We investigated the association between elevated depressive symptoms, incident MCI and dementia, and neuropsychological test performance in a cohort of oldest-old women. We found that, compared to oldest-old women without elevated depressive symptoms, those with elevated symptoms had more than 3 times the odds of dementia and 3.7 times the odds of MCI five years later, after accounting for potential confounders. We also found that elevated depressive symptoms were associated with more than a 70% decrease in the odds of being cognitively normal five years later. On neuropsychological tests, we found that oldest-old women with elevated depressive symptoms performed more poorly on tests of global cognitive function and working memory, five years later, than women without elevated symptoms. Taken together, our results indicate that depression remains an important risk factor for cognitive impairment and cognitive disorders in oldest-old women—a population in which this association has been understudied.
Our finding that elevated depressive symptoms predicted incident dementia in oldest-old women is generally consistent with results of previous studies in younger samples of older adults,(33
) including an early (1999) study in women from SOF.(12
) Although not all studies have found this association,(35
) results from meta-analyses of case-control and prospective studies support the association between depression and dementia.(37
) Nonetheless, the exact nature of the relationship between the two conditions (e.g., whether depression causes dementia, is a prodrome of dementia, etc.) remains to be determined.(37
Depressive symptoms are among the most common neuropsychiatric symptoms in MCI, which is commonly thought of as a transitional status between normal cognition and dementia.(39
) Investigations in two population-based studies, the Cardiovascular Health Study and the Mayo Clinic Study of Aging, found that depressive symptoms occur in 20% and 27% of individuals with MCI, respectively.(40
) We know relatively little, however, about depression as a predictor of incident MCI, and results in this area have been mixed. Some studies in population-based and clinical samples have found that depressive symptoms predict subsequent MCI,(13
) and that older adults with a history of depression often meet criteria for MCI even after successful treatment and remission of depression.(42
) Others have found that the association between depression and incident MCI only occurs in specific subgroups,(43
) and still others have found no association of depression with incident MCI.(44
) We found, in a sample of oldest-old women, that elevated depressive symptoms were associated with a 3.7-fold increase in the odds of MCI five years later. Although this association decreased and became statistically non-significant after removal of four influential observations, we believe that evidence of an association between elevated depressive symptoms and MCI is fairly strong, given consistent findings with all outcomes (i.e., dementia, MCI, and cognitively normal vs. impaired) and the fact that this association remained elevated (though not statistically significant) even after removal of four high-influence points.
Many other studies have investigated the association between depressive symptoms and neuropsychological test performance in younger samples of older adults, and our results are consistent with some, but not all of their findings. As in the present research, prior studies have found associations between depressive symptoms and decline in global cognition,(7
) and depression has been linked to reduced performance on digit span backward in adults over age 60.(45
) We did not observe significant associations, however, between elevated depressive symptoms and other cognitive tests, including measures of delayed recall, attention, verbal fluency, or executive function and psychomotor speed. Although others have observed cross-sectional differences in these cognitive domains between older adults with elevated depressive symptoms or major depressive disorder and those without, findings regarding longitudinal associations between depressive symptoms and cognition have been inconsistent, perhaps due to between-study differences in measurement and statistical analysis.(8
Our findings of independent associations between elevated depressive symptoms and subsequent diagnoses of MCI and dementia raise the question of whether prevention or treatment of depression could, in turn, prevent cognitive decline in the oldest-old. Indeed, this question has been asked before, based primarily on results from younger samples of elders.(7
) Ethical considerations preclude randomizing older adults to treatment vs. withholding treatment of depression to evaluate the impact on cognitive trajectories. However, trials aimed at preventing depression with prevention of cognitive decline as a long-term goal, would permit researchers to approach the answer to this question.
Several mechanisms have been hypothesized to link depression to poor cognitive outcomes. For example, it has been proposed that inflammatory processes associated with depression(48
) mediate the association between depression and cognitive decline.(49
) In addition, individuals of various ages with prolonged or repeated major depressive episodes have been shown to have smaller hippocampal volumes than controls, perhaps due to chronic exposure to elevated levels of stress hormones, such as cortisol.(50
) Further, researchers are examining the role of depression in the pathogenesis of Alzheimer’s disease (AD). Results from postmortem research suggest that AD pathology is common among older adults with major depressive disorder who develop dementia.(51
) In addition, some older adults with elevated depressive symptoms have been shown to have lower plasma levels of amyloid-β peptide 42 (Aβ42), and a lower ratio of plasma Aβ42 to Aβ40 than those without elevated symptoms; this has been called “amyloid-associated depression.”(52
) This depression subtype is being investigated as a potential prodrome of and risk factor for AD.(53
) Although these mechanisms could explain a causal link between depression and adverse cognitive outcomes in older adults, it also is possible that depression and cognitive decline both arise from a shared disease process. For example, cardiovascular disease is a known risk factor for dementia, and findings from epidemiologic and neuropathology studies support the vascular depression hypothesis, which implicates cardiovascular disease in the etiology of depression in a subset of older adults.(55
The present study has many strengths, including a sample of women from the largest ongoing cohort of oldest-old women, prospective study design, adjudication of clinical cognitive status, and multivariable adjustment for potential confounders; however, it also has several limitations. First, our primary predictor was elevated depressive symptoms on the 15-item GDS—a screening test for depression in older adults (19
)—rather than a diagnosis of major (or minor) depressive disorder by structured psychiatric interview. The GDS items do not neatly correspond to symptoms listed in the DSM-IV major depressive episode criteria, the gold standard for depression assessment. In addition, our sample consisted mostly of white women; our findings might not generalize to non-white populations of oldest-old women, or to men. Also, because we did not collect neuroimaging data as part of this study, we are unable to assess the impact of elevated depressive symptoms on brain structure or function. This limits the extent to which we can evaluate the neural mechanisms by which depression affects cognition in the oldest old. Also, it is possible that participants classified as being free of elevated depressive symptoms at baseline developed elevated depressive symptoms later on, although such misclassification likely would have biased our results toward the null, reducing the strength of the associations we observed. Similarly, we did not investigate the association between persistent depression (i.e., elevated symptoms at both baseline and follow-up) and cognitive diagnoses. Further, like other studies in prospective cohorts, our results might have been affected by selection bias; women who died, left the study, or were lost to follow-up between baseline and follow-up might have differed from those who remained in the cohort in ways that affected our results. Finally, we lacked the power to evaluate the effect of study site X covariate interactions on our outcomes. Future studies with larger, more heterogeneous samples are needed to determine whether our findings generalize to diverse populations of oldest-old men and women, and whether persistence of depressive symptoms over time modifies the association between baseline symptoms and cognitive outcomes.