We report that depression is a risk factor for the development of cognitive impairment, across domains of cognition, in a longitudinal study of older, community-dwelling women. The effect of depressive symptoms was considerable: for each 1-point increase in GDS, we found a 6–7% increase in annual risk of cognitive impairment in each cognitive domain, and baseline depression (defined as GDS ≥9) effectively doubled this risk for three of four domains. These results imply that the association of depression with incident cognitive impairment generalizes over a variety of cognitive domains.
These results replicate and extend prior findings, importantly reporting a very similar effect size. There are several studies examining the effect of depressive symptoms on incident MCI. Geda et al. reported a hazard ratio for incident MCI of 2.2, using a cutoff of 6 on the 15-item form of the GDS (4
). Barnes et al. reported an odds ratio for incident MCI of >2 for participants with Center for Epidemiological Studies Depression Scale (CES-D) >7 followed over 6 years (5
). Cross-sectional studies, while not directly comparable, report similar risk. Lopez et al. reported an odds ratio for prevalent MCI of 1.5 for participants with CES-D>7 (23
). Green et al reported an odds ratio of 2.8 for prevalent AD for participants with a history of clinically significant depression (24
); although the data collection was retrospective and subject to recall bias, they noted higher odds ratios when the depression was quite recent (within one year of interview) suggesting that depression was a prodrome to AD in their cohort. Our analysis differs from these prior studies in that we examined subsyndromal depressive syndromes, while the abovementioned studies used cutoffs for depression severity similar to Major Depressive Episode. We chose this approach because, if depressive symptoms are a prodrome or risk factor for incident cognitive impairment, there is likely to be a clinical spectrum of severity in this prodrome; to pick up the earliest symptoms requires using a more sensitive threshold, likes less severe than major depression. Additionally, our analysis examines incident cognitive impairment rather than incident diagnosis of MCI as an outcome. Even with these differences in analysis, our findings support these prior results and suggest that clinically significant depression approximately doubles the risk of developing clinically significant cognitive impairment.
Observational data cannot directly address the crucial mechanistic question of whether depression is a symptom of cognitive impairment (i.e., whether depression and dementia are different symptoms of the same underlying process) or whether depression adds independently to risk of incident cognitive impairment. Future studies can address these questions by examining the association of depressive symptoms and biomarkers in prodromal dementia states. One potential mechanism is the growing evidence that inflammatory mechanisms are important in the neurotoxicity of Alzheimer’s disease (25
) and in mood disorders (26
Other replicative findings include: 1) increased age and less education were associated with increased risk of incident cognitive impairment as has previously reported (5
). 2) the baseline (cross-sectional) association of depression with slower psychomotor speed has been observed in community-dwelling older persons (27
A diagnosis of diabetes was associated with increased risk of incident cognitive impairment (delayed recall and processing speed) paralleling prior studies of AD and MCI incidence (28
) and MCI prevalence (23
). However, other vascular conditions did not add significantly to the risk of incident cognitive impairment. This partly replicates the findings of two longitudinal studies examining similar vascular factors (5
) but is at odds with others (23
), particularly in the lack of added risk we found for hypertension despite a high prevalence of the diagnosis. However, our participants had adequate though not excellent control of blood pressure on average, and it is possible that medication treatment of hypertension modified the effect (not assessable with these data). There is not strong concordance in the literature concerning which vascular risk factors affect cognitive decline. One possibility is that some risk factors (diabetes) are associated with microvascular ischemia, some risk factors (angina, MI, and stroke) largely reflect the outcome of macrovascular disease, and some risk factors (hypertension and hypercholesterolemia) likely affect both. Diabetes has such pleiotropic mechanisms, affecting many organ systems, that it may be difficult to discern the specific mechanisms increasing risk of cognitive impairment. Given the discordance with the effects of other vascular conditions, our results would suggest that vascular mechanisms did not have a major effect on the cognitive outcomes of our participants. Another possibility is that the effect of risk factors varies according to age and disease stage; for example, higher serum cholesterol in mid-life is a risk factor increases the risk of late-life dementia (30
) whereas higher serum cholesterol in late-life decreases the risk of late-life dementia (32
). Our results only reflect the effect of late-life vascular risk factors and are unable to address effects more remote in time.
Strengths of the study include use of a population-based sample, availability of multiple cognitive outcomes, consensus diagnosis of medical conditions, low attrition, and long duration of follow-up. Limitations include a cohort limited to women and lack of clinical consensus diagnoses or MCI and/or dementia. The latter is especially important in terms of generalizability, because our analysis is of incident cognitive impairment not dementia, and the risk factor profile may be different for this important clinical outcome. An additional limitation is the lack of apoE genotyping: it is possible that the presence of an apoE4 allele underlies both depressive symptoms and incident cognitive impairment.
These results provide further support for the role of depressive symptoms as a prodromal marker of future cognitive impairment, and for the incorporation of depressive symptoms into profiles of clinical and biological markers for the identification of persons at risk for dementia. This has direct relevance to identifying candidates for disease-modifying therapies for dementia prevention.