Super-early signs of Alzheimer's revealed

A new study has revealed that people with a known, high risk for Alzheimer's disease develop abnormal brain function even before the appearance of telltale amyloid plaques that are characteristic of the disease.

Researchers at Washington University School of Medicine in St. Louis reported that these patients had a particular form of the apolipoprotein E (APOE) gene called APOE4. The 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 people. 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.

"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 Alzheimer's disease.

 Earlier PET scans of the study subjects had demonstrated that they did not have amyloid deposits in the brain. Amyloid is the protein that makes up the senile plaques that dot the brains of Alzheimer's patients and interfere with cognitive function.

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,' " said Sheline, a professor of psychiatry, of radiology and of neurology and director of Washington University's Centre 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."

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 don't need to perform any particular tasks for researchers to study the default mode network. They simply relax in the MRI scanner and reflect or daydream while the machine measures oxygen levels and blood flow in the brain.

"We make sure they don't go to sleep," Sheline said.

"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."

The study has been published in the Journal of Neuroscience.