Ways to Save a Brain
Current Alzheimer's treatments don't slow
the underlying disease process. Researchers are now testing
an array of new therapies intended to do just that.
By Anne Underwood
2005 - Elisabeth Harvey, 85, is not your typical Alzheimer's
patient. Sure, she reads the daily newspapers, forgetting
that she just read them. But five years after she was
diagnosed with Alzheimer's disease, she still lives at
home, dresses herself and fixes her own lunch. What's
more, her cognitive-test scores have not declined in over
two-and-a-half years. "That's unheard of," says
neuropsychologist Paul Solomon of the Memory Clinic in
Bennington, Vt. How is it possible? In late 2002, Solomon
enrolled Harvey in a trial for an experimental drug called
Alzhemed, which she's taken ever since, along with the
standard Alzheimer's drug Aricept. "Not everyone
in the trial performed as well as she did," Solomon
cautions. But still, he has to credit the test treatment.
If not for the drug, he says, Harvey might well be in
a nursing home by now.
Alzheimer's is a progressive, devastating
and incurable illness. It afflicts some 4.5 million Americans
at a cost of $100 billion a year. That number is expected
to hit 14 million by 2050. But delaying people's symptoms
by five years could reduce the burden by half—and
if better treatments could help patients like Harvey stay
out of nursing homes, that would mean even greater savings
in both cost and human anguish. These are becoming real
possibilities. Bill Thies, vice president of the Alzheimer's
Association in Chicago, foresees the day when everyone
will have a routine brain scan for Alzheimer's at the
age of 55 and begin a treatment program if there are signs
of trouble, much as they do for heart disease today. When
will it all happen? "I'll see it in my lifetime,"
the 63-year-old Thies replies, "provided I don't
take the wrong cab in Chicago."
Part of his optimism stems from the nature
of the treatments that are in development today. Whereas
current drugs serve mainly to mask symptoms for a while,
researchers are now mounting direct assaults on the underlying
disease process. Most of the experimental treatments focus
on taming a toxic protein called beta-amyloid, or A-beta.
It's the main constituent of the sticky plaques that gum
up Alzheimer's brains. Everyone has some of these plaques
after a certain age, but Alzheimer's brains generally
have many more. There are two basic ways to keep from
reaching crisis levels. As Dr. Dennis Selkoe, a neurologist
at Harvard's Brigham and Women's Hospital, puts it, "If
you want to stop a bathtub from overflowing, you either
turn off the spigot or open the drain. With Alzheimer's,
you can reduce the formation of A-beta or help clear out
what's already there." There are a score of potential
new ways to do that. Even if some of them ultimately fail
in testing, others seem likely to pass. Here are some
of the more intriguing:
1. Most of the next-wave treatments are
what Selkoe would call drain openers. Alzhemed, the experimental
drug that Elisabeth Harvey received, acts as a magnet
for strands of A-beta. Instead of clumping together and
later forming plaques, they bind to the drug and filter
harmlessly out of the body. In Harvey's trial, A-beta
declined by an average of 20 to 35 percent in the spinal
fluid of those who received treatment—and the decline
in A-beta often translated into clinical benefits. Seventy
percent of those with mild Alzheimer's held steady in
cognitive testing for close to two years. Unfortunately,
those with moderate disease continued to decline. "We
presume there's too much damage by then to help,"
says Denis Garceau, senior vice president of Neurochem,
the company that makes the drug. Larger trials are now
underway. If all goes well, Alzhemed could be on the market
in five years.
2. There are other ways to clear A-beta,
at least in theory. In 2002, doctors Norman Relkin and
Marc Weksler of Weill Cornell Medical Center discovered
that the immune system makes antibodies against amyloid,
but that Alzheimer's patients have lower levels. What
if you could raise them? In a pilot study, Relkin gave
eight patients six monthly injections with a natural blood
product called intravenous immunoglobulin (IVIg), which
contains the antibodies. His goal was simply to boost
antibody levels, but he says the patients' family members
found them more alert, engaged and articulate. "It
was like turning back the clock a year," he says.
Elan Corp. and Wyeth are now testing a bioengineered version
of an amyloid antibody. They have started human trials,
but approval is still at least four years away.
3. Opening the drain is a start, but if
you could shut off the spigot at the same time, you might
get even better results. Scientists have long known how
to block gamma secretase, an enzyme that helps make A-beta.
Unfortunately, the enzyme also makes dozens of proteins
that are critical for brain function. How do you nix the
bad without knocking out the good? Scientists at Torrey
Pines Therapeutics screened 80,000 compounds to find one
that would gently tweak gamma secretase to block A-beta
production alone. In fact, they singled out a compound
that blocks only the most toxic, long-chain versions of
A-beta, not the less harmful shorter forms. The drug is
not in human trials yet, but stay tuned.
4. In a novel approach that most scientists
say comes out of left field, a new company called Voyager
Pharmaceutical Corp. is using hormones to reduce amyloid
formation. Dr. Richard Bowen, a family practitioner in
Florida, stumbled on the approach when a patient noted
that her husband's Alzheimer's hadn't worsened for five
years, since he had begun taking a hormone treatment called
leuprolide for his prostate cancer. The drug inhibits
secretion of hormones called gonadotropins, which surge
at menopause and skyrocket in people with Alzheimer's.
Voyager has refined the drug for Alzheimer's, and early
trials look promising, but larger studies are needed.
5. Others researchers are gambling on more
radical approaches that wouldn't reduce A-beta, but build
the brain's defenses against another hallmark of the disease:
neurofibrillary tangles. These tangles cause the collapse
of so-called microtubules, structures inside cells that
help the cells maintain their shape. When microtubules
collapse, brain cells can no longer transmit messages
from one cell to the next. But Dr. John Trojanowski of
the University of Pennsylvania's Alzheimer's Disease Center
is studying drugs that may help reinforce the microtubules.
He's most excited about the cancer drug Taxol, which could
fight both cancer and Alzheimer's by the same mechanism.
Cells with rigid microtubules are less prone to uncontrolled
division, he says, and less likely to collapse. So far,
Trojanowski has tested the idea only in mice. But Taxol
is FDA approved. So if the animal work goes well, scientists
should be able to skip human safety tests and go straight
to large clinical trials with Alzheimer's patients.
6. If that sounds ambitious, Dr. Mark Tuszynski
of the University of California, San Diego, has the most
dramatic approach of all—gene therapy. In a much-heralded
trial published this year, he injected eight patients'
brains with specially engineered skin cells that work
as tiny pumps, churning out nerve-growth factors that
prevent the withering of brain cells. Almost two years
later, patients showed greater neural activity on PET
scans than untreated patients. "Most intriguing,
disease progression slowed by 36 to 51 percent,"
says Tuszynski. "Even in the presence of amyloid,
growth factors can prevent cell death or slow it down."
But he notes that the treatment is still highly experimental—and
because it is so invasive, it will have to prove more
effective than other therapies to win approval or acceptance.
7. While these scientists hunt for better
treatments, others are hoping to keep people from developing
Alzheimer's in the first place. Dr. Gary Small, director
of the Center on Aging at UCLA, has developed a way to
scan brains for both plaques and tangles. His ultimate
goal is to predict who's headed for trouble and start
those patients on a preventive program, including a healthy
diet, exercise and anti-inflammatory drugs, which in large
population studies appear to correlate with risk reduction.
Scientists are starting to figure out why. For example,
neuroscientist Greg Cole at UCLA has found that the fish
oil DHA lowers levels of A-beta, at least in mice. Intriguingly,
it appears to both reduce production and enhance clearance
of the toxic substance.
None of these treatments or preventive measures
will banish Alzheimer's, any more than science has eliminated
heart disease. But together, they could one day make it
a manageable ailment—something it is not at present.
When doctors told Marty Bahr, 56, of Bartlett, Ill., that
he probably had Alzheimer's, his wife actually hoped that
they would find a brain tumor or rare blood cancer instead—"something
we could actually do something about," she says.
If scientists succeed, wishes like that will one day be
Original source: http://www.msnbc.com