging-related memory impairment that was NOT exacerbated by adding a second gene that caused much of the amyloid beta to deposit as plaques. The mice that never developed plaques lifelong were just as impaired as those with plaques."

So where does this leave the amyloid theory of Alzheimer's and the billion-dollar drug-development effort that assumes it to be true? "I would not say that our results refute the amyloid hypothesis," Gandy told me diplomatically, "but we clearly raise some issues that must be resolved. Perhaps Dimebon"—the trade name under which Pfizer and the biotech company Medivation are developing dimebolin—"is such a potent neuroprotectant that doubling the amyloid concentration is still completely neutralized. Perhaps Dimebon raises amyloid acutely, but lowers it chronically. Maybe Dimebon does good by flushing amyloid beta out of the neuron." Or maybe targeting amyloid beta is a seriously wrong approach.

At this point, "there aren't enough data to even make an educated guess" about how dimebolin might turn back the symptoms of Alzheimer's, says Gandy. "The drug's beneficial actions might have nothing to do with amyloid, which, if true, indicates the existence of important therapeutic targets independent of beta amyloid."

That underlines the very real possibility that the stranglehold that the amyloid theory has had on Alzheimer's research has set back progress by years. But let me end on a positive note. Dimebon is no cure, but if it rolls back the memory loss and confusion of Alzheimer's by even one year, it will bring meaningful benefit to millions of people. "Given the hundreds of thousands of person-years of exposure that the drug had with no significant adverse effects while it was on the market for hay fever," says Gandy, "my bet would be that the FDA will approve it." Yes, a Russian antihistamine is the best bet we have against Alzheimer's.

© 2009