Abstract
Objective: To examine preclinical depressive symptoms 3 years before the diagnosis of AD.
Methods: The authors compared incident AD patients and nondemented individuals in terms of baseline mood- and motivation-related symptoms of depression, and assessed whether depressive symptoms in preclinical AD are related to self-perceived memory problems. Participants came from a population-based longitudinal study on aging and dementia in Stockholm, Sweden. The sample consisted of 222 persons older than 74 years who were followed for a 3-year interval. Thirty-four individuals had developed AD at follow-up, whereas 188 remained nondemented. Dementia diagnosis was made according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised. Depressive symptoms were assessed by the Comprehensive Psychopathological Rating Scale.
Results: The incident AD patients had more depressive symptoms than the nondemented persons at baseline. There was a dominance of motivation-related symptoms of depression (e.g., lack of interest, loss of energy, concentration difficulties) in preclinical AD. This association remained when adjusting for subjective memory complaints.
Conclusions: Depressive symptoms are elevated preclinically in AD, and this elevation is not merely a by-product of self-perceived cognitive difficulties. Thus, depressive symptoms may be part of the preclinical phase in AD.
Depressive symptoms occur more frequently in demented compared with nondemented older adults.1,2 The prevalence of depressive disorders in patients with AD varies between 15 and 50%,2-4 and in nondemented elderly people it ranges between 1 and 10%.5-7 The relationship between depressive disorders and dementia is not fully understood. Some researchers have argued that depression is a risk factor for AD.8,9 A substantial proportion of those nondemented elderly individuals who experience a first episode of depression in late life will develop a dementia syndrome within 3 to 8 years after the onset of depression.9,10 Other investigators have suggested that depressive reactions may be an early sign of an impending dementia disease rather than a risk factor for AD.11,12 Indeed, given that AD has a rather long preclinical period, the observation that depressive episodes several years before the clinical onset of dementia is associated with AD may be interpreted as an early sign rather than as a risk factor.13 However, some researchers have observed a relationship between depression and dementia only for late-onset cases.14,15
Many important issues are still unresolved concerning the relationship between depression and dementia. For example, little is known about depressive symptomatology in persons who will develop AD because research has focused on symptom expression in clinical samples using retrospective data16,17 or has relied on information from caregivers and other secondary informants.18,19 The current study provides information about depressive symptoms in the preclinical phase of AD using prospective data.
In addition to examining the specific symptoms for major depression cited in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R),20 we explored two symptom constellations that have been termed mood-related (i.e., dysphoria, appetite disturbance, feelings of guilt, and thoughts of death/suicidal ideation) and motivation-related (i.e., lack of interest, psychomotor change, loss of energy, concentration difficulties) symptoms.21 Knowledge pertaining to whether there is a predominance of either mood- or motivation-related symptoms of depression in preclinical AD may shed light on the nature of the depressive signs. Specifically, if mood-related symptoms dominate in preclinical AD, this may reflect in part emotional reactions to self-perceived cognitive difficulties and, possibly, insight into an emerging disease process. By contrast, the existence of motivation-related symptoms may be independent of self-perceived cognitive decline and may reflect disease-related changes in brain regions critical to the allocation of attentional energy. To address this issue, we also determined the relationship between self-perceived memory problems and depressive symptoms.
Thus, three specific research questions were asked: 1) Do individuals who will develop AD present with an elevation in depressive signs and symptoms compared with control subjects 3 years before diagnosis? 2) If elevated depressive symptoms could be demonstrated, is there a predominance of either mood- or motivation-related symptoms? 3) Are these symptoms related to perceived decline in cognitive functioning or are they independent of subjectively experienced cognitive problems?
Methods.
Participants.
The original sample was taken from all the inhabitants age 75 years and older in the Kungsholmen parish of Stockholm, Sweden (2,368 individuals), who were included in a population survey on aging and dementia. A more detailed description of the population and methods used has been reported elsewhere.22,23 At baseline, 1,810 individuals from the whole study population were administered a questionnaire, which included the Mini-Mental State Examination (MMSE),24 to detect suspected dementia patients. All those with an MMSE score less than 24 (n = 314) and a random sample, stratified by age and gender, of those with an MMSE score more than 23 (n = 354) were assessed with extensive medical, neurologic, and psychiatric examinations; social and family interviews; laboratory blood analyses; and a comprehensive cognitive test battery. At follow-up, all participants were invited back to be examined approximately 3 years later. The same protocol was administered at this time. The Kungsholmen Project has been approved by the ethics committee of the Karolinska Institute, Sweden, and informed consent was obtained from all participants after details of the procedure were fully explained.
The diagnostic criteria and procedure used to reach the clinical diagnosis of dementia, as well as type of dementia, at baseline and follow-up is described in detail by Fratiglioni et al.,23 and involved multiple steps: In the first step, a preliminary diagnosis was made after a common discussion among geriatricians who had examined the participants and reviewed their social and family history. Step 2 involved a second preliminary diagnosis of all participants by a physician expert in dementia. In step 3, the two preliminary diagnoses were compared, and patients with discordant diagnoses were reviewed again by the physicians to ascertain causes of agreement and disagreement. This eliminated most of the discordant diagnoses. In those patients in whom disagreement persisted, the final diagnosis was made by a supervising physician. This process yielded a diagnosis of dementia and dementia type according to the DSM-III-R.20 At baseline, there were 225 persons who received a dementia diagnosis, whereas 443 were found to be nondemented. The current study focuses on those who were nondemented at the baseline assessment.
Of the 443 persons in the nondemented group, 45 were excluded from the current study because of incomplete psychiatric or cognitive data. Using data from the baseline assessment, we also eliminated 46 persons with MMSE scores less than 24,25 20 persons with psychiatric disease (e.g., depressive disorders, psychosis), 17 persons with a history of stroke, and three persons with PD. Of the remaining 312 participants, 34 were diagnosed with probable or possible AD after approximately 3 years of follow-up (mean, 3.08 years; SD, 0.58). In addition, nine individuals were diagnosed with dementia other than AD (e.g., vascular dementia, mixed vascular, unspecified), 52 had died, and 29 dropped out (e.g., refused, moved, could not be located). Thus, the final sample consisted of 34 incident AD and 188 nondemented persons.
Measures.
Depressive signs and symptoms.
A psychiatric examination was administered by physicians using the Comprehensive Psychopathological Rating Scale (CPRS).26 The CPRS is a structured psychiatric instrument with both directed questions and observations related to a variety of conditions, including depressive, anxiety, and sleep disorders, as well as psychotic symptoms. Symptoms and signs were rated on a 6-point scale, with definitions at every second step.26 Specific items in the CPRS match the symptoms for major depression according to the DSM-III-R.20 Thus, the relevant CPRS items were reviewed to examine whether a particular DSM-III-R symptom of depression was present. The depressive symptoms were separated into two categories, reflecting either mood- or motivation-related disturbance.21 The mood symptoms included dysphoria, appetite disturbance, feelings of guilt, and thoughts of death/suicidal ideation. The motivational symptoms included lack of interest, psychomotor change, loss of energy, and concentration difficulties. Although sleep disturbance is not part of either symptom cluster, it was included in the current analyses because it constitutes a symptom of major depression according to the DSM-III-R. In addition, the item assessing subjective memory complaints in the CPRS (range, 0 to 6 points) was included in the analyses.
Information was gathered at follow-up concerning prior psychiatric disorders, contact with health care professionals for psychiatric symptoms, and antidepressant drug treatment. None of the incident AD patients had a history of depression or other psychiatric disorder.
Background variables.
In addition to age, gender, and years of education, information regarding the participants’ level of global cognitive functioning and functional ability was gathered. Global cognitive functioning was indexed by the MMSE.24 A Swedish version of the test was administered according to standardized procedures, and the total score was a maximum of 30 points. Functional ability was assessed using the Katz activities of daily living index.27 This measure inquires about the person’s ability to perform tasks such as bathing, dressing, going to the toilet, transferring, continence, and feeding. The scale ranges from 1 (independent) to 6 (dependent).
Results.
Background characteristics of the incident AD and nondemented participants at baseline are presented in table 1. A multivariate analysis of variance (MANOVA) revealed an overall effect of group status (Wilks’ λ = 0.75, F[1,220] = 18.38, p < 0.001). Univariate analyses showed that the incident AD patients were older (F[1,220] = 6.91, p < 0.01), had lower MMSE scores (F[1,220] = 59.81, p < 0.001), and were more functionally impaired (F[1,219] = 4.72, p < 0.05) compared with the nondemented persons at baseline.
Baseline background characteristics of incident AD and nondemented persons
Baseline differences in depressive symptoms.
Mean-level analyses.
Table 2 displays the means and SDs for the depressive symptoms at baseline in the two groups. MANOVA indicated that the incident AD patients had more depressive symptoms at baseline than their nondemented counterparts (Wilks’ λ = 0.935, F[1,220] = 5.06, p < 0.01). Interestingly, at the level of the symptom clusters, the incident AD patients had more motivation-related symptoms than the nondemented persons (F[1,220] = 15.00, p < 0.001), although the two groups did not differ reliably regarding mood-related symptoms (F[1,220] = 2.90, p > 0.05).
Means and SDs in baseline depressive symptoms and subjective memory complaints of incident AD patients and nondemented persons
With respect to the individual motivation-related symptoms, the incident AD patients reported more lack of interest (F[1,220] = 16.08, p < 0.001), loss of energy (F[1,220] = 4.34, p < 0.05), and concentration difficulties (F[1,220] = 4.26, p < 0.05) compared with nondemented persons. Although there was no overall group difference in mood-related symptoms, the incident AD group had more thoughts of death than the control subjects (F[1,220] = 11.12, p < 0.001). The groups did not differ in the additional depressive symptom of sleep disturbance (p > 0.10). Lastly, the incident AD patients complained more about memory problems than the nondemented persons (F[1,220] = 10.42, p < 0.001; see table 2).
Logistic regression analyses.
To determine whether the higher frequency of depressive symptoms in preclinical cases of AD was independent of age, gender, and education, a series of logistic regression analyses was carried out. Two types of regressions were conducted. In the first model, age, gender, and education were entered as covariates, and the two clusters of depressive symptoms were then entered in stepwise fashion. Table 3 shows that individuals who were going to develop AD had more motivation-related symptoms than those who remained nondemented, although there was no significant group difference for mood-related symptoms. In model 2, those individual symptoms of depression for which there were significant group differences were entered as predictors, using the same covariates. As shown in table 3, this analysis revealed that two symptoms—lack of interest and thoughts of death—were reliable predictors of dementia status at follow-up.
Logistic regression analyses for predicting group status at follow-up
Given that 1) the two groups differed in subjective memory complaints and 2) self-perceived cognitive problems may be related to depressive symptoms in preclinical AD, we repeated the two models, entering subjective memory complaints between the covariates and the depressive symptoms in the regressions. These analyses showed that, although subjective memory complaints at baseline predicted dementia status at follow-up (odds ratio, 1.46; 95% CI, 1.08 to 1.97; p < 0.05), the results concerning the predictive power of the depressive symptoms remained unchanged (see table 3).
Discussion.
We found that persons who would develop AD during a 3-year interval had more depressive symptoms at baseline assessment than persons who remained nondemented at follow-up. Although elevated depressive symptoms have been demonstrated in clinically verified AD patients,1,3,4 and although depression has emerged as a risk factor for AD in studies using retrospective data,8,17 the result of an increase in depressive symptoms demonstrated prospectively in preclinical AD patients from the population at large constitutes a novel finding. It is important to note, however, that the increase of depressive symptoms in the incident AD patients was relatively small, and that none of the participants received a diagnosis of clinical depression at baseline.
There was converging evidence for a dominance of motivation-related over mood-related symptoms of depression in the preclinical phase of AD. First, the mean-level analysis revealed an overall difference in motivational symptoms between the incident AD patients and the control group. Reliable group differences were seen for lack of interest, loss of energy, and concentration difficulties. By contrast, for the mood symptoms the overall group difference did not approach significance, and the incident AD group showed a reliable increase in only one symptom—thoughts of death. Second, controlling for demographic variables in a logistic regression analysis, the cluster of motivational symptoms predicted diagnostic status at follow-up, whereas the mood cluster did not. Lastly, although both lack of interest and thoughts of death emerged as significant predictors of group membership in the logistic regression analysis focusing on individual symptoms, the predictive power of lack of interest exceeded that of thoughts of death. An important point to note is that, although the incident AD patients complained more about memory problems than the control subjects, the relationship between depressive symptoms and diagnostic status remained unchanged regardless of whether subjective memory complaints were controlled statistically.
Thus, the current pattern of findings suggests that depressive symptoms in the preclinical phase of AD may be related mostly to motivational factors rather than to factors typically associated with depression (e.g., dysphoria). To the extent that symptoms such as lack of interest, loss of energy, and concentration difficulties are common in the normal older population,5,28,29 these symptoms may be overlooked easily as early markers of an emerging dementing disease.
The motivational symptoms of depression are primarily cognitively loaded, and have been linked to the individual’s basic processing resources, such as the ability to focus attention on the task at hand, while closing out irrelevant information.30,31 For example, it has been demonstrated that motivation-related, but not mood-related, symptoms of depression predict cognitive performance in clinically nondepressed and nondemented older adults.30 It is well established that deficits in memory and other cognitive functions are common during the preclinical phase of AD.32,33 The current finding that the incident AD patients had lower MMSE scores at baseline than the control subjects confirms that cognitive impairment occurs before the time at which a clinical diagnosis of AD is rendered. Cognitive deficits in preclinical AD have been linked to early changes in both limbic and neocortical brain structures.34,35 Following this line of reasoning, the observation that the incident AD patients showed elevated motivational symptoms of depression 3 years before diagnosis may reflect early changes in brain regions critical to the ability to allocate and to sustain attentional energy.
At the level of the individual symptoms, lack of interest and thoughts of death predicted group status at follow-up. The finding that thoughts of death at baseline was related to incidence of AD is particularly intriguing because this symptom belongs to the mood cluster that, overall, was unrelated to incidence of AD. One possibility is that the elevation of this symptom reflects weariness of life rather than concrete death wishes among the incident AD patients. Note also that a major reason for the group difference observed for thoughts of death was the low frequency of this symptom in the nondemented persons. Future research is required to assess the replicability of this finding.
As noted, the increase of depressive symptoms in preclinical AD was unrelated to subjective memory complaints. This result suggests that the elevation of symptoms was not a mere reaction to self-perceived cognitive difficulties. The fact that the effects were not mediated through subjective memory problems is interesting in light of the observed dominance of motivation-related symptoms. Specifically, had there been an association between memory complaints and depressive symptoms, this association may have reflected insight into an emerging dementia disease and resulted in mood changes. In this way, the lack of relationship between memory complaints and depressive symptoms observed in this study is consistent with the view that mood-related symptoms are relatively uncommon in preclinical AD.
An interesting question concerns whether the balance between mood- and motivation-related symptoms of depression changes during the pathogenesis of AD. In clinical AD, there is evidence that mood-related symptoms dominate in mild to moderate stages, and that motivation-related symptoms dominate in severe stages of the disease.21 Comparing these findings with those of the current study, an interesting picture emerges: Although mood-related symptoms of depression may dominate in early clinical AD, there is a dominance of motivation-related symptoms both preclinically and in severe stages of the disease. This intriguing pattern appears to reflect the facts that the preclinical cognitive deficits in AD are not strong enough to trigger marked mood-related reactions, but also that a certain level of cognitive ability is required to feel or to express mood-related symptoms of depression.
Acknowledgments
Supported by grants from the Swedish Council for Research in the Humanities and the Social Sciences (L.B.) and the Swedish Council for Social Research (B.W., L.B.), and by predoctoral stipends from the Swedish Alzheimer’s Disease Foundation and the Swedish Council for Social Research (A-K.B.).
Acknowledgment
The authors thank all members of the Kungsholmen Project Study Group for collaboration and data collection.
- Received March 8, 1999.
- Accepted July 20, 1999.
References
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