Study offers clues to failure of Alzheimer's drugs in trials

Researchers believe they know why so many drug trials for Alzheimer's disease fail and have found a clinically approved drug that has shown promise in research with animals. Photo by Italo Greco/Flickr

By Allen Cone, UPI

A new study has revealed a potential explanation for the failure of drugs for Alzheimer's disease in clinical trials, and researchers may have identified a clinically approved drug that could actually succeed at slowing the condition.

Researchers at King's College London discovered a vicious feedback loop underlies brain degeneration in Alzheimer's disease. Their findings were published Thursday in the journal Translational Psychiatry.

"We show that a vicious positive feedback loop exists in which beta-amyloid drives its own production," senior author Dr. Richard Killick, a researcher at the Institute of Psychiatry, Psychology and Neuroscience at King's College, said in a press release. "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."

Beta-amyloid attacks and destroys the connections between nerve cells in the brain, called synapses, resulting in memory problems, dementia and ultimately death.

When beta-amyloid destroys a synapse, the nerve cells make more beta-amyloid, causing even more synapses to be destroyed.

"Our work uncovers the intimate link between synapse loss and beta-amyloid in the earliest stages of Alzheimer's disease," said lead author Dr. Christina Elliott, a researcher at IoPPN. "This is a major step forward in our understanding of the disease and highlights the importance of early therapeutic intervention."

A protein called Dkk1, which may stimulate production of beta-amyloid, is the key to the positive feedback loop. In previous research at the college, Dkk1 was identified as having a central role in Alzheimer's.

The researchers say that Dkk1 is barely detectable in the brains of young adults, but its production increases as we age. They believe targeting Dkk1 can better prevent the progression of Alzheimer's disease by disrupting the cycle of beta-amyloid production and synapse loss.

"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," Killick said. "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."

When mice were treated with fasudil, the beta-amyloid deposits were reduced after two weeks.

"We now need to move this forward to a clinical trial in people with early stage Alzheimer's disease as soon as possible," said Dr. Dag Aarsland, a professor of old age psychiatry at Kings College London.

Several pharmaceutical giants have halted or failed in clinical trials for new drugs to treat Alzheimer's disease.

Pfizer said in January that it was abandoning all research into the disease, and Eli Lilly this year revealed two drugs failed.

Drugmaker Eli Lilly said in January that the drug solanezumab failed in a clinical trial to significantly slow thinking declines in Alzheimer's patients. In June, the company discontinued two global Phase 3 clinical trials of lanabecestat, an oral beta secretase cleaving enzyme inhibitor.

Also in January, Otsuka Pharmaceutical announced idalopirdine, which was intended to promote production of serotonin and other essential brain chemicals, failed in three trials to improve thinking or memory in Alzheimer's patients.


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Health News: Study offers clues to failure of Alzheimer's drugs in trials
Study offers clues to failure of Alzheimer's drugs in trials
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