Two decades of Alzheimer's liberal-led research may be based on deliberate fraud that has cost millions of lives

[Leroy N. Soetoro]

https://www.dailykos.com/stories/2022/7/22/2111914/-Two-decades-of-
Alzheimer-s-research-may-be-based-on-deliberate-fraud-that-has-cost-
millions-of-lives

Last month, drug company Genentech reported on the first clinical trials
of the drug crenezumab, a drug targeting amyloid proteins that form sticky
plaques in the brains of Alzheimer’s disease patients. The drug had been
particularly effective in animal models, and the trial results were
eagerly awaited as one of the most promising treatments in years. It did
not work. “Crenezumab did not slow or prevent cognitive decline” in people
with a predisposition toward Alzheimer’s.

Last year, the Food and Drug Administration (FDA) narrowly approved the
use of Aduhelm, a new drug from Biogen that the company has priced so
highly that it’s expected to drive up the price of Medicare for everyone
in America, even those who never need this drug. Aduhelm was the first
drug to be approved that fights the accumulation of those "amyloid
plaques" in the brain. What makes the approval of the $56,000-a-dose drug
so controversial is that while it does decrease plaques, it doesn’t
actually slow Alzheimer’s. In fact, clinical trials were suspended in 2019
after the treatment showed “no clinical benefits.” (Which did not keep
Biogen from seeking the drug’s approval or pricing it astronomically.)

Over the last two decades, Alzheimer’s drugs have been notable mostly for
having a 99% failure rate in human trials. It’s not unusual for drugs that
are effective in vitro and in animal models to turn out to be less than
successful when used in humans, but Alzheimer’s has a record that makes
the batting average in other areas look like Hall of Fame material.

And now we have a good idea of why. Because it looks like the original
paper that established the amyloid plaque model as the foundation of
Alzheimer’s research over the last 16 years might not just be wrong, but a
deliberate fraud.

The suspicion that something was more than a little wrong with the model
that is getting almost all Alzheimer’s research funding ($1.6 billion in
the last year alone) began with a fight over the drug Simufilam. The drug
was being pushed into trials by its manufacturer, Cassava Sciences, but a
group of scientists who reviewed the drug maker’s claims about Simufilam
believed that it was exaggerating the potential. So they did what any
reasonable person would do: They purchased short sell positions in Cassava
Sciences stock, filed a letter with the FDA calling for a review before
allowing the drug to go to trial, and hired an investigator to provide
some support for this position.

As Science reports, it was that investigator, Vanderbilt University
neuroscientist and junior professor Matthew Schrag, who tipped over the
whole applecart to discover that it wasn’t just that Cassava’s drug was
ineffective. There’s good evidence that for the last 16 years, almost
everyone has had the wrong idea about the cause of Alzheimer’s. Because of
a fraud.

In 2006, Nature published a paper titled “A specific amyloid-ß protein
assembly in the brain impairs memory.” Using a series of studies in mice,
the paper concluded that “memory deficits in middle-aged mice” were
directed caused by accumulations of a soluble substance called “Aß*56.”
This was a specific form of a group known as “toxic oligomers” that had
long been suspected as the possible precursors of amyloid plaques. The
paper then went on to directly connect that condition to “cognitive
deficits associated with Alzheimer's disease” independently of other
conditions affecting the aging brain.

The study didn’t come out of nowhere; it only seemed to confirm one of
several hypothesis about Alzheimer’s that had been circulating for many
years by that point. After all, the brains of Alzheimer’s patients do
contain plaques that can sometimes seriously alter the structure of the
brain. Those plaques do contain amyloids. It’s not much of a stretch to
suggest those amyloids are a primary cause of the associated memory loss
and dementia. Amyloids cause plaques, plaques cause damage, the damage
causes Alzheimer's. QED.

That 2006 paper was primarily authored by neuroscience professor Sylvain
Lesné and given more weight by the name of well-respected neuroscientist
Karen Ashe, both from the robust neuroscience research team at the
University of Minnesota. It was Ashe who produced the transgenic mice used
in the study, which genuinely do appear to have Alzheimer’s-like symptoms
and that have since been used as the favored animal models for a
generation of treatments. On her website, Ashe called Aß*56 “the first
substance ever identified in brain tissue in Alzheimer’s research that has
been shown to cause memory impairment.”

The results of the study seemed to demonstrate the amyloids-to-Alzheimer’s
pipeline with a clarity that even the most casual reader could understand,
and it became one of—if not the most—influential papers in all of
Alzheimer’s research. Not only has it been cited hundreds of times in
other work, roughly 100 out of the 130 Alzheimer’s drugs now working their
way through trials are directly designed to attack the kind of amyloids
featured in this paper. Both Ashe and Lesné became neuroscience rock
stars, the leaders of a wave based on their 2006 paper.

What intrigued Schrag when he came back to this seminal work were the
images. Images in the paper that were supposed to show the relationship
between memory issues and the presence of Aß*56 appeared to have been
altered. Some of them appeared to have been pieced together from multiple
images. Schrag shied away from actually accusing this foundational paper
of being a “fraud,” but he definitely raised “red flags.” He raised those
concerns, discreetly at first, in a letter sent directly to the National
Institutes of Health (NIH). Only when that letter failed to generate a
response did Schrag bring his suspicions to others.

Now Science has concluded its own six-month review, during which it
consulted with image experts. What they found seems to confirm Schrag’s
suspicions.

They concurred with his overall conclusions, which cast doubt on hundreds
of images, including more than 70 in Lesné’s papers. Some look like
“shockingly blatant” examples of image tampering, says Donna Wilcock, an
Alzheimer’s expert at the University of Kentucky.

After reviewing the images, molecular biologist Elisabeth Bik said of the
paper, “The obtained experimental results might not have been the desired
results, and that data might have been changed to … better fit a
hypothesis.”

Should this fraud turn out to be as extensive as it appears at first
glance, the implications go well beyond just misdirecting tens of billions
in funding and millions of hours of research over the last two decades.
Since that 2006 publication, the presence or absence of this specific
amyloid has often been treated as diagnostic of Alzheimer’s. Meaning that
patients who did die from Alzheimer's may have been misdiagnosed as having
something else. Those whose dementia came from other causes may have
falsely been dragged under the Alzheimer’s umbrella. And every possible
kind of study, whether it's as exotic as light therapy or long-running as
nuns doing crossword puzzles, may have ultimately had results that were
measured against a false yardstick.

In the face of the potential fraud unearthed by Schrag, it’s not as if the
world has changed overnight.

Four months after Schrag submitted his concerns to the NIH, the NIH turned
around and awarded Lesné a five-year grant to study … Alzheimer’s. That
grant was awarded by Austin Yang, program director at the NIH’s National
Institute on Aging. Yang also happens to be another of the co-authors on
the 2006 paper.

Science has carefully detailed the work done in the analysis of the
images. Other researchers, including a 2008 paper from Harvard, have noted
that Aß*56 is unstable and there seems to be no sign of this substance in
human tissues, making its targeting literally worse than useless. However,
Lesné claims to have a method for measuring Aß*56 and other oligomers in
brain cells that has served as the basis of a series of additional papers,
all of which are now in doubt.

There seems to be no doubt that oligomers may play a role in cognitive
impairment. However, that role may not be nearly as direct, or as
significant, as the 2006 paper and subsequent papers by Lesné have
suggested. It’s quite possible that the specific oligomer Aß*56 may not
even exist outside of Ashe’s transgenic mice.

And it seems highly likely that for the last 16 years, most research on
Alzheimer’s and most new drugs entering trials have been based on a paper
that, at best, modified the results of its findings to make them appear
more conclusive, and at worst is an outright fraud.


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