The stresses of everyday life may start taking a toll on the brain in relatively early middle age, new research shows. The study of more than 2,000 people, most of them in their 40s, found those with the highest levels of the stress-related hormone cortisol performed worse on tests of memory, organization, visual perception and attention.

Higher cortisol levels, measured in subjects’ blood, were also found to be associated with physical changes in the brain that are often seen as precursors to Alzheimer’s disease and other forms of dementia, according to the study published in October in Neurology.

The link between high cortisol levels and low performance was particularly strong for women, the study found. But it remains unclear whether women in midlife are under more stress than men or simply more likely to have their stress manifested in higher cortisol levels, says lead researcher Sudha Seshadri. A professor of neurology, she splits her time between Boston University and The University of Texas Health Science Center at San Antonio, where she is the founding director of the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases.

Working on the study “made me more stressed about not being less stressed,” Seshadri says, laughing. But, she adds, the bottom line is serious: “An important message to myself and others is that when challenges come our way, getting frustrated is very counterproductive—not just to achieving our aims but perhaps to our capacity to be productive.”

The study is the largest of its kind to look at these factors and tightens the link between cortisol, midlife stress and brain changes, says Pierre Fayad, medical director of the Nebraska Stroke Center at the University of Nebraska Medical Center, who was not involved in the new research. “It confirms some of the previous suspicions,” he says. “Because of its quality, it gives a lot more credibility.”

Bruce McEwen, a neuroscientist and cortisol expert at The Rockefeller University who also was not part of the study, says he found it “frankly remarkable.” Cortisol, he notes, is necessary for life—so it is obviously not all bad. But stress can lead people to potentially problematic behaviors such as smoking, drinking and eating unhealthy food. “Cortisol is itself the tip of the iceberg of things that are going on in a person’s life and a person’s body,” he says.

The new research included volunteers from the Framingham Heart Study, a 70-year-old study of residents from a Boston suburb. Researchers are now studying the grandchildren of the original participants, most of whom were white, middle class and suburban, Seshadri says. Although the scientists did not ask participants what kinds of specific stresses they were under on the day their blood was drawn, she says the volunteers were able to come in for a three-to-four-hour examination—so “you would say they were at a reasonably stable point in their life.”

Yet even these relatively young and apparently well-off people showed signs of brain changes, both in brain scans and in their performance. “This is the range of stress that a group of average Americans would experience,” Seshadri says. The highest cortisol levels were associated with changes that could be seen on an MRI scan of the brain, the study found.

Cortisol does not distinguish between physical and mental stress, so some of the people with high levels might have had physical illnesses such as diabetes that drove up their cortisol levels, Seshadri says. It is also possible levels of the hormone might spike in people’s blood if they are already undergoing brain changes—that is, the elevated cortisol could be the result of the changes rather than their cause—she says. But she thinks this is unlikely because the trial participants were so young. Each subject’s cortisol level was measured only once (in the morning), so the measurements do not reflect changes over time or variations throughout the day, she notes.

The volunteers were given tasks such as copying a shape they were shown, or being asked to repeat a story they had been told 20 minutes earlier. The differences in performance were subtle, Seshadri says. She could not immediately tell whether subjects had higher or lower cortisol levels based on how well they carried out the tasks. “It was more that in terms of group averages there was a real difference,” she explains.

Earlier research has shown weaker-than-average performances on tests like these are associated with a higher risk of dementia decades later, and Seshadri says high stress levels in midlife might be one of many factors that contribute to dementia. Understanding that link might offer a potential opportunity to reduce risk—but she cautions research has not yet shown conclusively that lowering cortisol levels will reduce the risk of Alzheimer’s.

Other research has shown cortisol levels can be reduced with adequate sleep, exercise, socializing and relaxing mental activities such as meditation. “There are a number of intriguing, fairly simple things that have been shown to change these levels,” Seshadri says. “But whether they will in turn translate into better preservation of the brain is something that can only be determined in a clinical trial.”

Rockefeller University’s McEwen says other research suggests it is never too late to adopt a healthier lifestyle by taking steps like reducing stress, exercising regularly, eating a healthy diet, getting enough good-quality sleep and finding meaning in one’s life. “The life course is a one-way street,” he says. But “the brain does have the capacity for repairing.”