Why do so many clinical trials for Alzheimer’s fail? New discovery sheds light

Written by Sharon Salt, Editor

Researchers have discovered a vicious feedback loop underlying brain degeneration in Alzheimer’s disease, which may explain why so many drug trials have failed.
The study also identifies a clinically approved drug – fasudil – that could break the vicious cycle and protects against memory loss in animal models of Alzheimer’s.

Overproduction of the protein β-amyloid is strongly linked to development of Alzheimer’s disease but many drugs targeting β-amyloid have failed in clinical trials. β-amyloid attacks and destroys synapses and results in memory problems, dementia and ultimately death.

In this new study, which is published in Translational Psychiatry, researchers found that when β-amyloid destroys a synapse, the nerve cells make more β-amyloid driving yet more synapses to be destroyed.

“We show that a vicious positive feedback loop exists in which β-amyloid drives its own production,” explained senior author Richard Killick (King’s College London, UK). “We think that once this feedback loop gets out of control it is too late for drugs which target β-amyloid to be effective, and this could explain why so many Alzheimer’s drug trials have failed.”

“Our work uncovers the intimate link between synapse loss and β-amyloid in the earliest stages of Alzheimer’s disease,” commented Christina Elliott (King’s College London), lead author of the study. “This is a major step forward in our understanding of the disease and highlights the importance of early therapeutic intervention.”

Additionally, the researchers also found that a protein termed Dkk1, which potentially stimulates production of β-amyloid, is central to the positive feedback loop.

Previous research by Killick and colleagues identified Dkk1 as a central player in Alzheimer’s, and while Dkk1 is barely detectable in the brains of young adults, its production increases as we age.

The researchers believe that instead of targeting β-amyloid itself, targeting Dkk1 could be a better way to halt the progress of Alzheimer’s disease by disrupting the vicious cycle of β-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,” said Killick. “We have convincingly shown that fasudil can protect synapses and memory in animal model of Alzheimer’s, and at the same time reduces the amount of β-amyloid in the brain.”

Researchers at King’s College London are now seeking funding to run a trial in people with early-stage Alzheimer’s to determine if fasudil improves brain health and prevents cognitive decline.

Dag Aarsland (King’s College London) concluded: “As well as being a safe drug, fasudil appears to enter the brain in sufficient quantity to potentially be an effective treatment against β-amyloid. We now need to move this forward to a clinical trial in people with early-stage Alzheimer’s disease as soon as possible.”

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Sources: Elliott C, Rojo AI, Ribe E et al. A role for APP in Wnt signaling links synapse loss with β-amyloid production. Transl. Psych. 8, 179 (2018); www.kcl.ac.uk/ioppn/news/records/2018/september/discovery-could-explain-failed-clinical-trials-for-alzheimers.aspx