The APOE ε4 allele and depression are each independent risk factors for cognitive decline (CD); however, there has been little research to date examining whether depressive symptoms moderate the relationship between APOE ε4 and CD. The purpose of the current study, therefore, was to determine whether depressive symptoms had a greater influence on CD among participants with the ε4 allele than those without the allele.
Using prospective linear regression analyses based on data from a large sample of community-dwelling older adults, we found depressive symptoms and the APOE ε4 allele to each separately predict CD over a 6 year period. Importantly, and consistent with our prediction, depressive symptoms moderated the association between the APOE ε4 allele and CD such that the influence of depressive symptoms was greater for individuals with the APOE ε4 allele compared to those without the allele.
Important for explaining the association between depressive symptoms and CD, several studies have shown a history of depressive symptoms to be associated with neuropathological changes in the brain that may impact cognition. In particular, depression has been shown to affect the hippocampus, a brain region which plays a pivotal role in memory formation [34
]. The hippocampus is thought to be affected through a depression-initiated glucocorticoid cascade associated with the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In support of this theory, Sheline and colleagues found a significant correlation between total lifetime duration of depression and hippocampal volume loss [35
]. Sheline and colleagues also demonstrated that middle-aged and older individuals with a history of recurrent major depression had smaller hippocampal gray matter volumes than a group of pair-wise matched normal controls [36
]. Additionally, some studies have found depression to have greater influence on the neurological functioning of individuals with AD compared to those without AD. For example, one study found that patients with AD and a lifetime history of depression showed both more rapid CD and higher levels of amyloid-beta (Aβ) plaque and tangle formation within the hippocampus than patients with AD but without a history of depression [37
]. Rapp and colleagues also found that persons with AD and comorbid depression had more advanced stages of neurofibrillary tangles than patients with AD without comorbid depression [38
Although the mechanisms through which APOE affects cognitive functioning are not entirely understood [39
], the APOE ε4 allele has also been shown to predict structural abnormalities in the brain. It has also been suggested that the APOE gene may be involved in stimulating Aβ deposition as well as in enhancing its production [39
]. For example, the APOE ε4 allele is associated with higher stages of both intraneuronal neurofibrillary changes and extraneuronal Aβ deposition [11
], as well as greater hippocampal volume loss [40
Although both APOE ε4 and depressive symptoms are implicated in pathological abnormalities within the brain, few previous studies have examined the combined effect of depressive symptoms and APOE ε4 in increasing risk for CD. This interaction may be best explained within the context of a cognitive reserve model. Specifically, the brain attempts to respond to brain insults by using neural networks that are less susceptible to disruption [41
]. When negative factors act on the brain, the brain may actively compensate for pathology through the use of other routes that have not been affected by this disruption. However, if the brain is damaged by multiple factors, it may be increasingly difficult to recruit alternative neurological networks because there are fewer unaffected routes from which to choose.
The influence of depression on individuals who already have neurological damage is likely to be one of the contributing causes to individual differences in cognitive reserve, or one's capacity to cope with advancing brain pathological abnormalities. Moreover, genetic factors (e.g., APOE ε4) may interact with other factors (such as depression) to produce even greater variations in cognitive functioning. Thus, the synergistic interaction observed between depressive symptoms and the APOE ε4 allele may be a result of the inability of the brain to compensate for this combined assault.
In evaluating this study, several limitations should be considered. First, although we found depressive symptoms to moderate the association between APOE genotype and CD, even after controlling for several known risk factors for CD, other potential third variables may have been operating and may account for this relationship. These variables may be genetic, environmental, or both.
Second, this study used single-item self report measures of health problems. Self report measures have demonstrated good reliability, validity, and agreement with physician's diagnoses [42
]. Nonetheless health assessments were dependent on the participants' ability to accurately recall medical diagnoses and also on their seeking health care. Therefore, some health problems may have been underreported, and the relationships between APOE ε4, depressive symptoms, and cognitive decline may be explained, in part, by unmeasured health problems.
Third, the present study assessed cognitive functioning using the SPMSQ, a brief, ten-point measure of global cognition. Although the SPMSQ has been shown to have good reliability and validity [31
], it is a broad, overall measure of cognitive functioning and is less sensitive to subtle changes in cognitive functioning. This may have obscured the associations among depressive symptoms, genotype and CD.
Fourth, it should be noted that we only included participants' current depressive symptoms in the analysis. Thus, although we used Time-1 depressive symptoms to predict Time-2 cognitive functioning, our measure of depression did not assess participants' past history of depression. Indeed, chronic or prolonged depressive symptoms appear to have a greater impact on cognition than more transient symptoms of depression [43
]. Our measure of depressive symptoms at Time-1 may be conceptualized as a proxy variable for a history of depression However, this is less precise than a measure of lifetime clinical depression, and it introduces two important confounds. Our analyses failed to take into account participants' history of depression if they had no depressive symptoms at Time-1. Second, depressive symptoms assessed at Time-1 may have been symptomatic of prodromal signs of dementia that were not yet observable on our measure of cognitive functioning. Thus, this possible prodromal sign of dementia may have increased, or even caused, the apparent relationship between depressive symptoms and CD.
Finally, it should be noted that our study had significant missing data due to participants' deaths, refusal of genotyping, and severe cognitive dysfunction interfering with their reports. Moreover, this missing data was not random. Participants with missing data were found to have higher levels of depressive symptoms and cognitive errors at Wave 1. Thus, missing data may have attenuated the gene-depression interaction found in the current study. However, we performed additional analyses to address this issue. In these analyses we assumed all participants with missing data to be carriers of the APOE ε4 allele. Results from these analyses were consistent with our original results (i.e., main effects of depressive symptoms, main effects of APOE genotype, and a significant interaction of depressive symptoms and APOE genotype). Nonetheless, given the large number of participants with missing data, the study's findings may not generalize to the population as a whole.
In sum, our findings suggest that the influence of depressive symptoms on CD is greater among participants with the APOE ε4 allele than those without the allele. Future research should investigate the mechanisms by which both depression and APOE together affect the internal structure of the brain and contribute to CD. Moreover, although the genetic vulnerability for CD cannot be modified, treatment for depression may help reduce the risk for subsequent CD or slow its progression. Given the availability of efficacious pharmacological and psychological treatments for depression as well as the recent interest and promising nature of depression prevention research in old age [44
], future research should explore the impact of interventions for depression on CD.