VIENNA – Dimebon–the abandoned Russian antihistamine that burst onto the Alzheimer's study scene with the only positive clinical data of 2008–may throw yet another curve ball into a research world that for years has focused almost entirely on the amyloid hypothesis.

Rather than lowering amyloid beta (Abeta) levels, as two failed investigational drugs–tramiprosate and tarenflurbil–have attempted, dimebon appears to almost immediately increase them, raising Abeta by as much as 200% in three mouse models of Alzheimer's disease (AD), Dr. Samuel Gandy reported at the International Conference on Alzheimer's Disease.

While preliminary, the findings–combined with the nearly unprecedented cognitive benefit dimebon conferred in its phase II trial–could be enough to dethrone the long-reigning amyloid hypothesis, according to Mark A. Smith, Ph.D., an Alzheimer's researcher. “This drug is clearly not targeting amyloid, but increasing it acutely,” said Dr. Smith of Case Western Reserve University, Cleveland. “If you believe the dogma, therefore, you should believe that this increase will cause Alzheimer's. These results question that dogma. If this holds up, it could be enough to wound the amyloid theory, potentially mortally.”

Dimebon's 2008 phase II study found that patients with mild to moderate AD who took the drug for 12 months gained about 2 points on the Alzheimer's Disease Assessment Scale-Cognition (ADAS-cog), while those taking placebo declined almost 6 points from baseline (Lancet 2008;372:207-15). A 6-month open-label extension trial found similarly positive results. Patients who completed a full 18 months of dimebon continued to show benefit on ADAS-cog. Former placebo patients who crossed over to dimebon stabilized their cognitive decline.

Dr. Gandy of the Mount Sinai School of Medicine, New York, investigated the drug's effect on amyloid in three models of the disease: cultured nerve cells, isolated synaptic terminals, and brains from mice that overexpress human amyloid. “In every single system dimebon stimulated amyloid secretion,” Dr. Gandy said in an interview. “The levels of the amyloid peptides in the interstitial brain fluid roughly doubled whenever the drug was given. If we think about the increased risk of Alzheimer's in Down syndrome patients who have a 50% increase in amyloid, this acute increase with dimebon could be significant over a period of many years of prescribed use.”

Dr. Gandy noted that similar results were obtained by John Cirrito, Ph.D., and Dr. David Holtzman of Washington University, St. Louis, who collaborated with him in studying the brains of freely moving transgenic mice that overexpress human Abeta.

Dr. Gandy's suggested that this acute release may be followed by a chronic lowering of Abeta–something he is now investigating. Combined with dimebon's positive clinical data, this finding would imply that neurons benefit from dumping their intracellular amyloid load.

“This is reminiscent of the evidence suggesting that healthy nerve cells seem to release more amyloid,” Dr. Gandy said, referring to another study from the Dr. Holtzman group, in which they reported that brain amyloid release increased as head-injured patients began to recover. “Why do happy, functioning neurons release more amyloid beta? The challenge now is how to reconcile that with research that is trying hard to develop medications to lower amyloid levels.”

The clinical and lab data highlight the essential mystery of amyloid, both researchers said. “It all seemed so simple when we discovered genes that implicated amyloid,” Dr. Gandy said. “It was all amyloid toxicity and that was the end of it. But the truth is, we still don't really know what amyloid does locally. It is clear to me that amyloid beta causes the rare genetic forms of Alzheimer's, but there remains the possibility that some injurious event [e.g., calcium dysregulation or oxidative injury] is both directly neurotoxic and pro-amyloidogenic. Gary Gibson, Ph.D., of Cornell University and I have seen this in an experimental oxidative stress model, and if something like this is the case in common forms of AD, then lowering amyloid won't be sufficient. Still, I don't think we'll know that until we succeed in purging the brain of amyloid oligomers at an early age and follow the natural history of the amyloid-free brain.”

Some researchers, including Dr. Smith, have contended that amyloid is not the direct cause of AD, but a downstream product of some other dysfunction. The plaques themselves might be largely inert, or even be protecting the brain by binding and neutralizing neurotoxins.

“It could very well be that releasing Abeta is good, and that's why drugs that lower it are ineffective, or even damaging,” Dr. Smith said. A wealth of recent data seems to support that idea: in the last 2 years, four antiamyloid agents have failed their phase III trials, and both active and passive immunotherapy studies have seen about a 10% rate of vasogenic brain edema associated with plaque dissolution.

“We have to face it,” Dr. Smith said. “We don't know what amyloid is doing in the brain and just trying to get rid of it may not be a good thing.”

Neither Dr. Gandy nor Dr. Smith had any relevant disclosures.

Dimebon's Action May Challenge Amyloid Theory