DIMENSIONS Summer 2001


by Cheryl Dawes

When the hypothalamus, a region at the base of the brain, detects stress from pain, difficult life events, or any other source, it leaps into action. Stress causes the hypothalamus to trigger a series of molecular events that result in production of a hormone called cortisol. The presence of cortisol in the blood stream sparks metabolic processes that produce a quick supply of energy, which is known as the "fight or flight" response. Normal amounts of cortisol perform a vital function, but animal studies have linked excessive amounts of cortisol with damage to brain cells.

Research has repeatedly found excessive levels of cortisol in patients with Alzheimer's disease (AD), but the biological mechanism responsible for this finding remains an open question. Results of a recent ADRC study shed light on this question and another important question in AD research-how does the presence of the e4 variation or allele of the apolipoprotein (APOE) gene increase the risk for developing AD?

In the study led by Dr. Elaine Peskind, professor of psychiatry and behavioral sciences, researchers found the amount of cortisol depended upon the person's APOE genotype-which form of APOE the person carried. Individuals with the e4 allele had significantly higher levels of cortisol than those with the other forms.

"Because cortisol may be harmful to neurons, particularly those exposed to any noxious influence, this finding represents a potential mechanism by which APOE genotype influences AD risk," explains Peskind.

Peskind and her colleagues measured cortisol concentrations in samples of cerebrospinal fluid collected from 64 patients with AD and a control group of 34 healthy older adults. The researchers also determined the APOE genotype for each participant in the study.

Three alleles or forms of the APOE gene are present in the general population-e4, e3, and e2. Because an individual inherits one allele of a gene from each parent, an individual's genotype for that gene consists of two alleles.

Comparing APOE genotype with cortisol concentrations across patients with AD and controls, Peskind and her colleagues found that study participants with the e4/e4 genotype had the highest cortisol concentrations. Participants with the e3/e4 genotype had higher concentrations than those with the e3/e3 genotype and participants with the e2/e3 genotype had the lowest concentrations of cortisol.

The e4 allele of the APOE gene increases risk for developing AD although there may be other factors that alter AD risk, Peskind points out. "There are persons with the e4/e4 genotype (and especially the e3/e4 genotype) that never get AD. Conversely, most people who do get AD are e3/e3 because that is by far the most common APOE genotype. Obviously, something else modifies risk for AD even if you have an e4 allele," she says. "We are hypothesizing that the something else is your brain's exposure to cortisol. Excess amounts of cortisol may be harmful to neurons and lower the threshold for damage to neurons from any cause, including the degenerative changes that happen in AD."

In the complex chain of molecular events involved in the stress response, APOE limits production of cortisol at the adrenal gland. It is possible that APOE-e4 does not inhibit cortisol production as well as APOE-e3, Peskind explains. It may be that the APOE-e4 allele increases risk for AD is by allowing increased production of cortisol, which increases the brain's exposure to excess levels of cortisol.

The researchers found no correlation between cognitive function and cortisol concentrations in patients with AD, but they did find a trend among the control group. Higher concentrations of cortisol in cognitively normal older adults were related to lower scores on cognitive function tests. The significant worsening of cognitive function in patients with AD probably masks the relationship between cortisol concentrations and cognitive functioning found in cognitively normal older adults, says Peskind. "However, at any level of cognitive function, either in a cognitively normal person or a person with AD, lowering cortisol may improve cognitive function for that person," she notes.

To further investigate how the APOE genotype and cortisol levels are related to the development of AD, Peskind and her colleagues propose a long-range study over time focused on older adults who do not have dementia. Such research would seek to determine if individuals who have high cortisol levels are more at risk for developing AD than those with the same APOE genotype who have lower cortisol levels. "Cerebrospinal fluid cortisol can be influenced by a number of factors," says Peskind. "The most important one is probably aging. Cortisol increases with increasing age. Also there are medications that can either increase or decrease cortisol. Exposure to stress increases cortisol, but an individual's response to stress may be more important than overall exposure to stress. Some people tend to have a lower cortisol response to stress than others."

The investigation conducted by Peskind and her colleagues Drs. Charles Wilkinson, Eric Petrie, Murray Raskind and Gerard Schellenberg may one day lead to development of new interventions for AD. "Because we haven't understood the mechanism by which the APOE-e4 allele increases risk of AD, we haven't been able to come up with strategies to decrease the risk," says Peskind. "In fact, we don't suggest that people find out their APOE genotype because we haven't known how to decrease risk if a person has an e4 allele. If we can prove that the mechanism by which APOE-e4 increases risk of AD is by increasing brain exposure to cortisol, then we can lower cortisol with medications and perhaps decrease the risk for AD or slow its progression."

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