Elderly individuals with High stress due to the impact of recent “real life” events and difficulties had worse memory performance than those with Low stress. This finding is consistent with the results of studies assessing memory in humans exposed to stress in laboratory settings (6
) and extends the results to more naturalistic causes of stress. In addition, elderly individuals with at least one APOE-ε4 allele performed worse than those without an ε4 allele on several memory measures, consistent with a number of previous studies (13
). A novel finding from the present study is that stress level and APOE genotype have an interactive effect in that High stress has a detrimental effect on certain aspects of memory performance only in APOE-ε4 positive elderly subjects. This interaction effect was observed in performance on the immediate and delayed conditions of the WMS-R Logical Memory Test and in the number of false positive errors produced on the delayed recognition trial of the CVLT, and is consistent with a model in which chronic stress in the presence of at least one ε4 allele can affect memory in the elderly over and above the effects of either factor alone.
A number of investigators have attempted to explain the mechanism by which memory loss occurs under specific conditions of age, stress level, and APOE status. The authors of a series of animal studies (25
) have postulated that the effects of stress are mediated by glucocorticoids and depend on the presence of APOE. The effects of APOE may alter susceptibility to environmental factors such as stress, or the threshold at which stress can result in damage to neurons may differ according to which APOE isoforms are present.
Observations concerning cortisol level included a stress by APOE genotype interaction effect on the measure taken 30 minutes after awakening. Although the higher cortisol level in the High ε4-neg group was consistent with our expectations, other cortisol findings were not. For example, for three of the five cortisol measures, the mean level for the Low, ε4-neg group was numerically higher than those for the Low, ε4-pos and High, ε4-neg groups (although these differences were not statistically significant). In fact, in one case (bedtime sample), the level for the Low, ε4-neg group was the highest of the four groups.
The failure to find significant correlations between cortisol level and measures 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. While there may be factors that affect these relationships (e.g., mood, level of activity, medical illness) (29
), there also may be other ways of interpreting the results. It is possible that Low, ε4-pos subjects in general have lower cortisol levels than the ε4-neg subjects, and that elevations in their cortisol levels occur only when these ε4-pos subjects are exposed to significant stress. There is also support for the possibility that the effects of elevated cortisol are apparent only after these levels are significantly elevated over a prolonged period of time (5
). Clearly, further study of how cortisol is involved in the relationship between stress and cognition, particularly memory, is needed to understand our observations.
As treatments for AD have become available, there have been numerous attempts to identify individuals with cognitive decline prior to a clinical diagnosis of dementia in order to intervene before symptoms progress. The most common approach has been the identification of individuals with MCI (48
), a state in which the person has objective evidence of cognitive decline but does not meet criteria for dementia. More recently, however, the emphasis is shifting to the identification of groups vulnerable to AD prior to symptom onset. For example, our findings suggest that an older individual carrying an ε4 allele and experiencing significant stress is more vulnerable to cognitive impairment than subjects without an ε4 allele or without recent stressful events. Because APOE-ε4 status and level of event- and difficulty-based stress can be assessed at any point in time, this approach could have the advantage of earlier identification of cognitive vulnerability in the elderly. Whether this decline represents the earliest stages of AD or some other progressive neurodegenerative disorder awaits the results of longitudinal studies.
Several limitations in the present study should be noted. First, the results involved multiple statistical comparisons running the risk of an increase in Type I errors. If we had taken a more conservative approach and only considered a p-value of .025 as significant, a number of significant findings concerning memory would have remained. Caution, however, should be used in the interpretation of the results. A second limitation concerned the generalizability of the results, since subjects were primarily Caucasian with relatively high levels of education. Future studies with a more diverse subject sample could ensure that the present results are not specific to a particular group or a particular set of stressors. Finally, we did not take into account coping strategies that could influence responses to stress. However, we defined the type of stress we were measuring and assessed potential relationships with depression and anxiety, factors that might accompany stressful experiences. Although the High stress group reported more trait anxiety than the Low stress group, the level for both groups was within normal limits. The High and Low stress groups did not differ in their report of symptoms of depression. The results suggest that High stress is relatively independent of depression but may evoke a mild level of persisting anxiety. Future studies to determine if coping strategies can modify the impact of stress on cognition in individuals with the APOE-ε4 allele are warranted.
Since a portion of our sample was comprised of individuals with a diagnosis of MCI, the question arises as to whether the neuropsychological results attributable to the effects of stress and genotype may be a function of existing AD pathological changes in the MCI participants. Based on data presented by Morris and Price (49
), it is likely that these individuals do have some degree of pathology associated with AD. Since the stress /genotype groups are reasonably matched on number of MCI participants, however, it is unlikely that AD pathology in the MCI subjects accounts for the results.
In summary, our study supports the notion that stress level alone can affect memory, as can possession of at least one APOE-ε4 allele. The results also provide evidence that cognitive functioning in older, non-demented individuals who possess at least one APOE-ε4 allele is more vulnerable to the negative effects of stress than those without an ε4 allele. Inexpensive, readily available strategies to reduce harmful responses to stressful experiences may prevent or slow progression of cognitive changes in genetically vulnerable, older individuals. Longitudinal data are needed to address the question of whether stress level and APOE status taken together are good predictors of cognitive decline and conversion to a clinical diagnosis of dementia.