In this issue of the Journal, Lee and colleagues (1) address relationships among genetic status (i.e., the gene for apolipoprotein E, APOE), response to stress (i.e., salivary cortisol), and cognitive functioning in a large cohort (N=962) of community-dwelling adults ranging in age from 50 to 70 years (mean=61.1). Given findings from recent studies showing relationships between stress and memory decline in older adults, investigations targeting these variables have the potential to add significantly to our understanding of factors that contribute not only to the cognitive changes associated with normal aging, but also to the more severe changes of degenerative illnesses such as Alzheimer’s disease. As a result, pharmacological and behavioral means of avoiding or minimizing harmful responses to stress become increasingly possible.

In a cross-sectional study, Lee et al. found that higher levels of salivary cortisol in their sample of older adults were associated with worse cognitive performance and that the slopes of the cortisol/cognition plots were steeper (i.e., had greater declines) when the participants had at least one APOE ε4 allele. Our laboratory (2) also addressed the interactive effects of stress and APOE status on cognition. We found a significant interaction driven primarily by worse memory performance in participants with the combination of high chronic stress and at least one ε4 allele. We also measured cortisol, but unlike Lee and associates, who organized cortisol sampling around a potentially stressful event (i.e., cognitive battery), we measured salivary cortisol from samples taken at home by participants at five designated times within 1 day. When analyzed to address a cortisol-by-APOE interaction similar to that reported by Lee et al. (not reported in our paper), our data consistently showed lower scores on a number of memory tasks for the group with high cortisol and at least one APOE ε4 allele when compared to groups with low cortisol and/or no ε4 allele. Although these interaction effects showed only trends toward significance, the findings are largely consistent with those from the study by Lee et al.

The results of our study and those of Lee and colleagues offer fairly robust evidence of an effect of APOE status on the relationship between stress and cognitive functioning despite a number of differences in study design. Our subjects were older (mean age=78.8 years, range=65—97), and our primary measure of stress was based on relatively recent life events, difficulties using a semistructured interview, and a detailed rating system to identify level of chronic stress (high, low), the Life Events and Difficulties Schedule (3). So, unlike Lee et al., we emphasized stress chronicity based on events and difficulties and assessed the effect of its interaction with APOE ε4 status on individual tests of memory rather than summary scores calculated for multiple neuropsychological domains. Other differences of note were in sample size and participant selection. The community sample in the Lee et al. study was much larger than the sample of convenience in our study and as a result, allowed for analyses that revealed an even greater effect of the stress-by-APOE interaction for individuals homozygous for APOE ε4 compared to those with only one ε4 allele. Despite differences between these studies, the results provide strong support for the notion that APOE-ε4 status significantly influences the relationship between stress and cognitive functioning in older adults.

A third study (4) divided participants into groups according to APOE ε4 status and found that correlations between serum cortisol levels (in response to cognitive testing) and memory performance were not significant for either group. These authors noted that under circumstances of more powerful, more sustained stressors, possession of an APOE ε4 allele could elevate cortisol levels and result in a stronger association between cortisol and memory performance.

The studies described here illustrate some of the problems comparing results due to differences in design and methodology. The duration of the study (e.g., cross-sectional versus longitudinal), nature of the cognitive screen at baseline (e.g., no screen versus diagnostic characterization), mean age and age range of participants, and instrument used to measure contemporary life events (e.g., checklist versus in-depth evaluation) are some of the factors that can significantly influence results. In addition, findings from studies targeting the cortisol response to stress may be influenced by the type, timing, and statistical handling of cortisol measures, as well as the variability of these measures due to factors such as diurnal rhythm, individual differences in basal levels and reactivity, and patient compliance with at-home sampling procedures (5). Fiocco and colleagues (4) emphasized the commonly found variability of cortisol secretion and identified random fluctuations in cortisol level that occurred over the duration of their study.

At this point, the mechanism by which APOE status affects the association between stress and cognition is poorly understood. On the basis of a series of animal studies, a group of investigators (6, 7) postulated that the effects of APOE alter susceptibility to environmental factors such as stress or that the threshold at which stress results in damage to neurons differs according to which APOE isoforms are present. Research concerning the mechanisms by which chronic stress influences pathological aging and cognitive decline is important for determining interventions, either pharmacological or behavioral. The growing evidence of significant relationships between chronic stress and cognitive changes may be particularly important in the study of Alzheimer’s disease. Recent animal studies have shown associations between chronic stress and neuropathological changes associated with Alzheimer’s disease, including synapse loss, increases in amyloid-β peptide, and tau accumulation and phosphorylation (8—10). Clearly, there are many factors that lead to the pathology and symptoms of Alzheimer’s disease, including environmental and genetic factors. Both Lee et al. and our group emphasize the importance of investigating interaction effects in order to target the individuals who are most vulnerable to the effects of chronic stress by virtue of risk factors that when combined, are more harmful than the expected additive effect of each factor alone.

We raise the question of how best to apply our current knowledge concerning stress and cognitive decline. We do not have a clear enough understanding of the relationship between HPA axis responses to stress and cognitive decline in older adults to advise screening for lone biomarkers (e.g., cortisol). However, a reasonable direction would be to assess the level of stress by using measures associated with cognitive decline (e.g., cortisol, in-depth measures of life events) in individuals with known risk factors for dementia (e.g., age, APOE ε4 status). The development of measures to assess individual differences in reactivity to stress could also prove useful. It is likely that interventions targeting the effects of chronic stress would work best in older adults before symptoms of Alzheimer’s disease pathology are detectable. Interventions, particularly behavioral (e.g., meditation, cognitive reframing, routine exercise), could provide affordable means of changing or reducing harmful responses to stress. There is evidence that damage to brain structures caused by stress is reversible (11). However, since there may be a point after which regeneration of neurons or their synaptic connections in response to waning stress is no longer a possibility, longitudinal studies that employ valid, reliable measures of chronic stress and that are designed to trace pathways from the experience of stress to cognitive decline are of critical importance.