Why Alzheimer’s drug trials fail

Schematic of Beta-amyloid deposits in the nerve cell network in the brain.

A new discovery by researchers at King's College London could be a major step in understanding Alzheimer’s disease and the basis of a new early therapeutic intervention.

The study, published in “Translational Psychiatry”, reports the detection of a potent feedback loop as the cause of brain degeneration that may explain why so many drug trials have failed. The study also identifies a clinically approved drug that breaks the vicious cycle and protects against memory loss in animal models of Alzheimer’s.

Overproduction of the protein beta-amyloid is strongly linked to the development of Alzheimer's disease. The protein is known to attack and destroy synapses, the connections between nerve cells, resulting in memory problems, dementia and ultimately death. However, drugs targeting beta-amyloid have all been found to fail in clinical trials.

King’s College researchers found that when beta-amyloid destroys a synapse, the nerve cells make more beta-amyloid driving yet more synapses to be destroyed. This work, according to its lead author Christina Elliott of the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), uncovers the intimate link between synapse loss and beta-amyloid in the earliest stages of Alzheimer’s disease.

“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,” says another author Richard Killick, also of the IoPPN.

A protein, Dkk1, which stimulates the production of beta-amyloid, was found to be the key to this destructive feedback loop. Previous work by Killick and colleagues had identified Dkk1, which is barely detectable in the brains of young adults, as central to Alzheimer’s. Instead of targeting beta-amyloid itself, the researchers believe targeting Dkk1 could be a better way to halt the progress of Alzheimer’s disease.

“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. Fasudil could protect synapses and memory in animal models of Alzheimer’s and at the same time reduce the amount of beta-amyloid in the brain. In mice engineered to develop large deposits of beta-amyloid in their brains as they aged, just two weeks of treatment with fasudil dramatically reduced the beta-amyloid deposits. Researchers at King’s College London now propose to run a trial in early stage sufferers of Alzheimer’s to see if fasudil improves brain health and prevents cognitive decline.