In this study of more than 13,000 long-term Kaiser members, depressive symptoms in either mid-life or late-life were associated with an increased risk of developing dementia. In addition, the risk of AD was approximately doubled in individuals with depressive symptoms in late-life (either alone or in combination with mid-life symptoms) while the risk of VaD was more than tripled in those with both mid-life and late-life depressive symptoms. These findings have important public health implications because they raise hope that adequate treatment of depression in mid-life may reduce dementia risk in late-life.
Our findings are consistent with a large body of literature suggesting that depression in late-life is associated with an increased risk of developing cognitive impairment, dementia and AD.9–16
They also are consistent with a small number of prior studies suggesting that depression earlier in life also is associated with an increased risk of dementia. An early case-control study found that depression was associated with increased dementia risk even if the first episode occurred 25 years prior to onset,33
and a more recent study found an association between the number of depressive episodes and risk of dementia over 25 years.15
However, these studies did not differentiate between single versus recurrent depressive episodes and, therefore, did not explicitly examine dementia risk in the subset of subjects who only had depressive symptoms in mid-life.
There has been an ongoing debate in the field as to whether the association between depression and dementia reflects an etiologic relationship or whether depression is a prodromal symptom of dementia.10,17
Our results suggest that the answer may differ depending on the dementia subtype. Depression that presents for the first time in late life may reflect the earliest symptoms of dementia, particularly AD, in some individuals. Future studies should examine whether it may be helpful clinically to monitor these individuals for symptoms of cognitive deterioration suggestive of dementia. It is possible that earlier recognition of dementia could facilitate better management of healthcare through earlier treatment with memory-enhancing agents, when they are most likely to be effective, as well as greater involvement of caregivers, simplification of medication regimens and earlier discussions regarding goals of care.
On the other hand, recurrence of depression in late life may reflect a long-term process of subclinical cerebrovascular changes that may predispose toward development of VaD. This hypothesis is consistent with the vascular-depression-dementia hypothesis18
and is supported by prior studies in which white matter hyperintensities on cerebral MRIs—which are considered to be markers of underlying cerebrovascular disease—are associated with greater risk of both depression and dementia in late life.34–37
Although our study provides support for the vascular-depression-dementia hypothesis, it remains possible that other hypothesized mechanisms also play a role in the association between depression and dementia. In particular, the hypothamalic-pituitary-adrenal (HPA) axis has been proposed as an alternative mechanism in which chronic or recurrent depression leads to hypercortisolemia which, in turn, results in hippocampal damage and increased vulnerability to dementia.9,10
Strengths of this study include the large sample size, which enabled us to study VaD as well as AD; the integrated health-care delivery setting, which minimizes the impact of access to healthcare and enabled us to adjust for other medical comorbidities over the life-span; and the availability of data from both mid-life and late-life, which enabled examination of depression over the life course. Limitations of the study include the mid-life depressive symptom measure, which was based primarily on a single self-reported question and likely resulted in lack of specificity. In addition, use of electronic medical record data for diagnoses of late-life depression and dementia likely resulted in low sensitivity and under-recognition of these conditions. We also were not able to confirm diagnoses of AD and VaD using operational criteria or through postmortem or neuroimaging studies. Given that vascular disease is an independent risk factor for AD, that pure VaD is relatively rare, and that the majority of individuals with dementia at the population level have mixed AD/VaD pathology, it is likely that some of what was diagnosed as VaD in this study may have reflected a more mixed etiology. To the extent that these misclassifications were non-differential (i.e., misclassification of depressive symptom status was similar in those with and without dementia diagnoses and misclassification of dementia status was similar in those with and without depressive symptoms), our findings would be biased toward the null; thus, the true magnitude of these associations may be stronger than observed in this study. We also were unable to analyze data related to use of anti-depressants or other psychotropic medications, which should be examined in future studies. In addition, our measures of vascular risk factors were relatively limited, so we were unable to directly examine the role of vascular disease as the etiologic mediator of the association between depression and VaD. Finally, since we excluded dementia cases diagnosed prior to 1/1/03, it is important to note that our findings are restricted to late-life dementia.