Institute for Research in Extramural Medicine, Vrije Universiteit, Amsterdam
Institute for Research in Extramural Medicine and Department of Psychiatry, Vrije Universiteit, Amsterdam
Institute for Research in Extramural Medicine and Department of Clinical Epidemiology and Biostatistics, Vrije Universiteit, Amsterdam
Department of Neurology, Universiteit van Amsterdam, The Netherlands
Correspondence: M. I. Geerlings, Department of Epidemiology & Biostatistics, Erasmus Medical Center Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands. Tel: +31 10 408 7478; Fax: +31 10 408 9382; e-mail: geerlings{at}epib.fgg.eur.nl
Declaration of interest Grants detailed in Acknowledgements. No conflict of interest.
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ABSTRACT |
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Aims To investigate whether depressed elderly people with normal cognition are at increased risk of cognitive decline and Alzheimer's disease.
Methods Two independent samples of older people with normal
cognition were selected from the community-based Amsterdam Study of the
Elderly (AMSTEL) and the Longitudinal Aging Study Amsterdam (LASA). In AMSTEL,
depression was assessed by means of the Geriatric Mental State Schedule.
Clinical diagnoses of incident Alzheimer's disease were made using a two-step
procedure. In LASA, depression was assessed with the Center for Epidemiologic
Studies Depression Scale. Cognitive decline was defined as a drop of 3 on
the Mini-Mental State Examination at follow-up.
Results Both in the AMSTEL and the LASA sample, depression was associated with an increased risk of Alzheimer's disease and cognitive decline, respectively, but only in subjects with higher levels of education.
Conclusions In a subgroup of more highly educated elderly people, depression may be an early manifestation of Alzheimer's disease before cognitive symptoms become apparent.
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INTRODUCTION |
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METHODS |
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Baseline measurements and study samples
AMSTEL
In 1990-1991 trained lay people interviewed all 4051 participants at home.
The interview comprised the Dutch version of the Geriatric Mental State
Schedule (GMSS) (Copeland et al,
1976; Gurland et al,
1976; Hooijer et al,
1991), questions on socio-demographic characteristics, current
health status, medical history, and four mental status tests, including the
Mini-Mental State Examination (MMSE)
(Folstein et al,
1975). Depression was measured using the GMSS, in conjunction with
its computerised diagnostic system AGECAT
(Dewey & Copeland, 1986).
The GMSS is a structured interview aimed at identifying various psychiatric
disorders, which has been specifically designed for use with elderly
individuals. AGECAT consists of the application of hierarchical rules to the
items of the GMSS in order to reach a diagnosis for various psychiatric
disorders (e.g. depression and dementia syndromes) with different levels of
confidence. The presence and absence of depression were indicated by
GMS-AGECAT depression syndrome levels 3-6 and 0-2, respectively.
To select a study sample with normal cognition, a cohort without dementia was first selected by excluding from the baseline sample all subjects (n=273) with a DSM-III-R dementia diagnosis (American Psychiatric Association, 1987) (for a more detailed description see Jonker et al, 1998) or a GMS-AGECAT dementia diagnosis (i.e. organic illness syndrome levels of 3-5). Second, from this cohort without dementia all subjects with sub-threshold levels of dementia were excluded: that is, with GMS-AGECAT dementia levels of 1-2 or MMSE scores of 25 and below (n=631). In all, 904 subjects were excluded, resulting in a study sample of 3147 non-demented subjects with normal cognition (i.e. MMSE scores of 26-30 and GMS-AGECAT organic illness score 0).
LASA
In 1992-1993, trained lay people interviewed all 3107 participants at home.
Cognitive functioning was measured with the MMSE. Depressive symptoms were
measured with the Dutch version of the Center for Epidemiologic Studies
Depression Scale (CES-D) (Beekman et
al, 1997). This is a 20-item self-report scale developed to
measure current depressive symptoms in the community. The CES-D generates a
total score which can range from 0 to 60. In order to identify respondents
with clinically relevant levels of depression, the generally used cut-off
score of 16 was also used. To minimise overlap between affective symptoms
and symptoms possibly due to physical illness, analyses were also performed
using a sub-scale constructed of seven items of the CES-D reflecting negative
affect (bothered, blues, depressed, fearful, lonely, cried and sad)
(Radloff & Teri, 1986).
Scores on the negative affect subscale range from 0 to 20 points, with higher
scores indicating greater severity.
For the present study, a sample with normal cognition was selected by excluding all subjects of the baseline sample with MMSE scores below 26, resulting in a study sample of 2399 people.
Follow-up measurements
AMSTEL
At follow-up in 1994, all the subjects who were available were interviewed
again by trained lay people, using the same interview procedure as in 1990-91.
A subsample of subjects who were suspected of having developed dementia were
invited for diagnostic evaluation. The screening procedure and diagnostic
evaluation have been described elsewhere
(Geerlings et al,
1999). In brief, all subjects with MMSE scores of 23 or less, or
with impairment in orientation in time, recent memory or learning, were
invited for diagnostic evaluation. During home visits, physicians specifically
trained for this purpose administered the Cambridge Examination for Mental
Disorders in the Elderly (including a structured psychiatric interview, the
Cambridge Cognitive Examination, and a physical examination)
(Roth et al, 1988).
Clinical diagnoses of Alzheimer's disease were made according to DSM-IV
criteria (American Psychiatric Association,
1994). Diagnoses were determined during weekly meetings with the
senior neurologist (C.J.) and the neuropsychologist (M.I.G.).
LASA
At follow-up in 1995-1996, all the respondents who were available were
interviewed again during home visits, using the same interview procedure as
was used at baseline.
Statistical analyses
AMSTEL
Multiple logistic regression analyses were performed to assess the effect
of depression on incident Alzheimer's disease. Covariates used in the analyses
were age, gender, level of education, memory complaints and psychiatric
history. Level of education was expressed as the number of full-time years of
education needed to obtain the highest grade of education completed. In the
analyses, it was used both as a continuous and as a dichotomous variable
(dichotomised at the median of the study sample into 8 years v.
>8 years of education; 8 years of education is comparable with 2 years of
secondary education after having completed primary school). Memory complaints
were assessed by the question: "Do you have complaints about your
memory?" Answers were coded "yes" or "no".
Psychiatric history was assessed by the question: "Have you ever had
emotional or nervous illness requiring treatment?" If answered
positively, age of onset was assessed. Psychiatric history was categorised as
no history, or first onset at age 60 or above, v. a psychiatric
history before age 60.
First, the analyses were performed, with adjustments for the potential confounders. Second, since the strength of the association between depression and incident Alzheimer's disease may be different for people with different demographic characteristics and for those with or without memory complaints or psychiatric history, we also tested possible interactions between depression and age, gender, education, memory complaints and psychiatric history, respectively.
LASA
Multiple logistic regression analyses were performed to assess the effect
of depressive symptoms on cognitive decline. Cognitive decline was defined as
a drop of 3 or more points (>1 standard deviation) in the MMSE at
follow-up. Depressive symptoms were used in the analyses as a continuous
variable (total CES-D score, and negative affect score), as a dichotomised
variable (CES-D 16 v. <16), and as a categorical variable (the
core depression item from the CES-D ("during the past week I felt
depressed") was used to examine the association between mild depressed
mood ("some of the time" v. "no") and
incident cognitive decline and a severe depressed mood
("often/always" v. "no") and incident
cognitive decline, respectively. The same covariates as in the AMSTEL sample
were used. However, in LASA, data on psychiatric history were not collected
and were not therefore used in the analyses of the LASA data. Interactions
between the different definitions of depression and the covariates were also
tested. Finally, to correct for possible differences in baseline MMSE scores
between the two groups with different educational levels, we also performed
the analyses with additional adjustments for baseline MMSE score (range
26-30).
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RESULTS |
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Table 2 shows the baseline characteristics for those who were and were not available for follow-up.
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Table 3 shows the crude and adjusted odds ratios of incident Alzheimer's disease associated with depression, age, gender, education, memory complaints and psychiatric history. Depression moderately increased the risk of Alzheimer's disease. In the multivariate model, with adjustments for all other variables, the odds ratio of Alzheimer's disease associated with depression decreased towards a statistically nonsignificant level.
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Interaction terms added to the model containing all covariates showed that the association between depression and Alzheimer's disease was modified by education (centred variable) (likelihood ratio test, P=0.023). The interaction term was also statistically significant when education was used as a dichotomous variable (P=0.004). There were no statistically significant interactions between depression and memory complaints or between depression and psychiatric history, nor were there between depression and age or gender.
To interpret the modifying effect of education on the association between depression and incident Alzheimer's disease, we performed logistic regression analyses within two groups having had education to different levels (dichotomised at the median value of the study sample). Depression greatly increased the risk of Alzheimer's disease among subjects with more than 8 years of education, but not among subjects with 8 years of education or less (Table 4).
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LASA
Table 5 shows the baseline
characteristics of the LASA study sample (n=2399) according to the
presence or absence of depression. The duration of follow-up averaged 3.1
years. Figure 2 shows the
numbers of people who were available for follow-up and who were lost to
follow-up.
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Table 6 shows the baseline characteristics for subjects who were and were not available for follow-up. At follow-up, 251 people showed a drop of three or more points on the MMSE.
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Multiple regression analyses adjusting for age, gender, education and
memory complaints showed that neither higher scores on the continuous CES-D
nor CES-D scores of 16 were associated with subsequent cognitive decline
(adjusted odds ratio (OR)=1.01; 95% confidence interval (CI)=0.99-1.03 and
OR=1.07; 95% CI=0.70-1.62, respectively). However, negative affect increased
the risk of cognitive decline (adjusted OR per point increase=1.05; 95%
CI=1.00-1.09). A severe depressed mood was also associated with subsequent
cognitive decline (adjusted OR=1.97; 95% CI=1.09-3.56), but a mild depressed
mood was not (OR=1.05; 95% CI=0.71-1.57).
When the interaction between CES-D (centred variable) and education (dichotomous variable) was entered into the model containing CES-D (as a continuous variable), age, gender, education and memory complaints, the association between depressive symptoms and cognitive decline was modified by education (P=0.012). A similar result was found when the dichotomised variable was used in the interaction term (P=0.047) and when negative affect was used in the interaction term (P=0.017). Finally, the interaction between a severe depressed mood and education was of borderline significance (P=0.076), but the interaction between mild depressed mood and education was not (P=0.74). No significant interactions between depressive symptoms and one of the other covariates was found.
Logistic regression analyses stratified by level of education showed that
depressive symptoms were associated with cognitive decline among subjects with
more than 8 years of education, but not among those with 8 years of education
or less (Table 7). Although the
association between CES-D scores of 16 and cognitive decline was
attenuated after adjusting for the possible confounders, higher scores on the
continuous CES-D, higher negative affect scores and a severe depressed mood
remained predictive of subsequent cognitive decline
(Table 7). Among less-educated
subjects, no association between depressive symptoms and cognitive decline was
found, regardless of the definition of depressive symptoms. When the
multivariate analyses were performed with additional adjustments for baseline
MMSE score, the results were very similar.
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DISCUSSION |
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Depression as a psychological reaction
Most commonly, two explanations have been suggested for the frequent
occurrence of depression in Alzheimer's disease patients. First, depression
may be a psychological reaction to perceived cognitive decline
(Migliorelli et al,
1995) that may particularly occur in mild stages of Alzheimer's
disease, when patients may still be aware of their failing cognitive
capacities (Ott et al,
1992). Although this explanation implies that depression is a
consequence of the dementia process, depressive symptoms may become apparent
before the diagnosis of Alzheimer's disease is made. The development of the
illness is a gradual process that may start long before the diagnostic
criteria are met, and patients may notice these changes in cognition at an
early stage of the disease, and develop depressive symptoms as a reaction.
However, although the prevalence of depression has been found to be inversely
related to the severity of dementia
(Fischer et al,
1990), others found no association between depression and insight
into cognitive deficits (Verhey et
al, 1993; Cummings et
al, 1995), suggesting that the association is not purely a
psychological one. Moreover, if the explanation were psychological, the
association between depression and incident Alzheimer's disease would be
modified by memory complaints, since these may reflect realistic
self-observation of cognitive decline
(Geerlings et al,
1999). Although memory complaints were more prevalent among
depressed subjects than among non-depressed subjects, we did not find that the
association between depression and incident Alzheimer's disease was stronger
among those with memory complaints. Finally, a psychological mechanism does
not explain the observed interaction between depression and education.
Depression as an early symptom of Alzheimer's disease
Our data may agree better with the second explanation, which hypothesises
that depression is an early symptom of the neuropathological process of
Alzheimer's disease. Studies on neurochemical and neuropathological changes in
the brain of people with Alzheimer's disease suggest either that they may have
lower thresholds for depressive disorders, or that the dementia process
contributes to the development of depression
(Zubenko & Moossy, 1988;
Zweig et al, 1988;
Förstl
et al, 1992). It could be that depression as an early
symptom or a subclinical expression of Alzheimer's disease may have become
more overt in more highly educated people, who may have greater reserve
capacity. This may be a brain reserve, reflected in a
greater number of large neurons, greater brain weight or increased neocortical
synaptic density (Katzman,
1993), or a cognitive reserve, reflected in greater
intellectual capacity or coping skills more adequate to deal with the dementia
process (Stern et al,
1994). Several studies suggest that the neuropathological process
of Alzheimer's disease may be more advanced in elderly people with higher
levels of educational and occupational attainment than in those with lower
levels (Stern et al,
1995a,
b), despite similar
clinical severity. Thus, it is possible that in people with greater
(cognitive) reserve the cognitive symptoms of Alzheimer's disease may be
delayed, but not the depressive symptoms of the disease.
In the LASA sample, the association between depressive symptoms and cognitive decline became stronger when the analyses were restricted to affective symptoms and to a more severe form of these symptoms. The observation that a severe depressed mood was strongly associated with subsequent cognitive decline may also support the hypothesis that depression is an early manifestation of a dementia process. A severe depressed mood is a more specific indicator of major depression (Meyers & Bruce, 1998), and this could indicate some biological relationship rather than a purely psychological one (Migliorelli et al, 1995).
Psychiatric history
In the AMSTEL sample, no modifying effect of psychiatric history on the
association between depression and Alzheimer's disease was observed, as might
have been expected if late-onset depression were associated with organic
illness (Alexopoulos et al,
1988). However, there may not have been enough observations in the
subgroups for the interaction term to be statistically significant, since at
baseline the majority (80%) of depressed people reported no psychiatric
history or a late-onset history. This finding in itself suggests that the
depression that we observed in our study sample is indicative of a dementia
process.
LASA and AMSTEL
The most notable strength of this study was that we were able to analyse
data from two independent samples. Both the AMSTEL and the LASA studies are
prospective community-based studies in The Netherlands; both cohorts contain
elderly people who were interviewed at home, and the follow-up interval
between the first and the second assessment was very similar in both studies.
An important difference is that the samples were drawn independently of one
another and for different purposes. Moreover, depression and cognitive decline
or dementia were assessed using different instruments. In the AMSTEL study,
depression was assessed with the GMSS, which is an instrument based on the
British tradition, while the CES-D, used in the LASA study, is more widely
used in the USA. Furthermore, although both instruments measure a broad
spectrum of depressive symptoms, the CES-D contains fewer items than the GMSS
and does not rely on the clinical judgement of the interviewer. With respect
to the outcome variable, the differences between a clinical diagnosis of
Alzheimer's disease and cognitive decline based on a subtraction score on the
MMSE may be even greater. In view of these differences in both determinant and
outcome, it is striking that the results of both the LASA and the AMSTEL
studies demonstrated that depression increased the risk of cognitive decline
and Alzheimer's disease only among subjects with higher levels of
education.
Loss to follow-up
We have to consider that our findings may be biased because of differential
loss to follow-up. Particularly in the AMSTEL sample, the proportion of
subjects lost to follow-up was considerable. Although depressed people were
not more likely to be lost to follow-up in this sample, in the LASA sample
depressed subjects did become lost more often. However, we consider it
unlikely that in the LASA sample the great difference in odds ratios between
the two groups with different levels of education for those with a severe
depressed mood is explained by differential loss to follow-up alone.
Highly educated elderly at greater risk
We observed in two independent community-based samples that depressed
elderly people with normal cognition and higher levels of education were at
increased risk of incident cognitive decline and Alzheimer's disease. The data
do not support the hypothesis that depression is primarily a psychological
reaction to deteriorating cognitive capacities. Instead, they support the
hypothesis that depression is a subclinical expression or an early symptom of
an underlying dementia process, which may become apparent in a subgroup of
more highly educated older people in whom commonly used mental status tests do
not yet detect a decline from a previous level of cognitive functioning. The
data do not provide proof of possible pathogenetic mechanisms, however, and it
remains to be determined whether treatment of depression would result in a
delay of the clinical expression of cognitive decline and dementia.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication May 27, 1999. Revision received October 20, 1999. Accepted for publication October 27, 1999.