Am J Psychiatry 158:872-877, June 2001
© 2001 American Psychiatric Association
Syndromic Validity of Apathy in Alzheimer’s Disease
Sergio E. Starkstein, M.D., Ph.D.,
Gustavo Petracca, M.D.,
Erán Chemerinski, M.D., and
Janus Kremer, M.D.
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Abstract
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OBJECTIVE: The study examined the usefulness and clinical correlates of specific diagnostic criteria for apathy in Alzheimer’s disease. Whereas apathy is a frequent behavioral change in patients with Alzheimer’s disease, the lack of standardized diagnostic criteria may explain the wide discrepancies in estimates of the frequency and demographic and clinical correlates of apathy. METHOD: A consecutive series of 319 patients who met the criteria for probable Alzheimer’s disease established by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, 117 patients who met the DSM-IV criteria for depression without dementia, and 36 healthy individuals were assessed with a structured psychiatric interview. On the basis of modified Marin’s criteria for apathy, they were classified into groups with or without apathy. RESULTS: Apathy was diagnosed in 37% of the 319 Alzheimer’s disease patients, compared to none of the healthy comparison subjects. In 24% of the Alzheimer’s disease sample, apathy coexisted with either dysthymic disorder or major depressive disorder, whereas 13% had apathy without depression. Apathy was diagnosed in 32% of the depressed nondemented patients, mostly in those with major depressive disorder. Apathy in Alzheimer’s disease was significantly associated with severe impairments in activities of daily living and cognitive functions, older age, and poor awareness of behavioral and cognitive changes. CONCLUSIONS: This study provides partial validation of specific clinical criteria for apathy in Alzheimer’s disease.
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Introduction
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Apathy is a term coined by the Greek Stoic philosophers to refer to the condition of being free from emotions and passions, such as fear, pain, desire, and pleasure. In the neuropsychiatric literature, apathy has been defined as the absence or lack of feeling, emotion, interest, concern, or motivation not attributable to a decreased level of consciousness, cognitive impairment, or emotional distress (1, 2). Among neurological disorders, apathy was reported to be highly frequent in patients with stroke, Parkinson’s disease, Alzheimer’s disease, or traumatic brain injury (3–10). An important methodological limitation is the lack of valid and reliable diagnostic criteria, as well as structured interviews for apathy. Some authors have reported correlations between apathy and other behavioral scores, but they did not categorize patients by whether they were apathetic (6), whereas other studies have diagnosed apathy on the basis of arbitrary cutoff scores on apathy scales (3–5).
The present study had several aims. The first aim was to examine the usefulness of and provide partial validation for Marin’s criteria for apathy (1). Since apathy has been identified as a frequent behavioral change in Alzheimer’s disease, we expected Marin’s criteria to demonstrate a significantly higher frequency of apathy in Alzheimer’s disease patients, compared to healthy comparison subjects. Finding a group of Alzheimer’s disease patients who met Marin’s criteria for apathy but not the DSM-IV criteria for depression would provide further validity. A second aim was to examine the related diagnostic problem of whether Alzheimer’s disease patients are able to provide a reliable account of apathy symptoms. To examine this issue, we assessed with the same apathy scale both the patients and their respective caregivers. Since the overlap of apathy and depression in Alzheimer’s disease may result from either the association of apathy and a specific type of depression or from an interaction between depression and the dementing process, we separated depressed Alzheimer’s disease patients into those with major or minor depression, and also assessed apathy in a consecutive series of nondemented patients with primary depression (i.e., no known brain injury). The final aim was to further validate the syndrome of apathy by examining whether Alzheimer’s disease patients who met the criteria for apathy had specific demographic or clinical correlates.
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Method
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Patients
Alzheimer’s disease group
This group consisted of a consecutive series of 319 patients examined for progressive cognitive decline at the dementia clinic of our institution. The patients met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria (11) for probable Alzheimer’s disease. None of them had a history of stroke, any evidence of focal lesions on a magnetic resonance imaging (MRI) brain scan (T1-weighted), or a Hachinski ischemic score >4 (12).
Depression group
This group included a consecutive series of 117 patients with depressed mood who were examined at the psychiatry clinic of our institution. The inclusion criteria were 1) a DSM-IV diagnosis of either major depressive disorder (hereafter referred to as major depression) or dysthymic disorder (hereafter referred to as minor depression), 2) no DSM-IV criteria for dementia, and 3) a normal MRI scan.
Healthy comparison group
This group included 36 healthy individuals (typically volunteers or personnel from our institution) with a normal neurological and psychiatric evaluation and a normal MRI scan. Hyperintensities on T2-weighted MRI images were not considered an exclusion criterion for any of the three study groups.
Neurological and Psychiatric Examination
After the study methods were fully explained, written informed consent was obtained from the patients and their respective caregivers and from the healthy comparison subjects. The Alzheimer’s disease patients and the depressed patients were assessed by a neurologist with the Unified Parkinson’s Disease Rating Scale (13), a widely used scale for assessing the severity of extrapyramidal symptoms.
Psychiatric evaluations were completed by a psychiatrist who was blind to the neurological findings. The evaluation included administration of the Mini-Mental State (14), a global measure of cognitive deficits; the Clinical Dementia Rating (15), a global rating device for dementia stages; the Structured Clinical Interview for DSM-IV (SCID) (16), a semistructured diagnostic interview for assessing signs and symptoms necessary for the major axis I DSM-IV diagnoses; the Hamilton Depression Rating Scale (17), a 17-item interviewer-rated scale for rating the severity of symptoms of depression; the Anosognosia Questionnaire—Dementia (18), which rates the severity of unawareness of cognitive deficits and behavioral changes; and the Functional Independence Measure (19), which assesses activities of daily living.
Diagnosis of Apathy
Marin (1) proposed diagnostic criteria for the syndrome of apathy on the basis of its distinction from the overt behavioral, cognitive, and emotional concomitants of goal-directed behavior. We operationalized Marin’s criteria into the set of criteria listed in Appendix 1. On the basis of Marin’s apathy scale (20), we designed a 14-item apathy scale that can be used with patients and caregivers (3–5). For the present study, the apathy scale was used to generate diagnoses by means of a specific diagnostic scheme (available from the authors). For the Alzheimer’s disease patients, diagnoses of apathy were generated on the basis of their caregivers’ ratings on the apathy scale.
The patients’ results on the SCID and Marin’s criteria for apathy were used to assign the Alzheimer’s disease patients to one of four groups: 1) those who met the DSM-IV criteria for either major or minor depression but not the criteria for apathy, 2) those who met the criteria for both depression and apathy, 3) those who met the criteria for apathy but not depression, and 4) those who did not meet the criteria for apathy or depression. The diagnostic criteria for apathy were also used to assign the patients with primary depression (major or minor depression) to groups with or without apathy.
Statistical Analysis
Statistical analysis was carried out by using means and standard deviations, one-way analysis of variance (ANOVA), and Tukey’s honestly significant difference post hoc tests. Frequency distributions were calculated with chi-square and Fisher’s exact tests. All p values were two-tailed.
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Results
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Frequency of Apathy
Forty-two (13.2%) of the 319 Alzheimer’s disease patients had apathy only (i.e., without depression), compared to none of the 36 healthy comparison subjects ( 2=10.7, df=1, p<0.001). Depression and apathy were both present in 75 Alzheimer’s disease patients (23.5%), whereas 69 Alzheimer’s disease patients (21.6%) had depression but no apathy, and the remaining 133 Alzheimer’s disease patients (41.7%) had neither apathy nor depression. Minor depression was diagnosed in 58 of the 144 depressed Alzheimer’s disease patients (40.3%), whereas the remaining 86 (59.7%) had major depression. The Alzheimer’s disease patients with either major or minor depression showed a significantly higher frequency of apathy, compared to those without depression (51.2%, N=44; 53.4%, N=31; and 24.0%, N=42; respectively) (2=26.9, df=2, p<0.0001).
Apathy was present in 35 of the 95 nondemented patients with major depression (36.8%), compared with two of the 22 nondemented patients with minor depression (9.1%) (2=6.36, df=1, p=0.01). The frequency of apathy in the Alzheimer’s disease patients with major depression was significantly higher than in the nondemented patients with major depression (51.2%, N=44, and 36.8%, N=35, respectively) (2=3.76, df=1, p=0.05). Similarly, the Alzheimer’s disease patients with minor depression had a significantly higher frequency of apathy, compared to the nondemented patients with minor depression (53.4%, N=31, and 9.1%, N=2, respectively) (2=12.9, df=1, p<0.001).
Clinical Correlates of Apathy in Alzheimer’s Disease
We examined significant differences in demographic and clinical variables between the four Alzheimer’s disease groups. There were no significant between-group differences in age, gender, or education, or in the proportion of patients who received neuroleptics, antidepressants, or anxiolytics (Table 1). Hamilton depression scale scores were significantly different between groups (Table 1). Post hoc tests showed that both depressed Alzheimer’s disease groups (with or without apathy) had significantly higher depression scores than the two nondepressed Alzheimer’s disease groups (p<0.0001, Tukey). There were no significant differences in Hamilton depression scale scores between the two depressed Alzheimer’s disease groups and between the two nondepressed Alzheimer’s disease groups (with or without apathy). There was an expected significant between-group difference in apathy scale scores (F=127.2, df=3, 315, p<0.0001). Post hoc tests showed that the Alzheimer’s disease patients with apathy (with or without depression) had significantly higher scores than those without apathy (p<0.0001, Tukey), and that the depressed Alzheimer’s disease patients without apathy had significantly higher apathy scores than the Alzheimer’s disease patients with neither apathy nor depression (p<0.05, Tukey). There was a significant effect for Functional Independence Measure scores (Table 1). The Alzheimer’s disease patients with apathy (with or without depression) had significantly more severe impairments in activities of daily living than those with neither apathy nor depression (p<0.01 and p<0.05, Tukey, respectively). Finally, there was a significant effect for Unified Parkinson’s Disease Rating Scale motor scores (Table 1). The Alzheimer’s disease patients with both apathy and depression (N=50) had significantly higher scores for extrapyramidal symptoms than nondepressed Alzheimer’s disease patients with apathy (N=29) (p<0.01, Tukey) or without apathy (N=104) (p<0.001, Tukey) (effect sizes 1.1 and 0.7, respectively) (Table 1).
A stepwise regression analysis that included apathy scale scores (rated by the caregiver) as the dependent variable, and age, Mini-Mental State score, and Hamilton depression scale score as the independent variables showed a significant correlation for all three comparisons (Hamilton depression scale score: R2=0.12, N=319, p<0.0001; Mini-Mental State score: R2=0.04, N=319, p<0.001, and age: R2=0.02, N=319, p<0.05).
Clinical Correlates of Apathy in Primary Depression
There were no significant differences in demographic variables between depressed patients with or without apathy, but patients with major depression and apathy had significantly higher Hamilton depression scale scores than those without apathy (mean Hamilton depression scale scores 24.4, SD=5.0, and mean=19.7, SD=5.9, respectively) (t=3.87, df=93, p<0.001, effect size=0.8). Patients with major depression had significantly lower Mini-Mental State scores than patients with minor depression, but patients with major depression, regardless of whether they had apathy, had similar Mini-Mental State scores (major depression and apathy: mean=24.0, SD=5.9; major depression without apathy: mean=25.7, SD=3.6; minor depression and apathy: mean=29.5, SD=0.7; minor depression without apathy: mean=28.0, SD=1.3). Nineteen patients with major depression and apathy (20.0%) received antidepressant medications.
Awareness of Apathy in Alzheimer’s Disease
Since Alzheimer’s disease patients have been reported to underrate their own cognitive deficits and behavioral problems (19), we examined discrepancies in apathy scale scores obtained in separate interviews from the Alzheimer’s disease patients and their respective caregivers. The last 97 Alzheimer’s disease patients from our present series were assessed with the apathy scale by a psychiatrist who was blind to their respective caregivers’ ratings. A one-way ANOVA analyzing the difference between the patients’ and the caregivers’ scores showed a significant effect (F=3.73, df=3, 93, p<0.01). Post hoc tests showed a significantly greater discrepancy in apathy scale scores (caregivers > patients) for the Alzheimer’s disease patients with apathy without depression (N=12) than for the nonapathetic Alzheimer’s disease patients with depression (N=25) (p<0.01, Tukey) or without depression (N=44) (p<0.01, Tukey). The Alzheimer’s disease patients with both depression and apathy (N=16) had a significantly greater discrepancy in apathy scale scores than those with depression only (p<0.05, Tukey). We also examined lack of awareness of cognitive impairments using the Anosognosia Questionnaire—Dementia scores from patients and caregivers. A one-way ANOVA analyzing the difference between caregivers’ and patients’ ratings showed a significant effect (Table 1). Post hoc tests showed that the Alzheimer’s disease patients with apathy only had a significantly greater discrepancy in Anosognosia Questionnaire—Dementia scores than Alzheimer’s disease patients with depression only (p<0.01, Tukey).
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Discussion
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We assessed a specific set of clinical criteria for apathy in a large cohort of patients with probable Alzheimer’s disease, in patients with depression but no dementia, and in a group of age-comparable healthy individuals. There were several important findings. First, apathy in the absence of depression was diagnosed in 13% of a consecutive series of 319 patients with Alzheimer’s disease. This prevalence was significantly higher than in a group of 36 healthy individuals. An additional 30% of the Alzheimer’s disease patients had symptoms in two of the three domains of the apathy criteria. Second, apathy in Alzheimer’s disease was significantly associated with more severe impairments in activities of daily living and with patients’ poor insight into their apathy syndrome and cognitive deficits. There was a significant correlation between apathy scores and both age and Mini-Mental State scores (i.e., more severe apathy was significantly correlated with older age and more severe cognitive deficits). Third, the Alzheimer’s disease patients with apathy but not depression and those with neither apathy nor depression had similar depression scores, suggesting that apathy may not artificially increase depression scores. Fourth, the prevalence of apathy in the Alzheimer’s disease patients with minor depression was significantly higher than in the patients without dementia who had minor depression, but the differences were less marked between the Alzheimer’s disease patients with major depression and those with major depression who did not have dementia.
Before further comments, several limitations of our study should be pointed out. First, the assessment of apathy symptoms was based on a rating scale and not on a structured interview. Second, the severity ratings and diagnoses of apathy were both based on the same scale, which may partly account for the higher apathy scale scores in the Alzheimer’s disease groups with apathy. Third, our healthy comparison group consisted of individuals who volunteered to participate in the study, which may account for the lack of apathy in this group. Finally, the group with major depression and no dementia was about 20 years younger than the group with Alzheimer’s disease and depression. Future studies should examine whether age has a specific interaction with apathy and depression in these different populations.
The nosological position of apathy is a debated issue. Marin (1) discussed different definitions of apathy and proposed specific diagnostic criteria. Using a slightly modified and more structured version of these criteria, we diagnosed apathy in 36% of a consecutive series of patients with Alzheimer’s disease, compared to none of the healthy individuals. Although this finding was expected, it provides partial validation for Marin’s criteria. In our previous study of a smaller sample of Alzheimer’s disease patients, we found a frequency of apathy of 46% (5), and other studies reported frequencies ranging from 48% to 80% (2, 7, 21–23). The present study also demonstrated that most Alzheimer’s disease patients with apathy were also depressed, which replicates our previous finding in a smaller cohort (5).
To our knowledge, this is the first study to examine the frequency of apathy among patients with primary depression and no dementia, and there were two main findings. First, about one-third of the patients in the study had apathy, and second, this frequency was significantly higher in patients with major depression than in patients with minor depression. Since patients with major depression had significantly lower Mini-Mental State scores than patients with minor depression, cognitive deficits may partly account for the high prevalence of apathy in major depression. On the other hand, patients with major depression with or without apathy had similar Mini-Mental State scores, suggesting that cognitive impairment may be necessary but not sufficient to produce apathy among depressed nondemented individuals. Hyperintensities in T2-weighted MRI images have been reported to be significantly related to depression (24), and future studies should examine whether these abnormalities are also associated with apathy or with an apathetic subtype of depression.
Whereas apathy was significantly more prevalent in nondemented patients with major depression than in those with minor depression, Alzheimer’s disease patients with either minor or major depression showed a similar prevalence of apathy. These findings suggest 1) that once depression occurs in Alzheimer’s disease patients, these patients may have a "lower threshold" for apathy, compared to nondemented depressed individuals; and 2) that the high prevalence of apathy in Alzheimer’s disease may result from an interaction between depression and the dementing process.
Given the large overlap of apathy and depression, the question arises of whether apathy is always related to at least subsyndromal depression, which could argue against considering apathy as a specific behavioral syndrome. However, our finding that the Alzheimer’s disease patients with apathy but no depression and those with neither depression nor apathy had similar depression scores supports the validity of apathy as a behavioral syndrome independent from depression. Apathetic Alzheimer’s disease patients (with or without depression) also had significantly more severe impairments in activities of daily living and more severe extrapyramidal signs than nonapathetic Alzheimer’s disease patients, suggesting that apathy may account for some of the functional impairments in Alzheimer’s disease.
There also was an interesting association between apathy and less awareness of behavioral and cognitive changes. When Alzheimer’s disease patients and their respective caregivers were separately assessed with the apathy scale (with caregivers providing reports about patients), the discrepancy in scores (with patients providing lower scores than caregivers) was significantly larger for the nondepressed Alzheimer’s disease patients with apathy than for those without apathy. Similar results were found on the Anosognosia Questionnaire—Dementia, which primarily rates awareness about cognitive impairments. These findings demonstrate that Alzheimer’s disease patients with apathy have only partial awareness of their cognitive and behavioral changes and may provide unreliable answers.
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Footnotes
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Received April 14, 2000; revision received Oct. 5, 2000; accepted Jan. 8, 2001. From the Department of Neuropsychiatry, Raúl Carrea Institute of Neurological Research–Fundación Lucha contra las Enfermedades Neurologicas en la Infancia (FLENI), Buenos Aires, Argentina. Address reprint requests to Dr. Starkstein, FLENI, Montañeses 2325, 1428 Buenos Aires, Argentina; ses{at}fleni.org.ar (e-mail). Supported in part by grants from the Raul Carrea Institute of Neurological Research-FLENI and the Fundación Perez Companc.
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Abstract
Introduction
