Brain compensates for memory loss in people genetically at risk for AD

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In the first study of its kind, UCLA researchers found that adults carrying an Alzheimer’s disease risk gene need to work harder mentally to perform simple memory tasks – even though individuals appear normal and show no outward symptoms of disease.

Study findings may lead to better testing methods to help diagnose and prevent the onset of Alzheimer’s, a fatal disease currently affecting four million Americans. The study appeared in the New England Journal of Medicine in August.

“The study indicates that the brains of people at risk for Alzheimer’s disease may need to work harder to reach the same level of memory performance as those without the Alzheimer’s risk,” said Dr. Gary Small, the study’s senior author and director, UCLA Center on Aging.

UCLA researchers performed genetic testing on 30 adults, aged 47-82, with very mild and common age-related memory complaints. Over half of the participants carried the apolipoprotein E-4 allele or APOE-4, a gene that increases the risk of developing Alzheimer’s disease.

Each study participant received a functional magnetic resonance imaging (MRI) brain scan, which produces signals reflecting brain activity, while the participants performed simple memory tests. Researchers determined brain activity patterns while subjects memorized and recalled words.

UCLA researchers found that people with the genetic risk for Alzheimer’s disease showed greater brain activity while recalling words than people without the Alzheimer’s gene. Such increased activity represents the brain working harder to accomplish a task, according to Small.

“The brain regions showing the greatest increase in activity were areas where Alzheimer’s disease is known to cause damage,” said Small.

The study subjects carrying the Alzheimer’s risk gene showed amplified brain activity in the parietal, temporal, and frontal regions of the brain, compared with the group without the APOE-4 gene. The temporal region is located at the temples, the parietal region is found above and behind the temples, and the frontal region is toward the forehead.

Two years later, UCLA researchers conducted follow-up memory tests on 14 study participants. During these tests, researchers asked questions to measure forgetfulness and changes in memory. Researchers found that the greater the brain activity recorded during the MRI scan, the worse the participants performed at the two-year memory test.

“We found that we could predict memory decline in individuals based on their brain’s performance during the scan,” said Small. “These are very subtle differences and individuals still appear normal with no disease symptoms. At this point, the brain is still successfully compensating for lost function.”

UCLA researchers combined genetic testing with functional MRI scanning to determine brain responses in people at risk for Alzheimer’s disease who still had normal memory function.

“Combining the memory task with functional brain imaging is essentially a cognitive stress test, which works like a cardiac treadmill test, but here we are stressing the brain,” said Small.

During a cardiac test, the physician stresses the heart to bring out subtle cardiac abnormalities, which the electrocardiogram cannot detect during rest.

“In the cognitive stress test, we asked volunteers to perform memory tasks during brain scans to observe subtle brain alterations not seen during mental rest,” said Susan Bookheimer, lead study author and associate professor of psychiatry and biobehavioral sciences. “Our study findings are consistent with our expectation that the brain may compensate for subtle deficits not obvious during mental rest.”

“The UCLA study provides additional evidence that subtle changes in brain function can be observed early in the disease course. This is an innovative approach to early disease detection that offers hope that we will eventually have an impact on Alzheimer’s disease through prevention,” said Dr. Neil Buckholtz, chief of the Dementias of Aging Branch at the National Institute on Aging.

The UCLA study was a collaborative effort between the UCLA Neuropsychiatric Institute, the UCLA Brain Mapping Center, the UCLA Center on Aging, the UCLA Alzheimer’s Disease Center, and the Center for Human Genetics at Duke University Medical Center.

Alzheimer’s disease afflicts nearly 10 percent of people over age 65. The United States annually spends approximately $100 billion on Alzheimer’s. Experts estimate that delaying disease onset even by one year would save nearly $10 billion after a decade.

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