New Scientist, 01 February 2003
only way to know for sure if someone has Alzheimer's is to wait until
they die and then autopsy their brain. On the outside, the disease can
look just like other forms of dementia. But inside the brain there's
something special a pathologist will be looking for: telltale tangles
and plaques in and around the brain cells, made from a protein called
The protein connection was first discovered in the
mid-1980s, and ever since, A has been considered the main culprit. The
amyloid hypothesis is still by far the most widely accepted explanation
for the disease. It proposes that A, which is usually soluble, for some
unknown reason spontaneously clumps together, killing off nearby
neurons and causing dementia. The tantalising implication was that if
you could get rid of the peptide clumps, you could cure Alzheimer's.
of research dollars have already been gambled on the idea. Scientists
around the world are either trying to persuade the body to produce less
A, suck out what has already been deposited, or crank up the body's own
systems for removing it. Some approaches are now being tested in
people. But even though it has proved relatively straightforward to
cleanse a rodent brain of the rogue protein, a cure for Alzheimer's
seems as elusive as ever. The path from lab mouse to cure is never
straightforward, but maybe there's a more fundamental problem. Despite
being such a characteristic marker of the disease, there is no hard
evidence that A is causing Alzheimer's. Are efforts to find the real
cause blinkered by the protein's presence? Could we be going after the
No one doubts the peptide is there. But is it
responsible for the slow, undignified decline of the brain's function?
Even though he believes the hypothesis, Bart De Strooper from the
Catholic University of Leuven in Belgium acknowledges that there's a
disconnect. "What's lacking is a clear link between amyloid and
neuronal toxicity," he says.
If A isn't to blame, then the
proposed treatments could well be worthless (see "In the works"). Or
worse. What if A is actually shielding the brain as it fights the real
killer of neurons? Getting rid of the peptide could actually accelerate
This worrying debate has been fuelled by
speculation about why several patients developed dangerous side effects
during one A-busting trial last year, forcing an abrupt halt to the
research. Researchers are still waiting for the full explanation. It
might prove an innocent one, and the strategy of ridding the brain of A
will be vindicated. On the other hand, proposed treatments for
Alzheimer's may need a radical rethink.
To be sure, there's
plenty of evidence that A plays an important part in the disease
process. First of all, clumps of protein in the body tend to be
associated with other kinds of poor health. People with diabetes, prion
diseases and amyotrophic lateral sclerosis - a type of motor neuron
disease - are all proof of that. More specifically, a small number of
Alzheimer's patients have mutations on chromosome 21. This is where the
gene for the amyloid precursor protein or APP, from which the amyloid
peptide is made, is found. The mutation seems to increase the amount of
amyloid their bodies produce.
Down's syndrome is caused by an
extra chromosome 21 and, interestingly, all people with Down's
eventually develop amyloid plaques in their brains. And mice that have
been genetically engineered to overproduce APP invariably develop brain
plaques, and experience some learning and memory problems that seem to
go away when the amyloid is removed.
Mutations in two other
genes, presenilin-1 and presenilin-2, are also associated with
Alzheimer's. Both have a hand in overproducing the longer, most
clump-prone form of amyloid beta, A1-42. Another Alzheimer's gene
produces a protein called ApoE4. The Apo family of proteins appears to
play a role in clearing out amyloid plaques, and the E4 form isn't very
good at it.
But after almost two decades in the limelight, the
theory still has some serious shortcomings. For one thing, lots of
people get dementia without plaques, and lots of others develop plaques
without dementia. Even in patients who clearly have Alzheimer's, the
number of plaques does not correlate well either with neuron loss or
the severity of their mental decline.
In fact, an intriguing
1991 study by Dennis Dickson, a neuropathologist now at the Mayo Clinic
in Jacksonville, Florida, left Alzheimer's researchers scratching their
heads. He and his team followed 14 elderly people for several years
until their deaths. None showed signs of Alzheimer's, but about half
were considered "high functioning" - minds as sharp as tacks - while
the others suffered a slight decline in their mental faculties. During
autopsy, Dickson observed a clear divide. Some had numerous plaques in
their brains, the others had few, if any. Surprisingly, however, the
ones with the plaques had all been in the high-functioning group.
the plaques indicate early-stage Alzheimer's, caught before the
patients had suffered any ill effects, or could the plaques have been
protecting the brains of the high-functioning individuals? "I think the
jury's still out," says Dickson.
Another weak point in the
hypothesis is that mice with plaques don't suffer the same fate as
people with plaques. Rodents never develop Alzheimer's naturally. And
while mice genetically modified to overproduce amyloid, used to test
potential drugs, do develop the characteristic plaques and perform a
little worse on tests of memory and learning, even when their brains
are packed with plaques they don't cause anything like the severity of
the human disease. "There was so much amyloid and so little
neurodegeneration," says De Strooper. "Even me, being a believer...I
had a big problem with that."
When drug giant Eli Lilly used the
mice to test the effects of an antibody against A, they too discovered
something odd. Steven Paul of Eli Lilly in Indianapolis says that they
found, to their surprise, that they could reverse the memory and
learning deficits very quickly without any reduction in A deposits or
blood levels of amyloid. Longer-term administration of the antibody did
dissolve the plaques, but the researchers admit that the immediate
results are extremely puzzling.
The theory also leaves a few
basic questions unanswered. For instance, APP is found in virtually all
our tissues and cells. What does it do in a healthy individual? No one
knows. If amyloid is inherently bad, why do we produce it? Again, no
answers. Also, what exactly is killing neurons in Alzheimer's? If it's
the plaques, how do they wreak their havoc? That's anyone's guess.
researchers think all these problems add up to a duff theory. Even
pro-amyloid researchers admit that they are eagerly awaiting some
clinching evidence to show that taking the peptide out of a human brain
The most promising test of the hypothesis so far
should have been a clinical trial conducted by pharmaceutical companies
Elan and Wyeth. They tested a vaccine, known as AN-1792, which
consisted of a synthetic form of the full peptide. The idea was to
provoke an immune response that would chase natural A out of the brain.
In earlier animal studies, the vaccine not only reduced pre-existing
deposits in the brains of older animals, but also prevented A
deposition in the younger ones. But 15 of the 360 human volunteers who
were given the vaccine developed serious brain inflammation and the
trial was called off in March last year. To the irritation of many
academics, the companies have revealed very little about what went
Elan has confirmed that at least one person who
participated in the trial has since died, of apparently unrelated
causes. Rumours are circulating that upon autopsy, no amyloid
whatsoever was found in the brain.
This could be strong support
for the amyloid camp. "The suggestion would be that the general premise
may have worked," says Larry Sparks, an Alzheimer's expert at the Sun
Health Research Institute in Sun City, Arizona. "But they would be
crazy not to report the data if there was clearance of A," he adds.
may not have released that information, but it certainly hasn't lost
faith in the overall approach. It has other vaccination strategies in
the pipeline, such as inoculating sufferers with fragments of the
peptide rather than the whole molecule, or just injecting the
ready-made antibodies. There is also talk of adding anti-inflammatory
drugs to the mix. "The story is far from over," says Dale Schenk of
But Mark Smith, a neurobiologist at Case Western Reserve
University in Cleveland, Ohio, thinks there could be another
explanation for the Elan vaccine's adverse effects: far from being the
cause of the disease, A could be fighting it. "The one thing that
nobody is raising is that removing amyloid is bad," he says. "No one is
even considering that."
He invokes his favourite analogy. A
doctor is called to the top of Everest to look into why so many
mountaineers get sick up there. Blood tests reveal that they are
producing more red blood cells than normal. Back in the lab, doctors
genetically alter mice to overproduce red blood cells and, sure enough,
they get sick. They bleed them, and the animals get better. But when
sick mountaineers are bled on Everest, they get even sicker. Needless
to say, the extra blood cells were an adaptation to low oxygen levels.
In other words, care must be taken not to confuse the symptoms with the
cause. "I think that's the situation with Alzheimer's disease," says
Smith. "If you remove amyloid you will make the patients worse. The
'better' the treatment, the worse it will make the patient."
suggests that A may actually be protective. This idea fits well with
his own findings of an inverse relationship between the amount of
amyloid in a brain and signs of "oxidative stress" - the more amyloid,
the less damage seems to have been caused by highly reactive molecules
called free radicals. He thinks that oxidative stress happens early on
in the disease process, years if not decades before dementia sets in,
and that amyloid could be playing a role in managing it. For instance,
following head trauma or stroke, deposits of A rapidly form. Smith
thinks amyloid might be a kind of brain scab, and that the most
important factor in Alzheimer's is the way ageing increases the brain's
sensitivity to harm, including that from oxidative stress. But the
amyloid camp point out that he has little direct evidence.
Smith, however, Glenda Bishop and Stephen Robinson at Monash University
in Clayton, Australia, argue that A is harmless and actually
contributes to normal brain function and aids in recovery from brain
injury. It does this, they suggest, by binding to toxic agents in the
brain - such as metal ions and excessive amounts of certain
neurotransmitters - and clumping them into plaques for easier removal
from the brain. They think A clumps are a consequence of Alzheimer's,
not the cause. Alzheimer's, they speculate, is a disorder in which the
brain's defences - including A - are overwhelmed.
Ashley Bush at
Harvard University agrees that A appears to be mopping up metal ions.
Several years ago, Bush's team found that in the test tube, adding
metals such as copper and iron made otherwise soluble A molecules clump
together. They also found that these metals were present in human A
plaques at levels much higher than would normally be found in a healthy
Bush claims that amyloid plaques are not themselves
responsible for killing neurons. Instead, he proposes that when soluble
A binds with iron or copper in the brain, it clumps together and begins
to act as an enzyme that churns out the powerful oxidising agent
hydrogen peroxide. And it's this that kills off neurons (New Scientist,
26 August 2000, p 36).
In collaboration with Colin Masters at
the University of Melbourne, Bush is now testing a disused antibiotic
called clioquinol on Alzheimer's patients. The drug should work as a
"chelator", removing excess metals from their brains. Results from his
phase II clinical trials are due out any day now, but he has already
confirmed that the treatment looks promising, slowing the progression
of the disease (New Scientist, 3 August 2002, p 14). Bush's theory
doesn't totally discredit the amyloid hypothesis. In fact, the more
success he enjoys, the more the amyloid folk are eager to consider him
one of their own.
But some amyloid aficionados are beginning to
question whether plaques are the main problem after all. Dennis Selkoe
at Harvard University recently proposed that short pieces of soluble
amyloid may pose the more serious danger. Correlations between levels
of soluble A and neuron loss or dementia are stronger, he notes. In his
lab, he was able to show that the short strings of A, at levels found
in humans, were themselves able to interfere with learning and memory
in rats (Nature, vol 416, p 535). If he's right, many of the proposed
anti-Alzheimer's treatments, including both Bush's and the Elan
vaccine, may be treading on dangerous ground by breaking down plaques
and raising levels of the soluble protein.
Mark Pepys of the
Royal Free and University College Medical School in London is not
convinced. He has identified a compound, dubbed CPHPC, that removes a
substance called serum amyloid P (SAP) from the blood. SAP is thought
to stabilise amyloid deposits by protecting them from digestion. CPHPC
has not so far been tested in Alzheimer's patients, but is currently
being tested in 30 patients with a disease called systemic amyloidosis,
in which amyloid clogs up various organs (New Scientist, 18 May 2002, p
The hope is that, when the drug is eventually tested on
people with Alzheimer's, it will break down the plaques, flushing
soluble amyloid into the bloodstream from where it will be removed by
the liver. Pepys believes this will halt or even reverse patients'
decline. The idea that dissolving amyloid will make things worse is
wrong-headed, says Pepys. "There's no evidence that amyloid is toxic,
or that getting rid of amyloid is bad for you." The body does it
naturally all the time. He stresses that the patients with systemic
amyloidosis in the trial, who have been treated with CPHPC for over a
year now, have experienced no ill effects. "It's very, very reassuring."
is amyloid guilty or not guilty? The jury will soon be in. "We will
know in five years," predicts De Strooper. Many of the proposed
therapies for treating Alzheimer's assume that amyloid plaques are
behind the disease. If this is so, patients will surely get better. If
they don't, it will be well past time to start listening to the
naysayers. Says Pepys: "The beauty of science is that what's true
always comes out in the end."
In the works
cholesterol levels increase the risk of developing Alzheimer's.
Cholesterol may encourage your body to produce A from amyloid precursor
protein (APP), whereas low cholesterol favours a different
APP-processing pathway. Cholesterol-lowering drugs appear to provide
some protection. Clinical trials are under way.
with the peptide seems to prompt an immune response that not only
prevented A from depositing in the brains of young mice but cleared it
from the brains of older mice. But there were side effects in the first
human trial. New strategies may now focus on vaccinating with smaller
peptide fragments or with antibodies.
use of nonsteroidal anti-inflammatory drugs significantly reduces the
risk of Alzheimer's, perhaps independently of their effect on
inflammation. NSAIDs such as ibuprofen and indomethacin seem to inhibit
production of the most plaque-prone kind of amyloid, A1-42.
tends to clump together when it binds to metals, so "chelating" agents,
which mop up metal ions, may dissolve A plaques from Alzheimer's
brains. The antibiotic and chelating agent clioquinol has been shown to
decrease A deposition in animals, and is now in clinical trials.
secretase enzymes cleave APP to produce A. One, known as BACE, is
considered a drug target. Mice that have been genetically engineered to
lack BACE appear to be anatomically and physiologically normal and
don't produce A. Of course, just because mice born without BACE are
normal doesn't mean everything will be fine in adult human brains.