The purpose of this study was to investigate the relation of a history of depression to risk for subsequent development of AD. Results of this meta-analysis show that persons with a history of depression were more likely to be diagnosed as having AD later in life. This finding was robust across analyses stratified by study type, retrospective vs prospective data collection, and strictness of diagnostic criteria used for AD and depression. The ORs were still significantly greater than 1 when adjusted in separate metaregression analyses for case-control and cohort studies for 8 quality indicators from the Newcastle-Ottawa Scale. The ORs were also significantly greater than 1 in metaregression analyses that controlled for the interval between the diagnoses of depression and AD.
Influence analysis showed no substantial difference in pooled ORs when any single study was excluded. This was important because 1 cohort study18
contributed more than 65 000 individuals to the total sample of more than 100 000. Although heterogeneity was found across studies, all but 1 study examined found an increased (although sometimes nonsignificant) risk for AD in persons with a history of depression. Although significant heterogeneity was observed in effect sizes, it should be noted that 19 of the 20 studies used in these analyses yielded a positive relation of history of depression to risk for developing AD. Previous reports of negative findings may thus be attributable to failure to find statistical significance rather than reduced or no change in risk for AD in individuals with a history of depression.
A secondary purpose of this study was to evaluate whether observed risk for developing AD was related to the interval between diagnoses of depression and AD. This interval was positively and significantly related to the odds of developing AD in a metaregression analysis. This finding is consistent with the interpretation that occurrence of depression is a risk factor for AD rather than a prodrome of the disease, and it is also consistent with the results of 1 large study that specifically examined the issue.9
Given the small number of studies included in the metaregression, however, this interpretation must be tentative, but it further strengthens the observation that depression is a distinct risk factor for AD. It should be recognized as well, however, that these findings do not rule out the possibility that depression is both a remote risk factor for AD and a proximal prodromal feature of it.57
Limitations of this study should be acknowledged. These data relate only the occurrence of at least 1 episode of diagnosable depression to later risk for AD and neglect the fact that both depression and AD are heterogeneous entities that may reflect multiple underlying pathologies.58
Several studies used data on hospitalizations due to depression as an indicator of clinical depression whereas others recruited nonpatients and then examined them for depression on the basis of current symptoms. Groups of persons who were so severely depressed as to require hospitalization may not be equivalent to outpatients whose depression was discovered during study evaluations. Data used in the meta-analysis do not distinguish among the risk for AD in persons who may have had 1 episode of depression and recovered compared with those who have had multiple episodes or who may have had chronic minor depression. In this connection, 1 study59
found that risk for dementia increased with multiple episodes of depression. By choosing to include studies that allowed us to calculate crude ORs, we excluded studies that provided estimates of the relation between depression and AD risk in the form of adjusted ORs or on the basis of continuous measures. Exclusion of these studies may have biased our results.
These data do not provide information about why depression and AD may be linked. There is increasing awareness of the possible role of vascular disease in the expression of the clinical symptoms of AD, and it has been reported that AD and depression may share risk factors for vascular disease.60,61
One possible link may be long-term occurrence of inflammatory processes that may underlie depression and AD.62
Several proinflammatory cytokines (eg, tumor necrosis factor a) have been linked to both vascular disease and depression,63–65
and the same cytokines may have direct effects on cognitive status.66
Possible genetic links between the 2 disorders have also been explored, most notably between apolipoprotein E ε4 and the disorders, because the ε4 allele is an established risk factor for AD. 67
Research on the co-occurrence of apolipoprotein E in depression and AD has been inconclusive, with at least 1 study68
finding a cross-sectional relation between the ε4 genotype and depressive symptoms whereas other studies48,69
have not found a relation. Other authors61,70,71
have speculated on potential mechanisms for the link between mood disorder and AD. The findings of this meta-analysis and meta-regression thus may have implications for those investigating the biochemical etiology of AD.
The clinical significance of the findings of the meta-analysis and metaregression should also be recognized. From one perspective, the absolute risk for AD conferred by a history of depression is small so that the importance of having a history of depression should not be overly emphasized in work with patients. On the other hand, however, depression may be viewed as a modifiable risk factor for AD if, in fact, depression is part of the same disease process that produces clinical AD, and its treatment will affect cognitive outcome. This possibility is intriguing in light of evidence that antidepressants can modify levels of inflammatory cytokines,72
but the possibility that treatment with antidepressants might reduce the risk for AD remains speculative without additional studies.
This meta-analysis and metaregression thus help clarify the relation between a history of depression and the subsequent risk of developing AD by drawing together data from numerous sources and exploring several possible reasons for the observed heterogeneity among studies. Results were found to be robust in several analyses stratified on study characteristics and in meta-analyses that controlled for study quality and explored the relation of the interval between the two diagnoses on risk for AD. These findings thus underscore the possible relation between the two disorders and the importance of continued research on the common and disparate factors in the etiology of depression and AD.