In the 1990s, the “amyloid hypothesis” provided a new and simple explanation for the cause of Alzheimer’s disease. The idea was that beta-amyloid proteins build up to form plaques that damage brain cells.
The brain plaque theory caught on bigtime and quickly became conventional wisdom. To this day it remains the most popular theory in spite of the fact that hundreds of pharmaceutical trials aimed at clearing away the plaques have ended in complete failure.
And on top of that, it’s now well known that many people with brain plaques don’t develop dementia, and many people who do get dementia don’t have brain plaques.
Earlier this year a drug from Merck successfully reduced beta-amyloid in the brain — but this made no impact on the cognitive abilities of the patients. The trial was terminated early.
Why hasn’t this approach worked? Scientists from the UK think they’ve hit on the answer and even have a solution. . .
Using cells in a Petri dish, the team of scientists from Kings College London found that when synapses — the connections between brain cells — are destroyed by beta-amyloid proteins, cells are induced to produce even more amyloid deposits.
This sets off another round of attacks and more synapses are destroyed, prompting additional amyloid production and so on — a deadly ongoing cycle of brain pathology.
The villain of the piece is a protein called Dkk1. This molecule strongly stimulates beta-amyloid production, and has previously been identified as a key player in Alzheimer’s in both animal models and in the brains of Alzheimer’s patients analyzed post mortem.
Dkk1 can hardly be detected in young adults, but with aging, production gets stepped up in the brain. The researchers think Dkk1 should be targeted instead of beta-amyloid. Doing so, they believe, would break the cycle of destruction.
My reaction to that is “maybe,” but keep reading. . .
Beta Amyloid Plummets with a New Drug
To test this idea, mice with advanced amyloid pathology were treated for two weeks with fasudil, a drug that targets Dkk1. The result was a dramatic reduction in amyloid.
According to senior study author Dr. Richard Killick, “We show that a vicious positive feedback loop exists in which beta-amyloid drives its own production. We think once this feedback loop gets out of control it is too late for drugs which target beta-amyloid to be effective. This could explain why so many Alzheimer’s drug trials have failed.
“We have convincingly shown 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.”
One of Dr. Killick’s fellow authors, Professor Dag Aarsland, is a world-renowned scientist in the field of neurodegenerative disease. He added, “As well as being a safe drug, fasudil appears to enter the brain in sufficient quantity to potentially be an effective treatment against beta-amyloid.”
Fasudil is not approved for use in the US or Europe, but it does have approval as a dilator of blood vessels and a neuroprotective agent in China and Japan. In these countries it’s used in critical care settings such as after a stroke.
US researchers wrote in 2009, as a result of their rodent study, that fasudil had potential “as a cognitive enhancer in humans that have age or neurodegenerative-related memory dysfunction.”
The Kings College group are now hoping to push ahead with the next stage — a human clinical trial to test whether the drug clears away amyloid and restores cognition in early Alzheimer’s disease patients. I won’t hold my breath…
Not Wild about the Brain Plaque Theory
As we’ve written before in this publication, the doctors who are enjoying the most success in treating dementia patients have largely abandoned the brain plaque theory.
The plaques give every sign of being the brain’s protective reaction against inflammation. They’re an effect, not a cause, of the illness that’s eating up brain cells – the causes most likely being poor sleep (which prevents elimination of brain waste), toxins, chronic infections, allergies and all the other multiple causes of inflammation.
This theory hasn’t been proven either, but at least it has the virtue of leading to clinical protocols that do reverse memory loss. And that makes them an improvement over the plaque-busting drugs. I hope fasudil does work and opens up a new way of treating dementia, but meanwhile there are proven ways you can use right now.
