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To evaluate the association of late life depression with mild cognitive impairment (MCI) and dementia and in a multi-ethnic community cohort.
Northern Manhattan, New York city.
2160 community-dwelling Medicare recipients aged 65 years and older.
Depression was assessed using the 10-item version of the Center for Epidemiological Studies-Depression scale (CES-D) and defined by a CES-D score ≥ 4. We used logistic regression for cross-sectional association analyses and proportional hazards regression for longitudinal analyses.
MCI, dementia, and progression from MCI to dementia. We also used subcategories of MCI (amnestic, non amnestic), and dementia (probable AD, vascular dementia including possible AD with stroke).
Baseline depression was associated with prevalent MCI (OR = 1.4; 95% CI: 1.11–1.9) and dementia (OR = 2.2; 95% CI :1.6–3.1). Baseline depression was associated with an increased risk of incident dementia (HR = 1.7; 95 % CI: 1.2–2.3), but not with incident MCI. Persons with MCI at baseline with co-existing depression had a higher risk of progression to dementia (HR = 2.3; 95% CI: 1.4–3.8), especially vascular dementia (HR = 4.3; 95% CI: 1.1–17.0), but not AD (HR = 1.0 95% CI: 0.5–2.5).
The association of depression with prevalent MCI and with progression from MCI to dementia, but not with incident MCI, suggests that depression accompanies cognitive impairment but does not precede it.
Depressive symptoms occur in 40–50%, and major depression in 10–20%, of patients with Alzheimer’s disease (AD) 1. In subjects with mild cognitive impairment (MCI), depressive symptoms occur in 3–63% 2. This wide range is probably attributable to sample differences (hospital vs. population-based) and operationalization of MCI and depression criteria 2. Both case-control studies and longitudinal studies have shown an increased dementia risk in persons with depression history 3, although a few longitudinal studies reported no increased dementia risk 4–6. Increased MCI risk in depression was recently reported in population-based studies 7,8, but this was not confirmed in two other population-based studies9,10. Increased risk of progression to dementia in MCI patients with depression has been reported in prospective studies in a memory clinic setting 11, but a population-based study found no association 9.
The mechanisms behind the association between depression and cognitive decline have not been elucidated and different mechanisms have been proposed 8,12,13. Depression could be a risk factor for dementia, an early dementia symptom, a reaction to cognitive and functional disability, or a symptom of a related risk factor, such as cerebrovascular disease. Vascular factors have been linked to late-life depression, and cerebrovascular disease might be an important contributor to MCI, dementia and depression in late life. 14–17 However, there is a paucity of data examining the association between depression and MCI. We previously reported an association between depressive symptoms and AD in a cohort recruited in 1992–1994 18,19. Our aim in this study was to explore the cross-sectional and longitudinal associations of depression with MCI and dementia and the progression from MCI to dementia in a new cohort recruited in 1999–2001 in the same community.
Participants were recruited by random sampling of healthy Medicare eligible persons aged >65 years in several low-income neighborhoods with a high proportion of Hispanics in Northern Manhattan. They were part of the Washington Heights–Inwood Columbia Aging Project (WHICAP)—a population-based cohort in which clinicaland epidemiologic data are collected at regular intervals andvital status is continually updated 20. This report pertains to a cohort recruited in 1999–2001. The geographic study area was Manhattan north of 145th street. Lists of persons in receipt of Medicare or Medicaid in this area were obtained from the Health Care Financing Administration. Potential participants were drawn by systematic random sampling into one of six strata formed on the basis of ethnicity (Hispanics, non-Hispanic Blacks and non-Hispanic whites) and age (65–74, 75+). Participants who reported a physician diagnosis of dementia were excluded. The total number recruited was 2174. Subjects who completed the baseline visit with neuropsychological and depressive symptoms information are included in this analysis (N=2160). Follow-up visits were scheduled with intervals of 18–24 months.
Neuropsychological testing according to a standardized protocol was performed at baseline and then at 18–24 month intervals.
Presence of depressive symptoms was assessed at baseline and follow-up visits using the short version (‘Boston-form’) of the Center for Epidemiological Studies-Depression scale (CES-D).21 This is a 10-item questionnaire with questions to be answered by yes (1 point) or no (0 points), leading to a total score of 0–10. A cut-off of 4 points or more on this scale has been used to ascertain depression in studies, including our 1992 cohort.22,23. We used absent or mild depression as the reference for comparison. Change in depression was assessed at first follow-up. The CES-D is comprised of items that can be subclassified as depressed affect (I felt depressed, I felt lonely, I felt sad), positive affect (I was happy, I enjoyed life), somatic/vegetative signs (I felt that everything I did was an effort, my sleep was restless), and interpersonal distress (People were unfriendly, I felt people disliked me)24. Affirmative responses in these questions scored as yes (1) or no (0) were added, with the exception of the positive affect items, which were scored inversely. Symptoms of one cluster were scored as present if one or more of the questions were answered affirmative. We used this classification of the CESD items to conduct secondary analyses examining symptom type as the exposure.
The diagnosis of dementia and MCI was based on all available clinical and neuropsychological information and was made by consensus of a panel of neurologists, neuropsychologists and psychiatrists according to international guidelines. Dementia was diagnosed based on the DSM III-R criteria, Alzheimer’s disease based on the NINDS-ADRDA criteria25 and vascular dementia based on the NINDS-AIREN criteria26. Subjects not fulfilling these criteria were categorized as ‘other dementia’ including subjects with dementia with Lewy Bodies, dementia associated with traumatic brain injury and dementia not otherwise specified. Probable AD was diagnosed when the clinical history suggested AD and no other contributors to dementia were found. Possible AD was diagnosed when AD was considered the most likely contributor to dementia, but there were other contributing factors. We analyzed 3 dementia outcomes: all dementia, AD (including probable and possible AD without cerebrovascular disease by history), and vascular dementia, including cases fulfilling NINDS-AIREN criteria and cases diagnosed as possible AD in whom cerebrovascular disease history was considered to contribute to the dementia (VaD). The rationale for this classification of the outcome was that late life depression has been linked to cerebrovascular disease, also known as vascular depression15, and we sought to separate cases of dementia with a vascular component from cases without a vascular component based on clinical assessment and consensus diagnosis. MCI was ascertained by the Petersen criteria 27 as previously described in our cohort 28. MCI was further characterized as amnestic MCI and non-amnestic MCI as previously described 29.
Age was calculated from the date of birth to the baseline evaluation. Ethnic group was determined by US census criteria. Education was measured in years. APOE genotypes were determined as described by Hixson and Vernier with slight modification.30 We classified persons either as homozygous/heterozygous or APOEε4 negative.
We adjusted for vascular risk factors using a modification of a composite score previously shown to predict dementia in our cohort.31 This score includes diabetes, hypertension, current smoking, low high density lipoprotein and high waist to hip ratio and ranges from 0–18. 31
Baseline variables were compared between subjects with (CES-D ≥ 4) and without depression (CES-D <4) using Student’s T-test or Chi-square test where appropriate.
The cross-sectional associations between the presence of depressive symptoms and MCI or dementia (and their subtypes) at baseline was assessed using logistic regression models. Proportional hazards models were used for longitudinal analyses. The time to event variable was time from baseline to incident dementia or MCI. Individuals who did not develop MCI or dementia were right-censored at the time of last visit. To assess whether depression in patients with MCI at baseline increased the risk of progression to dementia, proportional hazards models were used. For all analyses 3 basic models were used. Model 1 was adjusted for age and gender, model 2 was adjusted additionally for education, ethnicity and APOE genotype and model 3 was additionally adjusted for the vascular risk score. The rationale for model 1 was the adjustment of basic demographics, the rationale for model 2 was the adjustment for non-modifiable predictors of dementia in our cohort, and the rationale for model 3 was the adjustment for vascular burden. Model 3 was used to explore the potential mediation of vascular disease in the relation between depression and dementia; attenuation of the effect estimates in this model was interpreted as evidence of mediation, not confounding.
There were 2160 subjects out of 2183 (99%) with complete data on the CES-D at baseline and these were included in the study (Figure 1). Of these, 452 (20.9%) had a CES-D score ≥ 4 and 1708 (79.1%) had a CES-D score < 4. Subjects with depression were younger, more likely female, had less years of education, were more likely to be Hispanic, and more likely to use antidepressants (Table 1). Five hundred sixty-nine participants (25.9%) did not have a follow-up visit after the baseline assessment. These subjects were older (78.3 vs. 76.5 years, p <0.0001) and less educated (9.5 vs. 10.5 years, p <0.0001) than the participants with follow-up, but there was no difference in depression (Supplemental table 1).
At baseline, 429 subjects fulfilled MCI criteria: 222 (51.7%) had amnestic MCI and 207 (48.3%) had non-amnestic MCI. Subjects with MCI were more often depressed than cognitively intact subjects (Table 2); this association was strongest for non-amnestic MCI but not significant for amnestic MCI, and only slightly attenuated when adjusting for vascular burden (Table 2). The presence of depressive symptoms not meeting depression criteria (CESD < 4) was not associated with prevalent MCI.
Dementia was diagnosed at baseline in 217 subjects, of whom 164 (75.1%) were diagnosed as possible or probable AD (126 (58.1%) with probable AD), 33 (15.2%) as VaD and 20 (9.2%) as other dementia. Other dementia included dementia with Lewy bodies, toxic cause, and several rare causes of dementia. Subjects with dementia were depressed twice as often as subjects without dementia (OR 2.2, 95% CI 1.6–3.1) and this association was stronger for VaD compared to AD (Table 2). There was marked attenuation of the HR relating depression and VaD in the model adjusting for a vascular risk score. The presence of depressive symptoms not meeting the depression criteria was not associated with prevalent dementia.
Of 1514 participants without dementia or MCI at baseline, there were 1156 (76.4%) participants with follow-up for longitudinal analyses with MCI as an outcome. During an average follow-up of 5.4 years (range 1.1–10.1) MCI developed in 304 subjects, of whom 151 (49.7%) developed amnestic MCI and 153 (50.3%) developed non-amnestic MCI. Depression was not associated with incident MCI or MCI subtype (table 3). The presence of depressive symptoms not meeting the depression criteria was not associated with incident MCI.
Of 1943 participants without dementia at baseline there were 1483 (76.3%) participants with follow-up for longitudinal analyses with dementia as outcome. Two-hundred and seven subjects developed dementia, of whom 167 (80.7%) were classified as possible or probable AD (133 (64.3%) with probable AD), 29 (14.0%) as VaD and 11 (5.3%) as other dementia.
Dementia risk was higher in persons with depression at baseline (table 3) in all models. This risk was modestly higher for AD than for VaD. We conducted analyses examining probable AD cases as the outcome in order to exclude cases of AD with a cerebrovascular component and the risk estimate was weaker and not statistically significant (HR = 1.3; 95% CI: 0.9–2.0). Depressive symptoms not meeting the depression criteria was not associated with incident dementia. When we repeated the analysis excluding the subjects with MCI at baseline the risk of dementia in subjects with depression was attenuated (HR = 1.4, 95%; CI: 0.9–2.1). We conducted additional analyses exploring whether the report of depression at first follow-up changed the association between depression and incident dementia. Persons with persistent depression (HR = 1.9; 95% CI: 1.3, 2.8), depression at baseline but not at follow-up (HR = 1.6; 95% CI: 1.0, 2.5), and persons with no depression at baseline but depression at follow-up (1.9; 95% CI: 1.3, 3.0) all had increased risk of dementia compared to persons who persistently had no depression. We also conducted additional analyses exploring whether a particular type of depressive symptoms was more strongly related to dementia risk. We constructed a model with the 4 types of depressive symptoms in the CESD adjusting for demographics, education and APOE-ε4. Only depressed affect was related to incident dementia (HR = 1.9; 95% CI 1.4–2.7). Positive affect, somatic symptoms, and interpersonal distress had HR close to 1 in relation to incident dementia that were not statistically significant. The relation of depressed affect to dementia was stronger for VaD (HR= 4.1; 95% CI = 1.6–11.0) compared with AD (HR = 1.7; 95% CI = 1.1–2.5). Other types of depressive symptoms were not differentially related to AD or VaD.
There were 320 subjects with MCI at baseline who had at least one follow-up (average follow-up of 5.1 years; range 1.2–9.8 years), 160 with amnestic MCI and 160 with non-amnestic MCI. Of these, 67 progressed to dementia.
Subjects with MCI with depression had twice the risk of dementia compared with those without depression and this risk was highest for VaD (Table 4). When subjects with amnestic-MCI and non-amnestic MCI were analyzed separately, the HR relating depression to progression to dementia were similar (HR for amnestic MCI = 2.1; 95% CI:1.0–4.3 vs. HR for non-amnestic MCI = 2.4; 95% CI 1.1–5.7). There were no differences between amnestic and non-amnestic MCI in the HR relating depression to incident AD or VaD. In analyses with the CES-D as an ordinal scale, no association between a score of 0–1 or 2–3 (some depressive symptoms) and incident dementia was found. Analysis using the different clusters of symptoms within the CES-D showed again that depressed affect was associated with increased incident dementia risk (HR = 2.1; 95% CI: 1.1–4.0).
We found that depression was related to a higher risk of prevalent MCI and dementia, incident dementia, and progression from prevalent MCI to dementia, but not to incident MCI. We also found that the association of depression with prevalent dementia and with progression from MCI to dementia was stronger for VaD compared to AD, and was driven mostly by depressive affect.
Studies of the association of depression with MCI are inconsistent as well.2 An increased risk of MCI in subjects with depression was recently reported 7,8, although two other studies reported no association.9,10 Increased risk of developing dementia in MCI with depressive symptoms has been reported before in a hospital-based series 11, but population-based studies until now could not confirm this association as we did.9,34 We found that depression was related to prevalent but not incident MCI. It seems reasonable to postulate that persons with prevalent MCI have a more advanced stage of cognitive impairment accompanied by depression, whereas persons with incident MCI have earlier cognitive impairment not accompanied by depression. This could explain our findings and some of the inconsistencies in the literature.
Our finding that depression was associated cross-sectionally with both MCI and dementia and longitudinally only with dementia, suggests that depression develops with the transition from normal cognition to dementia. This agrees with a previous study that reported that in non-demented elderly depression is more common with increasing cognitive impairment.18 This speculation is further supported by the observation that the association of depression with incident dementia was attenuated when persons with MCI at baseline were excluded, and by our observation that persons with MCI and depression were more likely to develop dementia.
A potential link between depression and dementia in late life is through vascular factors, as postulated in the ‘vascular depression hypothesis’.15 Depression is associated with vascular risk factors 16,17, and with cerebrovascular lesions on neuroimaging.35,36 Our finding that depression is more strongly associated with VaD than AD (both cross-sectionally and longitudinally in subjects with MCI at baseline) and that this relationship is attenuated in models adjusting for vascular burden suggests that cerebrovascular disease has a role in this association. Most studies that examined depression as a predictor of dementia generally did not attempt to separate AD from VaD. However, these results should be interpreted with caution because of the possibility of chance findings due to multiple subanalyses, because of the lack of neuroimaging data, and because we did not find an association of individual vascular risk factors with depression at baseline. Depressed mood seemed to drive the association, in line with reports that depressed mood alone predicts dementia.18 We could not confirm the association of apathy with an increased risk of progressing from MCI to dementia, but we did not have an extensive apathy evaluation.37
Our study has several limitations. Our results for subtypes of MCI and dementia in longitudinal analyses should be interpreted with caution due to relatively low cell sizes which could result both in low power and chance findings. The CES-D inquires mainly about depressive symptoms within 2 weeks of its administration. Thus, the CES-D is likely to underestimate the presence of depressive symptoms and depression. To the extent that this measurement error is random (not related to the outcome), this measurement error will bias our results towards the null. In other words, our study may underestimate the true association between depressive symptoms and cognitive impairment (MCI or dementia).
Different explanations for the relationship between late-life depression and dementia have been suggested.3,12,13 Late life depression could be an early symptom in the progression to dementia; depression could affect the threshold for dementia to become manifest or could be a reaction to the cognitive impairment. Depression could also be a causal risk factor for dementia through hippocampal damage mediated by the influence of depression on the HPA-axis 38–40. Finally, common risk factors contributing to an increased risk of both depression and dementia, such as cerebrovascular disease, could explain the association between the two. 41 We could not address the exact mechanisms linking depression and dementia, but our results support the hypothesis that late-life depression accompanies the occurrence of cognitive decline and does not precede it. Our finding that the association of depression with probable AD was weaker compared to all AD (probable and possible) and VaD, suggests that other pathologies with AD may be more likely to manifest as depression.