How conclusive “amyloid
hypothesis” is?
At the beginning of February 2017, the pharmaceutical
company Merck has decided to pull 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 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.
What is Beta-amyloid?
Beta-amyloid is a protein that was found and identified
by Alois Alzheimer in 1906. Most scientists and researchers believe that when
beta-amyloid accumulates in the brain, it will cause Alzheimer’s disease. The
prevailing theory is that the protein is sticky and forms a plaque which
strangles healthy cells in the brain.
For over twenty years, researchers have been implicating
beta-amyloid as a leading cause of Alzheimer’s disease. They have reasons to do
so which include:
* The discovery of rare genes that increase beta-amyloid
production and almost guarantees the development of Alzheimer’s
* The observation that mice who develop amyloid plaques
also develop behaviors that mimic human dementia and Alzheimer’s
* Noting that people with Down Syndrome have three copies
of the gene that carries that beta-amyloid protein and they often develop
Alzheimer’s disease by middle age.
Competing Theories
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 a
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 the 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 his trainees’ research grant applications have negative
feedback from reviewers 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.
For example, In the 1990s, a team of researchers found
that the degeneration of tau is more directly linked to the development of
Alzheimer’s than beta-amyloid. Tau is another protein in the brain and its main
function is to hold cells open to receive nutrients. When tau clumps together,
the cells cannot get the necessary nutrients they die, resulting in Alzheimer’s
disease. A clinical study, sponsored by Wischick’s company TauRx, for a drug
called TRX-015, has been completed in 2016, as placebo-controlled trial, taking
place at over 100 clinical sites in North America, the EU, Russia, Australia
and Asia.
In another interesting study, scientists at Massachusetts
General Hospital found that mice who were producing the human version of
beta-amyloid proteins were able to fight off salmonella far more efficiently
than mice without it. While the clumping of proteins has traditionally been
seen as a negative sign it’s now thought that this process is in fact the
body’s immune system trying to break down microbe cell walls that are attacking
the brain. Dr Robert Moir, from MGH in the US points out that if true this
would require a completely new approach to fighting Alzheimer’s Disease.
“This widely held view has guided therapeutic strategies
and drug development for more than 30 years, but our findings suggest that this
view is incomplete.” “Our findings raise the intriguing possibility that
Alzheimer’s pathology may arise when the brain perceives itself to be under
attack from invading pathogens, although further study will be required to
determine whether or not a bona fide infection is involved.”
If true it would mean that future treatments should not
be focused on completely removing beta-amyloid protein from the brain as it
could in fact be the one thing that’s trying to fight off a previously unseen
infection. Instead treatments would find the root microbes, target that and
then work on reducing but not eliminating beta-amyloid protein from the brain.
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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