July 11, 2012
World
With more than 5
million Americans suffering from Alzheimer's
disease, the most common form of dementia, the
race is on to surface clues about causes and
prevention.
An important breakthrough for the research field
comes in the journal Nature this week.
Researchers say they found a rare genetic
mutation in Iceland that appears to protect
against Alzheimer's disease.
The mutation appears to slow the production of
the beta-amyloid protein, long considered to be
a cause of Alzheimer's. This mechanism helps
validate the theory that beta-amyloid plaques –
an accumulation of the protein - cause this form
of dementia for which no cure has been found.
The research team was led by Dr. Kari
Stefansson, chief executive of the Icelandic
company DeCode Genetics. They studied data from
the genomes of nearly 1,800 Icelandic people.
A genetic test for the protective mutation
wouldn't make sense, since it's so rare, experts
said. If you really wanted to know if you have
it, your doctor probably couldn't tell you; it
would require a specialized research lab, says
Dr. Sam Gandy, director of the Mount Sinai
Center for Cognitive Health.
Mutations like this are "not so good for
screening as they are for teaching what’s going
on," said Rudolph Tanzi, a Harvard Medical
School neurologist who was not involved in this
study.
Drugs attempting to clear some of those plaques
out have so far failed to reverse the effects of
dementia in clinical trials, but this new study
drives home that targeting beta-amyloid is still
correct, Tanzi said.
There are going to be more failures before a
successful treatment is found, Tanzi said.
Drugs that have failed so far weren't getting
into the brain, had harmful side effects or were
just defective. A new wave of clinical
trial results will come this fall - if they too
fall short, this study reinforces that
researchers should still go after beta-amyloid,
Tanzi said.
It might be another four or five years before
drugs under development start showing more
promising results, he said. "These are just not
yet the right drugs, and I think the right ones
are yet to come," he said.
A successful protective drug against Alzheimer's
would probably have to be taken for decades,
like a statin to reduce risk of heart problems,
said Dr. Robert Green, associate director of
medicine in the division of genetics at Brigham
and Women’s Hospital and Harvard Medical School.
It could be something everyone takes, and
perhaps the people most at risk of Alzheimer's
would start on it earlier.
This study suggests that when someone has this
specific mutation, the amount of beta-amyloid
protein released into his or her brain, which
contributes to Alzheimer's, might be reduced by
as much as 40%. This could explain lower rates
of dementia.
For most of us, who do not have this mutation,
beta-amyloid protein gets released when the
amyloid precursor protein (APP) on a brain cell
is cut by two enzymes: Beta-secretase and
gamma-secretase. (A third enzyme that snips it,
alpha-secretase, actually prevents
Alzheimer's-related plaques from forming).
Drug developers have tried inhibiting
gamma-secretase, but because that enzyme is
responsible for so many other important things,
these drugs were toxic. "You can't just hit it
with a sledgehammer," Tanzi explains. The same
goes for beta-secretase.
"You need an enzyme that will block
beta-secretase or gamma-secretase from clipping
just APP, but you need to allow it to do its
other jobs," Tanzi said. He and colleagues
received a grant from the National Institute of
Health to develop drugs along these lines.
The Nature study suggests when people have the
newly discovered mutation on the APP gene, they
naturally experience less cutting from
beta-secretase, resulting in lower amounts of
beta-amyloid getting into the brain from birth.
This seems to be a protection against
Alzheimer's.
In 1987, Tanzi led a group that discovered the
APP gene, on which the protective mutation was
found. This gene is associated with early-onset
Alzheimer's disease. In 2009, his research team
found two different rare mutations on this gene
that raise the risk of Alzheimer's.
Early symptoms of Alzheimer's include difficulty
remembering names and recent events, apathy and
depression. As the disease progresses,
patients often exhibit disorientation, confusion
and severe impairments in walking, speaking and
swallowing.
Lifestyle changes such as increased physical
activity, lowered stress and healthy diet have
found to be associated with staving off
dementia, but there has been no definitive proof
or treatment developed.
