Replies to post #1851 on Biotech Values

[bladerunner1717]

Dew,

It is an interesting article, but it is decidedly one-sided. It would have been nice if strong proponents of the amyloid these were, at least, allowed to answer the criticisms of their position.

Bladerunner

[DewDiligence]

Fevered Debate Over Alzheimer's Origins
Causes Deep Divisions

[It’s Friday (almost) and that means time for another WSJ column by Sharon Begley. For Begley's prior columns on Alzheimer’s, please see #msg-2829448 and #msg-2872262.]

http://online.wsj.com/article/0,,SB109174045915784238,00.html?mod=yahoo_hs&ru=yahoo

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August 6, 2004

Although the exchange did not quite descend to the level of name-calling, it was not what you usually hear at scientific conferences. Halfway into a debate on whether Alzheimer's disease is caused by the accumulation in the brain of sticky "plaques" made of a protein called beta-amyloid, as the leading theory holds, and whether therapies that target amyloid are the best bets, one scientist let loose.

"I think your treatment will kill people," said neuropathologist Mark Smith of Case Western Reserve University, Cleveland, referring to anti-amyloid therapies. To which neuroscientist Todd Golde of the Mayo Clinic, Jacksonville, Fla., responded, "Ethically, I would say you're not in the right place."

Behind the scenes at last month's 9th International Conference on Alzheimer's Disease (the amyloid debate was not part of the official program), you could almost trip on the ideological lines drawn in the sand.

Beliefs about what causes this merciless disease have taken on such a religious fervor that one group is called tauists, after a protein called tau that forms "neurofibrillary tangles" inside the neurons and, say these scientists, kills neurons responsible for memory and thought. Another is called baptists, after the beta-amyloid protein that forms plaques around brain neurons and, say its accusers, causes neuron-killing tau tangles or kills neurons directly, or both. Apostates think amyloid plaques sop up neurotoxic proteins along with poisonous metals such as zinc and copper, and that eliminating plaques could therefore harm patients. Hence Dr. Smith's accusation.

As I wrote last April, there are growing doubts that amyloid is guilty as charged. Autopsies of people with early-stage Alzheimer's show that the tangles form first, before plaques, in brain regions initially affected by the disease. "If you look at the evidence, it's the tangles that cause neuronal degeneration, and they come first, before the amyloid," says neurologist Patrick McGeer of the University of British Columbia, Vancouver, who was awarded one of the Alzheimer's Association's top scientific prizes at the meeting.

Another problem for the amyloid dogma is that "almost all aged brains have extensive amyloid deposition, even in people who die with no symptoms of Alzheimer's," says neurologist Peter Davies of the Albert Einstein College of Medicine in the Bronx. Worse, adds neurobiologist Nikolaos Robakis of Mount Sinai School of Medicine, New York City, autopsies of the brains of Alzheimer's victims show that "plaques don't correlate with neuronal death. The amyloid is here and the dead neurons are somewhere else."

The amyloid debate has taken on added urgency, for many Alzheimer's therapies now in the pipeline are predicated on the guilt of amyloid. A vaccine being developed by Elan Corp., Dublin, for instance, targets amyloid plaques; unfortunately, it also shrank the brains of many volunteers it was tested on. Drugs being developed by Eli Lilly & Co., Indianapolis, and Neurochem, Laval, Quebec, target amyloid, too.

"The question is, if we are successful in controlling amyloid, will we be successful in helping patients?," says Zaven Khachaturian, who ran the Alzheimer's program at the National Institute on Aging. "The field doesn't have a clue."

But it might soon. Scientists who believe that amyloid causes Alzheimer's have one indisputable fact on their side: Mutations in three genes which cause the familial, inherited form of the disease all pump up amyloid levels in the brain. Surely this proves amyloid's guilt?

In the huge diversity of views presented at the meeting -- there were 4,500 scientists and 2,000 presentations -- you could hear the beginnings of an answer. "There were some faint suggestions that these 'amyloid' mutations do something besides affect amyloid," says Dr. McGeer.

For instance, an Alzheimer's gene once thought to do nothing but make lots of amyloid turns out to have a second job, said Dr. Robakis: It also stabilizes proteins that help keep neurons alive. When this gene (it's called PS1) is mutated, it speeds the death of neurons by triggering those toxic tau tangles and by making neurons more likely to commit suicide. A second Alzheimer's gene, called APP and also thought to simply be a source of amyloid, also seems to moonlight. When mutated, it pushes neurons to change in ways that lead to suicide, finds Rachael Neve of Harvard Medical School, Boston.

In other words, mutations in "amyloid" genes wreak havoc in ways that don't involve amyloid. Interestingly, suicidal neurons seem to release amyloid. Perhaps that has fooled scientists into concluding that the amyloid around dead neurons is the killer, when it is actually an innocent by-stander.

No existing drug stops, let alone reverses, the inexorable cognitive and memory decline of Alzheimer's. The one thing baptists, tauists and apostates agree on is that drugs that prevent the disease will not cure it, and drugs effective against early Alzheimer's won't be the same as those that work against late Alzheimer's. We'll need a whole armamentarium.

Will any of the treatments target amyloid? "If amyloid were the answer," says Dr. McGeer, "the disease would have been solved by now."
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[DewDiligence]

Alzheimer's Research Makes Dramatic Shift

[This is an update of a 2004 article by the same author (#msg-2829448). You can follow the iHub “Reply” chain for additional on-topic material.]

http://online.wsj.com/article/SB116372280502725751.html

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By Sharon Begley
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 science.

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".

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 them.
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