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Gene Linked to Accelerated Brain Aging in Healthy Adults

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Duke Health News 919-660-1306

ORLANDO, Fla. – By studying a chemical marker in the brain
that reflects the health of brain tissue, researchers at Duke
University Medical Center have found new clues about why some
people experience more rapid age-related brain changes than
others.

The researchers have found an association between nerve cell
changes associated with aging and the presence of a variation
of the apolipoprotein gene known as apolipoprotein E4 (APOE4).
This form is carried by approximately 25 percent of the
population and has been linked to increased risk of Alzheimer's
disease, cardiovascular disease and memory loss after head
injury or bypass surgery.

Although the signs of age-related memory loss are widely
recognized, researchers are still unsure why some elderly
adults retain strong mental capacity well into their 90s while
others fall into progressive decline or dementia.

"The frontal lobe is the site where the earliest and most
consistent effects of aging occur in the brain," said P. Murali
Doraiswamy, M.D., a psychiatrist at Duke and lead researcher on
the study. "Virtually every mental symptom of normal aging
results from decline in frontal lobe functions. When we
examined this vital area of the brain by following a particular
genetic marker, we found a single gene variation that can
result in significant nerve cell changes associated with aging.
Of the people we studied, those who carried the APOE4 gene
experienced a more rapid loss of nerve cell functioning."

In other words, their brains showed signs of aging faster
than those without the gene.

The research team was scheduled to present their findings
today (Feb. 25, 2002) at the 15th annual meeting of the
American
Association for Geriatric Psychiatry
in Orlando, Fla.

Doraiswamy's team decided to measure levels of
N-acetylspartate (NAA), a brain chemical known to be closely
associated to nerve cells, and hence to mental functions. This
chemical is primarily found inside nerve cells within the
brain. The presence of NAA signals the health, or lack thereof,
of a nerve cell.

"It is generally accepted that dying nerve cells have lower
levels of NAA but little is known about the chemical's role in
a particular disease," said Doraiswamy. "It's what we call a
surrogate marker."

By using magnetic resonance spectroscopy (MRS), researchers
were able to detect nerve cell changes associated with aging in
people with dissimilar genetic makeup. MRS uses magnetic fields
and radio waves to provide researchers a way to detect subtle
changes in specific chemicals inside nerve cells to determine
the cells' health, damage and loss of function.

Using MRS in a baseline study, the researchers compared the
level of NAA in the brains of 165 healthy study participants
who ranged in age from 55 to 85. Of these, 84 participants were
postmenopausal women and 81 were men. All participants had
mental capacities representative of normal older people. The
subjects were divided into two groups based on whether they
were carriers of the APOE4 gene or not. After undergoing MRS
both groups were administered a battery of memory tests to
obtain their NAA and cognitive levels. After two years, a
subset of the participants was studied again with memory
tests.

The researchers found that those with lower NAA levels at
the beginning of the study had greater loss of short-term
memory and naming abilities after two years. To determine loss
of NAA across an age span (in this case as healthy adults aged
from their 50s to their 80s) the researchers simply compared
the age ranges within the APOE4 group and the non-APOE4
group.

"We found that NAA levels declined mildly with increasing
age for all participants in the study," said Doraiswamy. "But
when the sample was broken down by genetic makeup, the average
loss of NAA across the age span was nearly three-fold higher in
people with the APOE4 gene than in those who were not carriers
of this gene."

Thus, the researchers concluded that the brains of those who
carry the APOE4 gene show greater deterioration than those who
do not. "This is an important finding in the study of aging. I
believe it will lead to a greater understanding of age-related
memory loss and hopefully, one day, to ways of keeping our
brains sharper, longer," noted Doraiswamy.

This study was funded by the American Federation for Aging
Research and through the Paul Beeson Physician Scholar Award
(P. Doraiswamy).

Collaborators on the study included Cecil Charles Ph.D.; Dan
Barboriak, M.D.; and Gene Chen.

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