In this prospective study of 1,239 community-dwelling older adults at risk for dementia and MCI followed for up to 51 years starting from age 50, we found a monotonic increase in dementia risk as a function of the number of EDS. Participants with 1 EDS had an 87% increased risk of developing dementia, while those with 2 or more EDS were nearly twice as likely to develop dementia. Cox proportional hazards models showed a 14% increase in dementia risk with each occurrence of an EDS. Results remained significant when controlling for a variety of potentially confounding factors. MCI was not related to recurrence of EDS.
These results are consistent with previous studies which have reported a relationship between a history of depression or DS and risk for cognitive impairment and dementia.4,5,7,24,25
Most previous studies have relied on dichotomous depression groups or continuous measures of DS at 1 time point. A dose-dependent relationship between severe depressive episodes and dementia risk was found in a study that reported an average 13% increase in the risk of dementia with every episode leading to hospitalization for depression.11
Our findings add to the existing literature by demonstrating a monotonic increase in dementia risk as a function of EDS in a community sample. In contrast to a previous report of increased dementia risk only in severe depression,26
we observed an increased risk in individuals whose CES-D scores were sufficiently elevated to be considered clinically significant but whose symptoms were not severe enough to warrant hospitalization, and for most participants, did not result in treatment of any kind.
Not all studies have shown an association between depression and dementia risk,27–29
and some found that only first episodes of depression occurring proximal to dementia onset are associated with dementia, suggesting that depression is a prodromal feature of dementia.2,3
Moreover, evidence that individuals with dementia have an increased probability of developing DS following the onset of cognitive impairment27
and that DS accompany the progression of cognitive decline suggests that DS may be a reaction to perceived loss of cognitive ability.30
Our finding of a monotonic increase in dementia risk for each EDS suggests that depression is not merely a prodrome of dementia. Indeed, we would not expect the number of previous EDS to increase dementia risk if only the episode proximal to dementia diagnosis were significant. Moreover, the average 5.92 ± 4.23-year interval between first EDS and dementia diagnosis is not consistent with depression as a prodromal symptom of dementia. Because participants in the BLSA who develop dementia do not return for regular visits, we are unable to examine the course of DS following the development of dementia to determine whether symptoms might be a reaction to cognitive loss. Thus, our findings lend the most support to the hypothesis that DS are a risk factor for the development of dementia or perhaps are related to a common neurophysiologic substrate.
Our findings would be predicted by the glucocorticoid cascade hypothesis8
since repeated EDS would result in repeated insult to the hippocampus based on this model. Research in the traumatic brain injury31
literature also supports the proposition that recurrent brain injury increases the risk of dementia. Because depressive disorders are a treatable cause of neural insult, understanding the relationship between recurrent depression, hippocampal damage, and dementia risk is important for identifying and treating a group of older adults who are at risk for dementia.
Vascular disease is associated with late-life depression and dementia.7
Although detailed psychiatric information is not available to determine the presence of vascular depression, we were able to distinguish between incident AD and vascular dementia in our sample. The majority of participants were diagnosed with AD, and our results remained significant when we limited the analyses to individuals with AD. Moreover, significant associations between EDS and dementia risk were found when controlling for a variety of vascular conditions. Altogether, this suggests that our findings are not completely explained by the presence of vascular depression or vascular dementia in our sample.
In a previous study of BLSA participants, only men with a history of at least 1 CES-D score ≥16 had an increased risk of dementia.25
Similarly, other studies have found that men appear to be more vulnerable to the adverse impacts of depressive syndromes on cognitive functioning and brain integrity.33,34
We did not find such a sex difference in the present study. This may be due at least in part to statistical power since the number of men in our sample, particularly in the incident dementia analysis, was smaller than the number of women. Previous demonstrations of an increased dementia risk only in men have used dichotomous depression variables or continuous measures of depression severity, rather than numbers of depressive episodes. In contrast, we compared multiple levels of depressive symptom recurrence. This approach, combined with our long follow-up period, may have provided more sensitivity in detecting the relationship between recurrent EDS and dementia risk in both men and women.
Recurrence of EDS was not associated with risk of MCI in our sample, contrary to previous reports of an increased risk of MCI as a function of either a history of depression or depressive episodes at baseline. For example, DS were associated with incident dementia in the Cardiovascular Health Study35
and Mayo Alzheimer's Disease Patient Registry36
cohorts. There are several possible explanations for our discrepant findings. First, our MCI analyses were based on a group that excluded individuals who converted to dementia during follow-up. As a result, the cognitive impairment in this group may be attributable to transient factors (e.g., current stressors) rather than incipient dementia. In that case, DS would not be expected to predict the cognitive impairment observed in those individuals. Previous demonstrations of a relationship between depressive syndromes and MCI risk may have included a mix of individuals with transient cognitive difficulties and those with prodromal dementia. Second, the association between MCI risk and depression may be greater for nonamnestic MCI than amnestic MCI,37
consistent with the well-documented relationships of depressive syndromes with executive functions and frontal lobe abnormalities.38
Consequently, we may have failed to find a relationship between DS and MCI because of the preponderance of amnestic MCI in our sample. Finally, the characteristics of the DS in our sample may differ from previous studies. It has been suggested that the relationship between DS and MCI risk is mediated by confounding factors such as chronic distress39
or antidepressant use.37
Few participants with MCI in our sample have a history of antidepressant use (19.32%), which may contribute to our null findings. Because we do not have data regarding psychological distress for our sample, we cannot rule out the possibility that our sample included fewer individuals with chronic distress.
Our study has several strengths. First, it is based on a large prospective cohort study with long follow-up time and extends previous findings by examining recurrence of DS in relation to dementia and MCI risk in a community sample. The well-characterized nature of the BLSA sample, including extensive information regarding potentially confounding lifestyle and medical variables, allows us to more confidently rule out extraneous variables that could impact our findings. Further, time-dependent exposure variables were studied, avoiding both issues of temporality and reliability due to single measurement. Study limitations include the lack of detailed information regarding psychiatric history, such as age at onset of first DS. Moreover, our measure of EDS was based on participant report of DS experienced in the week preceding testing and did not include episodes of significant DS that participants may have experienced at other times. In addition, the BLSA is a sample of convenience and is limited to primarily white, highly educated individuals. Finally, secular trends in some of the effects of certain variables were possible. However, after controlling for year of birth in our longitudinal analyses, our main findings were not altered.
Our findings contribute to a growing body of literature linking late-life depression and dementia. Because the direction of the relationship between these 2 common conditions has not been completely clarified, more longitudinal work is needed to understand the nature of the association. Our findings provide support for the contention that depression is a risk factor for dementia. Moreover, our finding of a dose-dependent association between EDS and dementia provides indirect support for the hypothesis that depression results in neural insult to the brain and in turn increases the risk for dementia. This line of work has important implications. Depression is a potentially treatable risk factor for dementia. Because the occurrence of 1 depressive episode greatly increases the risk of future episodes,40
our findings suggest that older adults with a history of depression should be closely monitored for both DS and cognitive decline. Early detection and treatment of at-risk older adults may ultimately delay the onset of cognitive impairment and dementia.