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Alzheimer’s May Begin in Early Adulthood with
Default Mode Switch
It may be the normal cognitive function of the brain
that leads to Alzheimer’s later in life
Aug. 24, 2005 – Alzheimer’s possibly begins in
early adulthood, according to researchers who made the surprising
discovery that the areas of the brain that young, healthy people use
when daydreaming are the same areas that fail in people who have
Alzheimer's disease.
On the basis of their data, the researchers are
proposing a new hypothesis that suggests that Alzheimer's disease may be
due to abnormalities in the regions of the brain that operate the
“default state.” This is the term used to describe the cognitive state
people defer to when musing, daydreaming, or thinking to themselves.
“The regions of the brain we tend to use in our
default state when we are young are very similar to the regions where
plaques form in older people with Alzheimer's disease,” said the lead
author of the study, Randy L. Buckner, a Howard Hughes Medical Institute
(HHMI) investigator at Washington University in St. Louis. “This is
quite a remarkable convergence that we did not expect,” Buckner adds.
The new findings are important because they could
help scientists and clinicians identify and understand the beginnings of
what is probably a cascade of events that ultimately leads to
Alzheimer's.
The most common form of dementia among older
people, Alzheimer's is characterized outwardly by the erosion of
language, thought and memory. Within the brains of people with
Alzheimer's disease, abnormal clumps of plaque and tangled bundles of
fibers form and characterize the physical manifestation of the disease,
which may affect as many as 4.5 million Americans. The causes of the
disease are unknown.
The researchers used five different medical imaging
techniques to study the brain activity of 764 people, including those
with Alzheimer's disease, those on the brink of dementia, and healthy
individuals, in making their discovery.
| |
 “It
may be the normal cognitive function of the brain that leads to
Alzheimer’s later in life. This was not a relationship we had
even considered.”
Randy L. Buckner |
|
Writing in the August 24, 2005, issue of the
Journal of Neuroscience, the researchers state that “the default
activity patterns of the brain may, over many years, augment a
metabolic- or activity-dependent cascade that participates in
Alzheimer's disease pathology.”
The availability of powerful imaging techniques and
the ability to merge different sets of imaging data through new
bioinformatics and statistical methods enabled Buckner and his team to
construct a picture of Alzheimer's from molecular changes to the
structural and functional manifestations of the disease. In the process,
the team unexpectedly observed that the regions of the brain that light
up when we slip into comfortable patterns of thought are the same as
those that, later in life, exhibit the disabling clumps of plaque
characteristic of Alzheimer's, a disease that most frequently manifests
itself after age 60.
That remarkable correlation, said Buckner, suggests that dementia may be
a consequence of the everyday function of the brain.
“It may be the normal cognitive function of the
brain that leads to Alzheimer's later in life,” said Buckner. “This was
not a relationship that we had even considered. The hypothesis is that
the cascade of events that leads to Alzheimer's begins at young
adulthood.”
Scientists have long known that when the mind is
not concentrated on a task — reading, engaging in conversation or
solving a math problem, for example — it switches to a default mode, a
state of mind where we may muse, daydream or retrieve pleasant memories.
When a young person is asked to concentrate on a specific task, they are
easily able to shut off the default mode — and the corresponding regions
of the brain that run this mode. With the help of powerful imaging
technologies such as positron emission tomography (PET) and magnetic
resonance imaging (MRI), scientists, including Buckner's HHMI team, have
begun to map the activity of the brain in its different states,
including the default state.
Among the observations they are making is that when
a person who has clinical Alzheimer's disease is asked to concentrate on
a specific task, the default mode actually becomes more active — rather
than showing less activity, as it would in a young, healthy adult.
The default state, according to Buckner, is
characterized by metabolic activity in specific regions of the brain,
notably the posterior and cortical regions. “These regions were active
in the default states in young adults and also showed amyloid (plaque)
deposition in older adults with Alzheimer's disease,” the researchers
write in the new Journal of Neuroscience paper.
“The key insight is that brain activity and
metabolism are not uniform across the brain,” Buckner said. “When we
looked at people on the cusp of dementia, we saw a loss of brain tissue
in the regions we predicted it would occur,” based on our observations
of metabolism.
Insight from the new study may help explain why the
memory systems of the human brain are vulnerable. “We appear to use
memory systems often in our default states. This may help us to plan and
solve problems. Maybe it helps us be creative. But it may also have
metabolic consequences,” Buckner explained.
The newfound correlation may also have future
clinical implications as Alzheimer's is typically diagnosed when it is
too late to intervene. To develop and administer effective treatments,
clinicians will need to figure out ways to detect the disease in its
earliest stages, said William Klunk, associate professor of psychiatry
at the University of Pittsburgh and a co-author of the Journal of
Neuroscience paper.
“You have to get to this pathology before it has
its biggest effect, before it has done its damage,” said Klunk, who has
developed techniques for imaging the amyloid plaques in Alzheimer's
patients.
The findings reported in the new study, he said,
suggest that there is now the potential to begin to trace the patterns
of the disease and develop methods to detect it before the clinical
symptoms set in.
Buckner emphasized that the notion of a causative
relationship between everyday metabolic functions of the brain and
Alzheimer's remains a hypothesis. However, new studies may help “show if
amyloid (plaque) deposition is really dependent on metabolism. Can we
find a biologically plausible reason for how metabolism causes
Alzheimer's disease?”
Moreover, looking to see if the phenomenon varies
or is the same among many individuals will be required to firm up the
link between brain metabolism in early life and Alzheimer's pathology
later in life. Understanding variation may also help us to explain why
some people are at high risk for Alzheimer's disease.
“We are very interested in exploring these new
observations to understand who is at risk and who is protected from
Alzheimer's,” said Buckner.
In addition to Buckner and Klunk, authors of the
Journal of Neuroscience article include Abraham Z. Snyder, Benjamin J.
Shannon, Gina LaRossa, Rimmon Sachs, Anthony F. Fotenos, Yvette I.
Sheline, John C. Morris and Mark A. Mintun, all of Washington
University; and Chester Mathis of the University of Pittsburgh.
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