New research may answer why many recent Alzheimer's clinical trials have failed
For several years, research into an effective treatment preventing cognitive decline associated with Alzheimer's disease has constantly failed in human clinical trials, but a new study from an international team of scientists may finally explain the reason behind these failures, and offer a solution in the form of a drug currently used to treat stroke.
Since the 1980s the overriding hypothesis behind the cause of Alzheimer's disease has suggested the build-up of a protein called beta-amyloid resulted in the neurodegenerative symptoms associated with the condition. But, virtually all of the drugs developed to target these amyloid build-ups have failed in human clinical trials.
A new study could help explain this string of drug failures, discovering that when a synapse in the brain is destroyed by beta-amyloid it triggers nearby nerve cells to produce more beta-amyloid. This sets off a feedback loop that drives further neurodegeneration.
"We show that a vicious positive feedback loop exists in which beta-amyloid drives its own production," says Richard Killick, senior author on the new study. "We think that once this feedback loop gets out of control it is too late for drugs which target beta-amyloid to be effective, and this could explain why so many Alzheimer's drug trials have failed."
The research reveals that a protein called Dkk1 is fundamental to this damaging feedback loop. The protein has been found to significantly stimulate production of beta-amyloid and it appears in increasing volumes in the brain as we age. The study hypothesizes that inhibiting Dkk1 could disrupt the damaging beta-amyloid production feedback loop and prevent cognitive decline associated with the disease.
Perhaps most compelling is the study's experiments with a drug called fasudil, a new compound used to treat stroke patients. In a mouse model that had been engineered to develop beta-amyloid the researchers found that as little as two weeks of fasudil treatment significantly reduced these protein build-ups in the brain and effectively disrupted this negative feedback loop.
"Importantly, our work has shown that we may already be in a position to block the feedback loop with a drug called fasudil which is already used in Japan and China for stroke," says Killick. "We have convincingly shown that fasudil can protect synapses and memory in animal models of Alzheimer's, and at the same time reduces the amount of beta-amyloid in the brain."
Dementia researchers not affiliated with this new study are cautiously optimistic about the discovery, but keen to reiterate that a vast chasm is often seen between laboratory results and human trials in Alzheimer's research.
"While this study provides solid molecular evidence about an important molecular mechanism driving damage in Alzheimer's, it is based on research in cells and mice," explains Carol Rutledge from Alzheimer's Research UK. "Fasudil is an approved drug for other health conditions, but is currently used in a critical care setting and would need to go through robust safety tests in trials of people with Alzheimer's disease."
Diego Gomez-Nicola, from the University of Southampton, also notes that some research has suggested clearing beta-amyloid deposits does not always correlate with improvements in cognition, meaning that although this new research is interesting, it doesn't necessarily mean it will correspond with cognitive improvements in humans.
"To put it in other words," says Gomez-Nicola, "cognitive decline was still able to progress in spite of a successful clearance of amyloid, which would contradict the authors claims about the amyloid production process being autonomously self-perpetuated."
However, the team behind the new study is keen to move forward with human clinical trials. The pre-established safety profile of fasudil means it can be quickly accelerated into phase 2 trials, and the researchers are currently raising funds to begin work with early stage sufferers of Alzheimer's.
"We now need to move this forward to a clinical trial in people with Alzheimer's disease as soon as possible," explains Clive Ballard, co-author on the new study. "We'll do so through our innovative phase 2 trials platform designed to accelerate discovery of effective treatment in dementia."
The new study was published in the journal Translational Psychiatry.
Source: University of Exeter