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Why drugs for Alzheimer's disease are failing
Lane Simonian
Posted: Saturday, February 25, 2017 10:27 AM
Joined: 12/12/2011
Posts: 5158

Two more drugs based on the amyloid hypothesis have recently failed: Merck's beta secretase inhibitor (Verubecestat) and Eli Lilly's amyloid monomer antibody (solanezumab).  I understand, given the money and reputations staked on the amyloid hypothesis, why drug companies and researchers want to drag this out to the bitter end, but a change in paradigm is desperately needed.

One of the little gems that came out last year is probably the key to understanding what causes Alzheimer's disease and how to treat it.

"Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active."

Protein kinase C is the early trigger for oxidative stress in Alzheimer's disease.  So to put the above quote in a different way, amyloid only damages the brain when it causes oxidative stress. And without oxidative stress there is no Alzheimer's disease.

Oxidative stress is what leads to amyloid in the first place (beginning with the secretion of the amyloid precursor protein by protein kinase C).  More importantly, dozens of factors other than amyloid can cause oxidative stress ranging from air pollutants to chronic smoking to an unhealthy diet (a diet high in sugar, carbohydrates, high fructose corn syrup, and salt).  If you remove amyloid, you are only removing one cause of oxidative stress.  Removing it may delay the onset of Alzheimer's disease and slow down its early progression, but unless you remove the other factors causing stress or remove the oxidants themselves you cannot effectively treat Alzheimer's disease.

As the disease progresses, protein kinase C activity slows down and amyloid plaques form that do not cause oxidative stress.  So removing amyloid at this point does no good at all.

The amyloid hypothesis is backing people into a corner.  The idea is that if you wait too long the damage done by amyloid is irreversible.  Therefore, the only thing you can do is to prevent the disease or slow it down for awhile at its very early stages.  If this were true (and it isn't) it means there is no hope for those who currently have the disease.

But oxidative stress can be partially reversed at any stage of the disease.  Damage done to critical receptors, transport systems, and enzymes by oxidation and nitration can be reversed by compounds that donate hydrogen atoms.  This includes eugenol in various essential oils via aromatherapy and syringic acid and ferulic acid in panax ginseng.

I don't know if it makes me laugh or cry that some people try to find success in failed trials and try to find failure in successful trials.  I suppose some diseases were treated before the cause was known but knowing the cause makes it much easier to find effective treatments.   The cause of Alzheimer's disease is not amyloid, it is oxidative stress and certain antioxidants can be used to improve cognition and behavior in people with Alzheimer's disease.

Posted: Saturday, February 25, 2017 12:42 PM
Joined: 7/24/2015
Posts: 3020 Buddhist mind always thinks, "but of course...another failure, how could it be otherwise?"

While the other side my mind looks at the metaphorical watch on my arm and rhetorically asks the world, just exactly how many more of these failed trials will it take before you all wake up? 

Meanwhile my heart goes out those people who are blindly counting on these doomed trials.