Much of health research is a search for simple, bio-molecular causes for our medical problems. These can result in pill-solutions. Diseases tend to be more complex, but Alzheimers seemed to work that way, until this summer when it turned out that the data supporting the simple theory was faked. Alzheimer’s is a devastating cognitive disease that is accompanied by a degenerating brain, with sticky, beta-amyloid plaques and tangles. About 16 years ago, this report, published in Nature seemed to show that a beta-amyloid, Aβ*56, caused the plaques and caused cognitive decline independent of any other Alzheimers indicators.
We were on the way to a cure, or so it seemed. Several studies by this group backed the initial results, and much of Alzheimer’s research was directed into an effort to fill in the story, and find ways to reduce the amount and bonding of this amyloid and others like it. Several other groups claimed they could not find the amyloid at all, or show that amyloids caused the symptoms described. But most negative results went unpublished. The theory was so satisfying, and the evidence from a few so strong, that the NIH poured billions into this approach, over $1B in this year alone. The FDA approved aducanumab, a drug from Biogen, on the assumption that it should work, even though it showed little to no benefit, and had some deadly side effects. Other firms followed, asking for approval of related anti-amyloid drugs that should work.
When news of the fraud came out, detected by Matthew Scragg and a few lone curmudgeons, stock prices plummeted in the drug companies. It now appears that the original work was made up, presented to journals and to the NIH using photoshopped images. For the group that did the fake work, it may mean jail time, for most other groups, the claim is that their work is still relevant. Doctors still prescribe the medications as they have nothing better to offer (Aducanumab therapy costs $50,000 per year). Maybe it’s time to start looking at alternative approaches and theories, sidelined over the last 16 years.
Some alternative theories posit that another molecule is responsible, particularly tau, associated with the tangles. Another sidelined theory is that amyloids are good. For example, that it’s the loss of soluble amyloids that causes Alzheimer’s. Alternately, that inflammation is the root cause, and that the amyloid plaques and tangles are a response to the inflammation, a bandage, perhaps. These theories could explain why the anti-amyloid drugs so often resulted in patient death.
It’s also possible that the inability of nerve cells to dispose of waste is the cause of AZ. In heathy people, waste is removed through acidic enzymes within lysosomes. Patients with decreased acid activity have a buildup of waste that includes amyloids. Perhaps the cure is to restore the acid enzymes.
My favorite theory is based on statistical data that shows that fat people are less likely to develop Alzheimers. This might lead to a junk-food cure. The fitness industry is very much against this theory–It’s debated here. They tend to support the inflammation model, claiming that diseases cause Alzheimer’s and cause patients to loose weight first. Could be. I note that Henry Kissinger is the only active politician of my era, the early 70s, still alive and writing intelligently.
Robert Buxbaum, November 17-19, 2022. I hope that Matthew Schragg comes out OK, by the way. Ben Franklin pointed out, that “No good deed goes unpunished.”
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Another remark re. Casava. Again, I have a small investment in the company.
It has long been known that there is an active group of short-sellers attempting to crash the company’s stock prices, and there is some suspicion that they are behind efforts to besmirch the company’s reputation.
Consider the following (the latest from https://en.wikipedia.org/wiki/Cassava_Sciences#Allegations_of_research_fraud):
‘In November 2022, Dr. Elizabeth M. McNally, the editor-in-chief of Journal of Clinical Investigation, issued an Editorial Letter, “Conflicts interests: when Whistleblowers profit from allegations of scientific misconduct”. McNally acknowledged ongoing investigation of potential image manipulation outlined in Science and the New York Times articles, but expressed concerns about short sellers making allegations and profiting from them, saying “However, these articles only lightly touched upon the concept of short selling stock”. She states there now appear to be new “short and distorters”. McNally is expressing concerns “because this represents a new means of manipulating the scientific publishing industry”.’
As a published scientist, I do believe that fraud in scientific publications (quite distinct from simply being wrong!) it a horrible blot on the scientific effort. The public awareness of the possibility of fraud is arguably a good thing, but it also empowers those alleging fraud for their own advantage. After all, to the general public, an accusation is sometimes as good as a conviction. A step in the right direction would be for those alleging fraud to make public any financial gain they stand to accrue should the allegation prove correct.
Hi,
“The FDA approved drugs too, including Simufilam from Casava Sciences….”
Simufilam has not been approved of the FDA and its proposed mode of action does not rely on the plaque hypothesis.
Full disclosure: I have a small investment in Casava.
Further disclosure: I have looked on the web to see check on FDA approval, and could not find ANY indication of this. If I am wrong, please pass on a reference.
Comment: One set of articles has been subject to accusation of fraud, but these articles were never the sole source of belief in the plaque hypothesis. The plaque hypothesis has increasingly been called into question over the years, especially since drugs were developed (by Eli Lilly, if I recall correctly) that prevented plaque formation but did not slow down, reverse, or prevent Alzheimer’s. On the other hand, most workers in the field do think that plaque has “something to do with it”, but are not sure what. For example, some feel that the precursor molecules that later form the plaque constitute the active agent and that the plaque is simply those molecules’ “final resting place” after they have done their dirty business.