In 2007 Nobel laureate James Watson eyed his genome for the very first time. Through more than 50 years of scientific and technological advancement, Watson saw the chemical structure he once helped to unravel now pieced into a personal genetic landscape that lay before him.
There was one small stretch of DNA on chromosome 19, however, that he chose to leave under wraps. That region coded for the apolipoprotein E (APOE) gene. Since the early 1990s APOE has been a telling genetic marker of Alzheimer’s risk: certain forms of it correlate strongly with the development of the disease. Watson’s grandmother suffered from Alzheimer’s, but without any reasonable treatments or proved preventive strategies, the discoverer of the double helix decided the information was too volatile, its revelation creating more potential harm than good.
Watson’s apprehension is understandable. Treatments for Alzheimer’s have consistently failed. But as scientists learn more and more about the brain, they have come to realize that genetics alone rarely dictates the course of an illness. Instead brain disorders result from a complex interaction between our genes and the environments to which we are exposed. Indeed, a set of recent studies has just uncovered an important environmental instigator of neurodegenerative disease: stress.
Researchers have catalogued the effect of stress on numerous psychological conditions, including depression and chronic anxiety. The idea that stress may figure into neurodegenerative diseases, however, is relatively new. Although the notion that our high-pressure jobs and hectic lives might be doing additional damage could be worrisome, stress is at least something we can theoretically control. That is, trying to relax might be a first step toward raising the chances of keeping your brain free of disease in old age.
Tight Quarters
Since Alois Alzheimer first documented “presenile dementia” in a patient at the beginning of the 20th century, doctors have often observed that the disease runs in families. But not until the early 1990s, about the same time the APOE link surfaced, did researchers glean hints that nongenetic factors contribute to it.
Epidemiologist Brenda Plassman of Duke University and her colleagues teased out this environmental effect by studying identical twins, who share virtually the same genetic material. If a disease is driven purely by genetics, then when one twin develops it, the other will be stricken as well. By analyzing data from a large cohort of identical twins (all of them male veterans of World War II) collected by the National Academy of Sciences and the National Research Council, Plassman and her co-workers reported in 2000 that when one twin developed Alzheimer’s, the other twin developed the disease only 40 percent of the time. Concluding that factors besides genetics must be at play, the investigators have since been searching for those contributors. Among the possibilities: subtle medical conditions, occupational characteristics and physical activity levels.
Of course, your job and the amount you exercise both have an effect on your level of psychological stress, the mind and body’s response to challenge and change. But only this year did evidence suggest that stress might be a key ingredient in the recipe for cognitive decline. To explore how different environments might affect the development of Alzheimer’s, neuroscientist Mark H. Tuszynski of the University of California, San Diego, and his colleagues examined the brains of aged rhesus monkeys that had spent their early lives in either small or standard-size cages. Tight quarters have been shown to stress these animals, elevating levels of glucocorticoid hormones in their blood. The exact cause of this hormonal rise—whether it comes from a feeling of being trapped or an inability to get adequate exercise, or both—is still an open question.
Cortisol, a glucocorticoid hormone released when humans experience stress, influences the brain through specialized molecular receptors on neurons in a number of brain regions. When cortisol binds to its receptor, the interaction triggers molecular events that reduce communication at synapses, the junctions between neurons, which may ultimately cause the connections to wither away. Using protein stains that adhere specifically to synapses, enabling them to be seen, Tuszynski’s team determined the relative number of synapses in all the monkeys. Using a similar method, the researchers also assessed the amount of sticky amyloid plaques, a pathological hallmark of Alzheimer’s.
Compared with the monkeys raised in standard-size cages, those that lived in smaller cages had, on average, a significantly higher density of plaques and fewer synapses in one part of their brain—the same pattern seen in the brains of Alzheimer’s patients at autopsy. The finding suggests that the size of an animal’s cage—and perhaps the amount of stress it endures as a result—may shape that animal’s brain in a way that affects its vulnerability to certain types of degeneration as it ages. Interestingly, the amount of plaque riddling the brains of the monkeys housed in smaller cages varied a lot, indicating that stress affects individuals differently. After all, we all know people who seem to take even mildly negative events to heart as well as others in similar situations who take their plight in stride.
The evidence from Tuszynski’s group has its limitations. Observations in monkeys living in labs do not precisely mirror the human condition. In addition, these findings correlate only one aspect of early-life experience with pathological signs of degeneration. We do not know that the stress caused the changes, nor do we know whether those changes resulted in true cognitive slipups, because the scientists could not test the animals’ cognitive function.
Toxic Tension
Nevertheless, additional studies in rodents suggest that even intermittent strain can tip the scales toward dementia, even if it does not lead to cognitive breaks on its own. In March 2010 neuropharmacologist Karim Alkadhi of the University of Houston and his colleagues put rats at risk for dementia by injecting them with very low concentrations of beta-amyloid peptides, the molecules that form plaques in humans. The researchers then stressed some of the animals by placing an intruder rat in their home cage. As expected, blood levels of corticosterone, a glucocorticoid, rose in the stressed rats.
Then the scientists placed each rat in a water tank containing a maze. A rat had to find the path that led to a platform to escape the water—a rodent test of learning and memory. Usually after a few tries, a rat will remember the correct route; it will then swim directly to the platform, even a day or two later. Most of the experimental rats—including those that had been given amyloid injections and those forced to face intruders—performed well. The rats that had received both the shots and the unwanted visitor, however, had difficulty. So although stress alone does not degrade memory, it does seem to push at-risk animals over the edge, making them less able to learn and remember new things.
Other work hints that stress may hasten the onset of Parkinson’s disease, a neurodegenerative disorder characterized by motor difficulties rather than cognitive deficits. The loss of brain cells that produce dopamine, a neurotransmitter essential for voluntary movement, causes Parkinson’s patients to shake, become rigid and lose coordination.
To re-create these deficits in rats, behavioral neuroscientist Gerlinde A. S. Metz and her colleagues at the University of Lethbridge in Alberta infused a toxic drug into a brain area rich with dopamine neurons. Some of these animals were put into a Plexiglas tube for 20 minutes a day for two weeks, producing a temporary boost in stress hormone levels. Another group received corticosterone shots, which kept the animals’ stress hormones high throughout the experiment. Metz’s team then tested the motor skills of all the animals. In one exercise, for example, the rats had to slip their paws through a narrow opening in a Plexiglas box to extract a small food pellet, an action that requires precise and careful movements.
The Metz team’s toxic treatment is transient; usually the treated rats’ motor skills improve with time. But the animals with elevated corticosterone levels—both the ones that spent time in a stressful environment and those that received hormone shots—continued to struggle with the pellet extraction task long after the other animals had recovered. The results suggest that stress impedes the ability of dopamine cells to recover from insults, triggering or aggravating Parkinson’s symptoms.
Indelible Mark
Using such eye-opening studies as these, scientists are learning that stress is more than a fleeting emotional setback. Rather, in certain situations, stress can leave an indelible mark on our brain.
But there is good news, too. Stress is a contributor to neurodegeneration that can be controlled. Just as many individuals with high cholesterol levels now take preemptive action to stave off heart disease, one day people may use, say, their APOE status to motivate them to adjust their lifestyles. Evidence suggests that simple interventions such as exercise, meditation and getting enough sleep can help reduce the stress of life’s encounters. Such measures might even ease the anxiety of knowing which APOE stamp adorns your genome.
