Brain Function Disrupted in Healthy Women with Alzheimer's Risk Gene
(American Health Newswire)- Research at the Stanford University School of Medicine reveals that the most common genetic risk factor for Alzheimer's disease disrupts brain function in healthy older women compared with the brain function of healthy older men.
Alzheimer's is a neurodegenerative disease that affects about 5 million people in the United States and nearly 30 million worldwide. Possession of the gene variant ApoE4 is known to be a strong risk factor for the disease. Women who have this gene variant show brain changes that are characteristic of Alzheimer's before any other outward symptoms are shown. Both men and women who inherit two copies (one from each parent) of ApoE4 are at an enormously high risk for Alzheimer's. However, this combination is uncommon as it affects only about 2 percent of the population compared with the 15 percent of people that carry a single copy of this version of the gene.
This is the first time there has been evidence of a gender distinction among outwardly healthy older people who carry the ApoE4 variant. In this group comparing women with men, only women exhibit the two characteristics that are linked to Alzheimer's: a signature change in brain activity, and raised levels of a protein called tau in the cerebrospinal fluid.
This study suggests that men who are found to carry a single copy of ApoE4 by genetic tests shouldn't be assumed to be at a higher risk for Alzheimer's. It also potentially explains why more women than men develop this disease. This study also paves the way for similar research in the future; identifying the relationship between ApoE4 and gender can help researchers to better understand how ApoE4 increases the risk for Alzheimer's disease.
On average, women live longer than men and old age is the greatest risk factor for Alzheimer's, "but the disparity in Alzheimer's risk persists even if you correct for the difference in longevity," Michael Greicius, MD, assistant professor of neurology and neurological sciences and medical director of the Stanford Center for Memory Disorders, was quoted as saying. "This disparate impact of ApoE4 status on women versus men might account for a big part of the skewed gender ratio."
Apart from age, another well-studied risk factor is genetic: possession of a certain version of the ApoE gene. This gene is a recipe for a protein involved with cholesterol transportation into cells. Although cholesterol typically gets a bad rap as something to avoid, cholesterol is actually important as a crucial constituent of all cell membranes (including those of nerve cells). Nerve cells constantly respond to experiences by developing or enhancing small, bulblike electrochemical contacts to other nerve cells, or diminishing or abolishing them. Cholesterol is critical for all of these processes.
There are three differing versions of the ApoE protein: E2, E3, and E4. Most people have two copies of the E3 version. A small percentage contain only copy of E3 and one of E2, and an even fewer percentage contain two copies of E2. The protein specified by the E4 gene seems to be defective in comparison to the one specified by either E2 or the E3. Only 10-15 percent of the population carry one copy of E4, but more than 50 percent of people who develop Alzheimer's are E4 carriers. However, the heightened risk of E4 may be largely restricted to women.
To demonstrate this, scientists acquired functional MRI scans of 131 healthy people with a median age of 70 to analyze the connections in the brain's memory network. Their brain-imaging analysis showed that older women carrying the E4 variant exhibited a loss of synchrony in a normally synchronized pattern of activity in the interconnected brain regions (a pattern typically seen in Alzheimer's patients). In healthy older women (but not men) with at least one E4 allele, the activity in the precuneus area of the brain seemed to be out of synch with other regions that generally have closely coordinated firing patterns.
Greicius and his colleagues used a brain-imaging technique known as functional-connectivity magnetic resonance imaging, or fcMRI. It is performed on resting subjects that are awake in the scanner but not focusing on any particular task. It can discern on the order of 20 different brain networks, each containing a set of dispersed brain regions that are physically connected by nerve tracts and have synchronized pulses of activity ("in phase"). It has been shown previously that the synchronous firing pattern of a certain network critical to memory function, the "default mode network," is targeted specifically by Alzheimer's and declines as the disease grows.
In order to confirm their image-based observations, the scientists evaluated records from a large public database from the Alzheimer's Disease Neuroimaging Initiative, a multi-site study of healthy aging and Alzheimer's disease. This Stanford study focused on healthy 55-90 year old volunteers who underwent a spinal tap so the researchers could analyze their cerebrospinal fluid.
The researchers then extracted the records of 91 subjects with an average age of 75 and divided them into four groups representing women with or without a copy of the E4 variant, and men with or without the copy. In each group, the researchers looked at recorded concentrations of a protein named tau in the cerebrospinal fluid; high levels of tau are a key biomarker of Alzheimer's disease. The brain-imaging findings were confirmed by the results of the cerebrospinal fluid of women who carried at least one E4 allele.
These findings mark another important first for this kind of research: "It was only possible to see these differences in tau levels when we separated the patients by gender," Greicius was quoted as saying.
It was notable that all of the men and women in the study were screened for cognitive status. The only people admitted were those who had an ability to think and remember normally for their age. This means that the observed changes in brain activity and cerebrospinal fluid composition were occurring well before the onset of typical Alzheimer's symptoms like memory loss, disorientation and dementia. The study implicates the value of using fcMRI rather than a spinal tap as a noninvasive diagnostic tool.
Source: Neuroscience, August 2012
