Gene Linked To Accelerated Brain Aging In Healthy Adults

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.