See other stress stories 1 and 2.

Feeling stressed? If unchecked, the pressures of modern life may increase the chance of developing Alzheimer disease down the road. A report in the June 12 Neurology suggests that elderly people most prone to chronic psychological distress are more likely to develop mild cognitive impairment (MCI), often a forerunner of AD. “This is another demonstration that negative emotions, particularly chronic negative emotions, are bad for our health, and that we should be particularly attentive to negative emotions in old age,” said Robert Wilson, Rush University Medical Center, Chicago, Illinois, senior author on the study. In other stress-related news, Guerry Peavy and colleagues at the University of California, San Diego, reported in the June 4 Biological Psychiatry online that people carrying the ApoE4 allele may be particularly susceptible to the stress-related cognitive decline. The ApoE4 allele is a major risk factor for late-onset AD.

The Neurology paper comes hot on the heels of two papers last week describing how physical and/or psychological stress can lead to elevated amyloid-β. Our companion stories described how trauma-induced apoptosis elevates BACE activity in cell and animal models of trauma, leading to increases in Aβ (see ARF related news story), and how psychological stress can also increase Aβ through enhanced neuronal activity (see ARF related news story). This latest report helps decipher the relationship between stress and AD in people.

Wilson and colleagues previously reported that “distress proneness,” in other words, a greater likelihood to experience negative emotions such as depression and anxiety, is associated with AD. Curiously, they found that this trait does not appear to be related to the rate of progression of the disease, merely its incidence (see Wilson et al., 2004), suggesting that stress may primarily affect disease onset. This would imply that people who are prone to distress might be more likely to develop MCI. To test this, Wilson and colleagues followed subjects taking part in two ongoing longitudinal studies of aging, the Religious Orders Study and the Rush Memory and Aging Project.

The researchers report that out of a total of 1,256 people eligible for analysis (mean age 76.8 years), 482 developed MCI over a 12-year period. Because people were tested annually for distress proneness, the researchers were able to determine, after adjusting for age, sex, and education level, that a person in the ninetieth percentile for chronic stress was about 40 percent more likely to get MCI over that period than someone in the tenth percentile. The researchers calculated that on a distress scale ranging from 0 to 44, an increase of one point equated to a 2 percent increase in relative risk for MCI. (The scale is based on six of 12 items in the neuroticism scale of the NEO Five-Factor Inventory, which measures response to statements such as, I feel inferior to others, or, I feel tense and jittery). The relative risk per point increase was higher in men. The ApoE4 allele as a strong risk factor for late-onset AD has been linked to elevated cortisol, which may cause neuronal atrophy in the brain. For this reason, the researchers reanalyzed their data for subjects carrying at least one ApoE4 allele, but found no indication that the ApoE4 allele contributed to distress.

Likewise, Peavy and colleagues did not find a main effect between stress and ApoE4 status, but they did find a relationship among stress, ApoE4, and age. In their study of 91 non-demented subjects (mean age 78.8 years), they found that those classified as having high stress were significantly younger if they also tested positive for one or more ApoE4 alleles. They also found that both stress and ApoE status affected memory. In immediate and delayed recall tests, highly stressed subjects performed worse than their unstressed fellow subjects, and this difference was amplified if subjects were ApoE4-positive. Whether this is related to elevated cortisol levels is unclear. The authors did find that in the high-stress group, salivary cortisol measured 30 minutes after awakening was significantly higher in ApoE4 carriers. However, there were no significant differences in cortisol measured at other times. The researchers found no relationship between cortisol levels and memory. “The failure to find significant correlations between cortisol level and measure of memory dampens support for the idea that the effects of stress on memory are the result of the influence of cortisol on the hippocampus,” write the authors. They emphasize that there may be other factors to consider, such as the length of time that cortisol is elevated.

A key question in these types of studies is whether stress or proneness to distress is a risk factor for, or a sign of cognitive decline. Wilson and colleagues acknowledge that the latter is possible but favor the idea that chronic distress is a risk factor because distress does not seem to increase in old age, even in AD. “In our hands, we have not found an association between this measure of chronic distress and plaques and tangles, for instance,” said Wilson, though he emphasized that that does not mean there is no such relationship. Instead, the researchers favor the idea that chronic distress affects the limbic system, including the hippocampus and parts of the brain that regulate stress-related behavior and memory systems. Indeed, when looking for associations between chronic distress and cognitive decline, the researchers found stress was related to loss of episodic memory, which is highly dependent on the hippocampus, but not to decline in other forms of cognition. “We think that the people who are high in this [distress proneness] trait have experienced a much higher cumulative level of negative emotion over their lifetime than a person low in the trait,” said Wilson.

Anecdotally, centenarians often talk about their philosophical outlook on life’s trials and tribulations when asked why they lived so long. This is not to suggest that everyone can stay healthy by adopting a positive attitude to stressful events. To be sure, the risk for AD depends on many things and cannot be simply willed away with a “don’t-worry-be-happy” attitude to life. That said, there is some longitudinal evidence that it is possible to lower one’s chronic stress. Psychotherapy, or possibly antidepressants, and regular exercise might modify it slightly, suggested Wilson. “To me, the exciting part of this research is not that we are necessarily going to be able to, from a public health standpoint, modify the levels of [distress proneness] in a large group of people, but that animal research suggests that the adverse effects of this trait, or of high levels of stress on individuals, may be modifiable,” he said.—Tom Fagan


  1. It is very important and interesting to read Wilson and his colleagues' research on whether stress or proneness to distress is a risk factor for, or a sign of, cognitive decline. They acknowledged that the latter is possible, but favor the idea that chronic distress is a risk factor because distress does not seem to increase in old age, even in Alzheimer's disease.

    In more detail, Wilson et al. (2007) found that people who scored high on a test of chronic mental distress were over 40 percent more likely to develop mild cognitive impairment than those who were the most laid back. In a simple proportional hazards model analysis of the prospective data from two large studies of aging and the brain, the risk of developing mild cognitive impairment over a 12-year follow-up increased by over 2 percent for every one-point increase on a measure of chronic distress. The findings come from 1,256 volunteers with a mean age of 76.8 years. The hazard ratio was 1.02, with a 95 percent confidence interval from 1.01 to 1.04. Nevertheless, depressive symptoms were associated with increased risk, but the association became non-significant when the researchers controlled for distress score.

    It is also important to recognize that depression, although known to predict cognitive impairment and dementia, appeared in the study as well as a few other recent studies (e.g., Caracciolol et al. 2011; Geda et al. 2006) to be merely a "proxy for the enduring tendency to experience negative emotions."

    Geda et al. (2006) suggested that mild cognitive impairment, which is considered a transitional step to dementia, implies mild memory or cognitive decline, but no significant disability. Recent research such as the findings of Geda et al. and Wlison et al. (2007) suggest that over a lifetime, chronic stress affects the area of the brain that governs stress response and, unfortunately, that part of the brain also regulates memory.

    As suggested by Caracciolo et al. (2011), people are considered to differ in the way they tend to deal with negative emotions and psychological distress, and such coping means or styles tend to remain relatively unchanged throughout their later life. That is possibly why chronic distress may be a risk factor for cognitive or emotional problems in older age.

    Moreover, another unexpected, interesting finding of recent research like the study by Wilson et al. is that the association of distress with risk of impairment was higher in men than in women, although the two genders do not differ in the likelihood of experiencing distress. Future research to understand this gender difference on the association between chronic distress and risk of cognitive impairment is recommended.


    . The symptom of low mood in the prodromal stage of mild cognitive impairment and dementia: a cohort study of a community dwelling elderly population. J Neurol Neurosurg Psychiatry. 2011 Jul;82(7):788-93. PubMed.

    . Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study. Arch Neurol. 2006 Mar;63(3):435-40. PubMed.

    . Chronic distress and incidence of mild cognitive impairment. Neurology. 2007 Jun 12;68(24):2085-92. PubMed.

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News Citations

  1. Stress and Aβ—A Fluid Connection in Mice
  2. Stress and Aβ—The Apoptosis Connection

Paper Citations

  1. . Premorbid proneness to distress and episodic memory impairment in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Feb;75(2):191-5. PubMed.

Further Reading

Primary Papers

  1. . Chronic distress and incidence of mild cognitive impairment. Neurology. 2007 Jun 12;68(24):2085-92. PubMed.
  2. . The effects of prolonged stress and APOE genotype on memory and cortisol in older adults. Biol Psychiatry. 2007 Sep 1;62(5):472-8. PubMed.