[sociate] WSJ - Begley - Alzheimer's Research Makes Dramatic Shift To Widen Perspective

  • From: "Jerry Michalski" <jerry@xxxxxxxxxxx>
  • To: "Sociate News" <sociate@xxxxxxxxxxxxx>
  • Date: Thu, 16 Nov 2006 23:31:16 -0500


Alzheimer's Research Makes Dramatic Shift To Widen Perspective
November 17, 2006

For any normal field of science, the conclusion that "there is more to [fill
in a disease] than [fill in leading but unproved hypothesis] alone" wouldn't
cause anyone to bat an eye. After all, science is supposed to consider all
reasonable ideas. But Alzheimer's disease is not your normal field of

Proponents of the leading theory of Alzheimer's have been in pitched battle
with scientists who have other ideas about this awful neurodegenerative
disease. For more than 20 years, the leading theory has held that sticky
blobs in the brain called amyloid plaques cause Alzheimer's. Because that
idea has numerous problems, doubters argued that the plaques might be
innocent bystanders to the real, "upstream" culprit. If so, targeting the
plaques, or the rogue protein called beta-amyloid that forms them, would do
nothing to help the 4.5 million Americans who suffer from Alzheimer's.

You might think this debate would play out with each side conducting
research, in a "may the best science win" approach. But as I've written
before, many scientists whose work challenges the amyloid dogma have been
unable to publish in top journals, and their grant proposals, "go down in
flames," as Mark Smith of Case Western Reserve University School of Medicine
told me. "Among the major journals and funding agencies, the attitude was,
'if it isn't amyloid, it isn't AD.' "

Hence the impact of that "there is more to" statement. It is the focus of a
paper in the October issue of the journal Alzheimer's & Dementia reporting
on a "research roundtable" convened by the private, nonprofit Alzheimer's
Association. Finally, academic scientists and leaders in biotech, medical
imaging and big drug companies recognize "there is more to AD than B-amyloid
alone," the paper concludes. Which is why the roundtable's goal "was to
address, primarily, strategies that do not hinge on directly modulating
levels of B-amyloid" (my emphasis).

It's a remarkable turnaround. "This is the first concerted effort by the
Alzheimer's Association to focus on things beyond beta-amyloid," says John
Trojanowski of the University of Pennsylvania, who has done pioneering work
on the role of so-called neurofibrillary tangles in the disease.

To get a sense of what a sea change this is, consider the Alzheimer's drug
pipeline. Five drugs have been approved in the U.S. One (tacrine) causes
liver toxicity, so is rarely prescribed anymore. None of the other four
treat what anyone considers the real cause of the disease. Instead, they
nibble around the edges, using strategies to maintain the brain's "cognitive
reserve" so that when Alzheimer's sets in you don't become senile quite so
fast. None of the drugs provides more than marginal benefit, if that, and
help only some patients. And the disease keeps marching through the brain.

Some of the estimated 100 Alzheimer's drugs in clinical trials also nibble
around the edges, such as by trying to lower cholesterol or inflammation
(thought to worsen Alzheimer's). But of those that aim at a suspected cause
of the disease, "the pipeline is full of antiamyloid therapies," says
William Theis, vice president for medicine and science at the Alzheimer's
Association. "The field was lulled into a false sense of confidence that
beta-amyloid was the culprit," says Dr. Trojanowski. "But there is a great
deal of uncertainty that the beta-amyloid hypothesis will be validated,
although some stalwarts still strongly believe in it. We need to have a
balanced portfolio of targets."

Thankfully, there are other suspects for what causes the disease. This month
marks the 100th anniversary of Alois Alzheimer's report on his senile
patient, Auguste D.: Her brain had stringy tangles inside neurons and
"senile plaques" around them. The tangles, it turns out, are made of a
protein called tau that gets transformed in such a way that strands of it
stick together like cold pasta. The plaques are those globs of beta-amyloid.
For many reasons, including the discovery of genes having to do with
amyloid, the search for causes and treatment focused on that.

But when you think about it, concluding that B-amyloid and plaques cause
Alzheimer's is like believing a scab on your knee causes pain. The scab is
the body's response to an earlier injury. Similarly, there is evidence that
amyloid plaques don't cause Alzheimer's.

Some elderly people who die with the disease don't have senile plaques. Some
who show no sign of dementia do. When an Alzheimer's brain has plaques, they
often are not where neurons have died, casting doubt on their toxicity.
Also, in people with early Alzheimer's, tau tangles sometimes form before
plaques, suggesting that plaques are a response (and maybe a therapeutic
one), not a cause. If so, ridding the brain of plaques could cause harm.

"I definitely think it's time to think along other lines of treatment, and
that's finally becoming more widespread," says Robert Mahley, president of
the nonprofit J. David Gladstone Institutes, San Francisco, and a leading
Alzheimer's researcher. "Big pharma has had all its eggs in [the amyloid]
basket, and is starting to worry about that."

As a result, there is new emphasis on finding pathologies that lie upstream
of beta-amyloid and plaques, or that have nothing to do with them. Next
week, I'll discuss some of these ideas and experimental treatments based on


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