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Is the Leading Theory About Alzheimer's Wrong?

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Last week, the pharmaceutical company Merck pulled the plug on a closely watched Alzheimer’s drug trial. The drug verubecestat, an outside committee concluded, had “virtually no chance” of benefit for patients with the disease.

The failure of one drug is of course disappointing, but verubecestat is only the latest in a string of failed trials all attempting the same strategy to battle Alzheimer’s. That pattern of failure has provoked some rather public soul-searching about the basic hypothesis that has guided Alzheimer’s research for the past quarter century.

The “amyloid hypothesis” began with a simple observation: Alzheimer’s patients have an unusual buildup of the protein amyloid in their brains. Thus, drugs that prevent or remove the amyloid should slow the onset of dementia. Yet all drugs targeting amyloid—including solanezumab from Eli Lilly and bapineuzumab from Pfizer and Johnson & Johnson, to add a few more high-profile flameouts to the fail pile—have not worked so far.

After Merck’s announcement last week, one neurologist told Bloomberg that “there is mounting evidence—of which this is another piece—that removing amyloid once people have established dementia is closing the barn door after the cows have left.” An advisor to a life-sciences venture-capital firm tweeted, “I've been a long-term adherent of the amyloid hypothesis, but starting to feel like this”: “This” was a gif of the Black Knight from Monty Python, arms missing but still adamant he had suffered nothing worse than a flesh wound.

And well, the amyloid hypothesis is not dead yet. Large clinical trials targeting are amyloid are still underway—either using new, potentially more powerful anti-amyloid drugs or trying out the previously failed drugs in patients with less advanced Alzheimer’s. These trials will likely affirm the amyloid hypothesis or kill it for good.

With the benefit of hindsight, the story of the amyloid hypothesis will be written either as one where scientists soldiered on despite setbacks, or one where a wrong idea derailed a field for 25 years. And the field of Alzheimer’s research is no stranger to ideas inflated, abandoned, and sometimes resurrected.

* * *

In the 1980s, the importance of amyloid was not the dominant idea in a field that might need shaking up. It was the upstart idea doing the shaking up. At the time Alzheimer’s researchers were considering the cholinergic hypothesis, which posits that a decline in the neurotransmitter acetylcholine is a cause of the disease. The handful of available Alzheimer’s drugs come out of this line of research. But it never produced an outright cure, and lack of acetylcholine has since been abandoned as a root cause of Alzheimer’s.

Dennis Selkoe—who is now a leading proponent of the amyloid hypothesis and a neurologist at Harvard—was not that interested in acetylcholine at the time either. He actually started out studying the buildup of tau protein, which is behind yet another hypothesis for the cause of Alzheimer’s. But he moved on to the nascent amyloid field when he met George Glenner, who was gathering data on how amyloid can build up into waxy plaques throughout the body. Amyloid deposits in the kidneys can cause kidney failure; in hearts, it can cause heart failure. Wouldn’t it follow then, that amyloid deposits in the brain can cause brain failure? The apparent a-ha moment came in 1984, when Glenner indeed found the protein in the brain tissue of Alzheimer’s patients and purified it. (Glenner himself had systemic senile amyloidosis, where amyloid builds up in the body. He died in 1995.)

Selkoe’s lab eventually worked out some of the molecular mechanisms behind the amyloid build-up. Then, geneticists found that people with a family history of Alzheimer’s also had mutations in the very genes that encode for making amyloid. “The genetic evidence is so strongly supported,” says Selkoe, “People gravitated toward it.” A 1992 paper in Science by John Hardy and Gerald Higgins laid out the case for the amyloid hypothesis.

The discovery of these genes created a sense of optimism in Alzheimer’s research. Scientists had a roadmap to a cure. Drug companies just needed to follow it. But of course, a quarter century later, there are still no drugs for Alzheimer’s that target amyloid.

“When you have a setback, there’s understandably questioning, are you sure about the science,” Selkoe says about the latest Merck trial. But he remains convinced that targeting amyloid could still succeed with a few changes—like when patients start treatment. By the time an Alzheimer’s patient starts suffering memory loss, that may be too late. So the A4 trial, coordinated out of the University of Southern California, is testing an previously unsuccessful drug in patients with elevated amyloid levels but no outward cognitive symptoms yet. Even if anti-amyloid drugs can’t reverse symptoms, perhaps they can prevent full-blown Alzheimer’s. The prevailing view in the field, Selkoe says, is still that dealing with amyloid can treat the disease.

One of the loudest contrarian voices is George Perry, a neuroscientist at University of Texas at San Antonio, who has gone so far as to declare the amyloid hypothesis “dead.” Perry favors an explanation where neurons are damaged by an imbalance of overreactive molecules containing oxygen—also known as oxidative stress. Of course, the evidence that amyloid has something to do with Alzheimer’s is strong, and Perry is not discounting that. Perhaps, he says, amyloid buildup is a protective response to oxidative stress, though the root cause of the stress is unknown.

To be clear, this is a minority view in the research community. Perry says reviewers on his trainees’ research grant applications have gotten negative feedback for working with him because of his outspokenness against the amyloid hypothesis. The problem, he contends, is that people invested in the hypothesis are entrenched. “The government and the pharmaceutical industry have invested almost all their resources, and some of the brightest people have been in the amyloid area,” he says. “Think about all that talent that has been invested and that so far as yielded zero therapeutic value.”

Other skeptics of the amyloid hypothesis are coming back to tau, the protein Selkoe left decades ago to focus on amyloid. In the brains of Alzheimer’s patients, tau gets twisted into tangles that block the internal transport system of neurons. A recent failed trial aside, several drugs targeting tau are in early phases of clinical trials.

The waxing and waning of animating ideas is just how science works. For scientists, says Bart de Strooper, an Alzheimer’s researcher at the University of Leuven, these failed trials still have something to teach. “The failed trial doesn’t have to be a failure. We learn from it,” he says. “Only because a trial is done do we know now we have to go further.” The question is how much further. Refine the amyloid hypothesis, or abandon it altogether? Without the benefit of hindsight, it’s hard to know which is the side of history.

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mwclarkson
3 hours ago
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Providence RI USA
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White House Defers to “States’ Rights” on Transgender Protections — But Not on Legalizing Marijuana

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White House Press Secretary Sean Spicer cited “states’ rights” on Tuesday in defending the Trump administration’s decision to end the Obama administration’s federal protections for transgender students.

“The president has maintained for a long time that this is a states’ rights issue and not one for the federal government,” he said. “All you have to do is look at what the president’s view has been for a long time that this is not something that the federal government should be involved in. This is a states’ rights issue.”

But on Thursday, asked about federal marijuana enforcement, it was like the states had no rights at all. Arkansas-based reporter Roby Brock asked Spicer about the administration’s posture towards Arkansas’s new medical marijuana law.

Spicer suggested that the Trump administration would respect state laws related to medical marijuana — but not offer the same respect for recreational marijuana.

Watch the contrast:

 

 

“There are two distinct issues here. Medical marijuana and recreational marijuana,” Spicer said. “Medical marijuana, I’ve said before that the president understands the pain and suffering that many people go through who are facing especially terminal diseases and the comfort that some of these drugs including medical marijuana can bring to them.”

But Spicer compared recreational marijuana use to deadly opioid addictions. “I think that when you see something like the opioid addiction crisis blossoming in so many states around this country the last thing that we should doing is encouraging people, there’s still a federal law that we need to abide by in terms of…when it comes to recreational marijuana and other drugs of that nature.”

Shannon Pettypiece of Bloomberg followed up by asking if the federal government would take action against recreational marijuana.

“I think that’s a question for the Department of Justice. I do believe that you’ll see greater enforcement of it. Because again there’s a big difference between the medical use, which Congress has through an appropriations rider in 2014 made very clear what the intent, what their intent was in terms of how the Department of Justice would handle that issue,” he replied, referring to a 2014 law that directed the federal government to respect state medical marijuana laws. “That’s very different than the recreational use which is something the Department of Justice I think will be further looking into.”

Top photo: White House Press secretary Sean Spicer points as he answers questions from reporters, seen reflected in an exit sign, during the daily briefing in the Brady Press Briefing Room of the White House in Washington on Feb. 14, 2017.

The post White House Defers to “States’ Rights” on Transgender Protections — But Not on Legalizing Marijuana appeared first on The Intercept.

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mwclarkson
4 hours ago
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"States' rights" only exist when somebody wants to be a bigot.
Providence RI USA
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This Is Very Concerning

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Last night, passengers on a domestic flight from San Francisco to New York disembarked, only to be greeted by customs agents demanding to see their "documents."


Anne Garrett, who is a video editor for Vice, further commented: "They had to explain what they meant by documents bc everyone was so confused."

This is not normal.
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mwclarkson
11 hours ago
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Providence RI USA
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1 public comment
skittone
10 hours ago
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Papers, please.
HarlandCorbin
8 hours ago
Isn't this proven to be unconstitutional?

Collapse of Aztec society linked to catastrophic salmonella outbreak

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Collapse of Aztec society linked to catastrophic salmonella outbreak

Nature 542, 7642 (2017). http://www.nature.com/doifinder/10.1038/nature.2017.21485

Author: Ewen Callaway

DNA of 500-year-old bacteria is first direct evidence of an epidemic — one of humanity's deadliest — that occurred after Spanish conquest.

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mwclarkson
1 day ago
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Practice good kitchen hygeine, folks.
Providence RI USA
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Show Me Your Budget, And…

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I’ll tell you what you value:

Book3_19072_image001

Trump’s draft budget calls for eliminating these programs (except for the Melania protection).






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mwclarkson
1 day ago
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Providence RI USA
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Righties scream and shout about how hard work and personal responsibility are the only things that determine a person's economic and social conditions. Yet whenever someone commits a public act of racism they can't wait to excuse their actions by citing the person's upbringing, the society they grew up in, the institutions they frequented and all manner of environmental factors. Can't racists be consistent? I'd love to see one demand that Jim Bob pull himself out of racism by his bootstraps.

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Here’s a handy guide to racist thought: When something bad happened, white people are always victims of circumstance, people of color are always responsible for their shortcomings.

When something good happens, whoops, the converse.

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mwclarkson
1 day ago
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Providence RI USA
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