Neuroimaging Reveal Brain Changes in Individuals at Genetic Risk for Alzheimer's

People with a known, high risk for Alzheimer's disease (AD) develop abnormal brain function even before the appearance of characteristic amyloid plaques that are characteristic of the disease, according to a new study.

Researchers from the Washington University School of Medicine in St. Louis (MO, USA) reported in the December 15, 2010, issue of the Journal of Neuroscience that these patients had a particular form of the apolipoprotein E (APOE) gene called APOE4. The study's findings suggest that the gene variant affects brain function long before the brain begins accumulating the amyloid that will eventually lead to dementia.

Researchers identified functional differences in the brains of APOE4-positive and APOE4-negative individuals. Red indicates increased connectivity among regions at rest while blue shows decreased connectivity. "We looked at a group of structures in the brain that make up what's called the default mode network,” said lead author Yvette I. Sheline, MD. "In particular, we are interested in a part of the brain called the precuneus, which may be important in Alzheimer's disease and in pre-Alzheimer's because it is one of the first regions to develop amyloid deposits. Another factor is that when you look at all of the structural and functional connections in the brain, the most connected structure is the precuneus. It links many other key brain structures together.”

The research team conducted functional MRI scans on 100 people whose average age was 62. Just under half of them carried the APOE4 variant, which is a genetic risk factor for late-onset AD. Earlier PET scans of the study subjects had demonstrated that they did not have amyloid deposits in the brain.

Participants in the study also underwent spinal puncture tests that revealed they had normal amyloid levels in their cerebrospinal fluid. "Their brains were ‘clean as a whistle,'” noted Dr. Sheline, a professor of psychiatry, radiology, and of neurology and director of Washington University's Center for Depression, Stress, and Neuroimaging. "As far as their brain amyloid burden and their cerebrospinal fluid levels, these individuals were completely normal. But the people who had the APOE4 variant had significant differences in the way various brain regions connected with one another.”

Dr. Sheline's team focused on the brain's default mode network. Typically, the default network is active when the mind rests. Its activity slows down when an individual concentrates. Subjects do not need to perform anyspecific tasks for researchers to study the default mode network. They simply relax in the MRI scanner and reflect or daydream while the system measures oxygen levels and blood flow in the brain. "We make sure they don't go to sleep,” Dr. Sheline stated. "But other than not sleeping, study participants had no instructions. They were just lying there at rest, and we looked at what their brains were doing.”

This is the latest in a series of studies in which Dr. Sheline and her colleagues have looked at brain function in people at risk for AD. At first, her team compared the default mode networks in the brains of people with mild AD to the same structures in the brains of those who were cognitively normal. In that study, her team found significant differences in how the network functioned. Then, using positron emission tomography (PET) imaging to identify cognitively health individuals who had amyloid deposits in their brains in a second study, they compared those cognitively normal people whose PET scans revealed that their brains contained amyloid to others whose PET scans showed no evidence of amyloid. Again, the default mode network performed differently in those with amyloid deposits.

In the current study, there was no evidence of dementia or amyloid deposits. However, in those with the APOE4 variant, there was irregular functioning in the default mode network. APOE4 is the major genetic risk factor for sporadic cases of Alzheimer's disease. Other genes that pass on inherited, early-onset forms of the disease have been identified, but APOE4 is the most important genetic marker of the disease identified so far, according to Dr. Sheline.

The study participants, all of whom participate in studies through the university's Charles F. and Joanne Knight Alzheimer's Disease Research Center, will be followed to see whether they eventually develop amyloid deposits. The goal is to identify those with the highest risk of AD and to develop treatments that interfere with the progression of the disease, keeping it from advancing to the stage when amyloid begins to build up in the brain and, eventually, dementia sets in. "The current belief is that from the time excess amyloid begins to collect in the brain, it takes about 10 years for a person to develop dementia,” Dr. Sheline concluded. "But this new study would suggest we might be able to intervene even before amyloid plaques begin to form. That could give us an even longer time window to intervene once an effective treatment can be developed.”

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Washington University School of Medicine in St. Louis