We found in our community-dwelling cohort of cognitively high-functioning Chinese older adults that the presence of the APOE-ϵ4 allele was a significant factor modifying the association between depressive symptoms at baseline and the subsequent risk of cognitive decline. Among non–ϵ4-carriers, depressive symptoms were not associated with cognitive decline, but among ϵ4-carriers, depressive symptoms were associated with a significantly increased risk of cognitive decline, independent of other risk factors. Our findings of a significant interaction between APOE-ϵ4 status and depressive symptoms have not been reported by previous investigators and may explain the variations in findings from many previous studies of the relationship between depression and cognitive decline.
A number of published reports (12–23) have failed to show a significant association of depression with cognitive decline. We also found that when the modifying presence of APOE-ϵ4 was ignored, there was an overall lack of association between depressive symptoms and cognitive decline in the total sample.
Also, the presence of the APOE-ϵ4 allele is consistently shown to be a major genetic risk factor for dementia (39
), but reports of the associations of APOE-ϵ4 with global cognitive decline are also variable. Although some studies have shown greater cognitive declines in ϵ4-carriers (25
), others have observed a lack of association (27
). We also observed that overall there was no association between APOE-ϵ4 and cognitive decline in the whole sample (OR = 1.10, 95% CI: 0.86–1.41). It is possible that the effect of APOE-ϵ4 on cognitive function is manifested when it is present as a genetic susceptibility factor together with a modifiable risk factor such as depression (Gene × Environmental interaction).
Variations in findings across different studies may be explained by the selection characteristics of the study populations among other reasons such as sample size. Population studies with relatively high concentrations of participants with APOE-ϵ4 and depression may be more likely to show such a positive association in the whole sample, whereas studies that are selected with relatively low prevalence of APOE-ϵ4 and depression may show a lack of association without stratified analyses. This was also the case in this study; our cohort showed a low frequency of depressive symptoms as well as subjective memory complaints because of their baseline selection characteristics: Participants in the follow-up study had fewer depressive symptoms than nonparticipants, and they were cognitively well functioning. For these reasons, depressed and nondepressed participants showed little or no differences in gender, age, and vascular factors at baseline, but still showed significantly great differences in activities of daily living dependency and subjective memory complaint.
The biological mechanisms for the modulating effect of the APOE-ϵ4 genotype on cognitive decline are not fully understood. APOE is a polymorphic 299–amino acids protein, which has critical functions in redistributing lipids among central nervous cells cells, repairing injured neurons, maintaining synapto-dendritic connections, and scavenging toxins (40
). Although APOE-ϵ4 genotype is not a specific risk factor of cognitive decline, its presence may render individuals more vulnerable to a specific environmental risk factor. It has been postulated that APOE-ϵ4 allele carriers may have less effective neural protection and repair mechanisms (40
), which may subsequently make them less protected against the negative impacts of depression on cognitive decline.
So far, the precise underlying mechanisms of the association of depression with cognitive decline, the principal preclinical marker of dementia, remain poorly understood. A risk factor common to both depression and cognitive decline such as vascular diseases (41
) may mediate the relationship, but as shown in multivariate analyses in this and other studies (8
) did not completely explain the relationship. Short-term situational factors such as physical functional disability (43
) may also confound the relationship but were also controlled in our multivariate analyses.
A common underlying neurodegenerative process, such as white matter and subcortical abnormalities, may cause depression as well as cognitive decline in elderly participants (44
). However, there are some evidence to suggest that the association of depressive symptoms with clinical Alzheimer's disease and cognitive impairment appeared to be independent of cortical plaques and tangles (42
Depression may be an early manifestation or prodrome of dementia because of the loss of noradrenergic and cholinergic neurons associated with dementia in the locus coeruleus and substantia nigra (47
). In the present study, we excluded cognitively impaired participants at baseline (those with MMSE score ≤23), but this may not completely eliminate the possibility of an intrinsic relationship with incipient dementia. Finally, it is possible that depression in old age may be an independent risk factor of cognitive decline, operating via the “glucocorticoid cascade” pathway in the hypothalamic-pituitary-adrenal axis (48
), to increase cortisol level, ultimately leading to hippocampal atrophy.
The strengths of this prospective cohort study included an adequately large sample size and statistical adjustment for a wide range of potential confounders. A limitation is possible attrition bias. We observed that those who remained in the study had better baseline cognitive function and were less depressed; hence, our findings were likely to be biased toward underestimating the negative association of depression and cognitive decline. Cognitive decline was based on changes in global cognitive function measured by the MMSE; hence, our findings did not pinpoint declines in specific cognitive domains, nor did they amount to a diagnostic determination of dementia. Also, we used the GDS to determine the presence of depressive symptoms, not clinical depression. Although self-report of somatic conditions have been shown to have good validity (49
), differential self-reporting of somatic conditions by depression (possible overreporting) and cognitive status (possible underreporting) may potentially bias the results in unknown ways. As the principal finding was based on subgroup analysis of a small number of APOE carriers with depression (n
= 32), this finding should be replicated in future studies in a different population.
In conclusion, the risk of cognitive decline associated with depressive symptoms was significantly enhanced among APOE-ϵ4 carriers. This may have implications for identifying depressed individuals with higher risk of cognitive decline, who could be selected for more targeted treatment.