Apathy is associated with faster global cognitive decline and early nursing home admission in dementia with Lewy bodies

Apathy, defined as reduced motivation, reduced voluntary and goal-directed behavior, or reduced social interests and emotional blunting [1], is one of the most prevalent and important neuropsychiatric symptoms in dementia [2‐4]. Reported apathy prevalence rates for outpatients with Alzheimer’s disease (AD) lie between 25% and 93%, and estimates exceed 50% for patients with mild dementia with Lewy bodies (DLB) [2, 5]. Apathy can be divided into cognitive, motor, and affective symptoms, depending on the most affected prefrontal-basal ganglia circuits. However, the neurobiology of apathy is still not well understood [4].

Symptoms seen in neuropsychiatric disorders can mask, mimic, or enhance apathy. Apathy is highly correlated with depression in patients with AD [6], and the two can be difficult to separate owing to overlapping symptoms. Nonetheless, apathy is a distinct syndrome from depression [7]. It is characterized by a lack of negative thoughts, less emotional distress, less sadness, less vegetative symptoms, and fewer somatic complaints than typically seen in depression [4].

Apathy in AD is associated with increased caregiver burden [8], decreased functioning in activities of daily living (ADL) [9], and more morbidity [10]. The presence of apathy in patients with mild cognitive impairment increases the risk of conversion to AD [11]. Previous findings regarding cognitive dysfunction in patients with apathy are contradictory. It has been reported that in AD, patients with apathy have lower Mini Mental State Examination (MMSE) scores than patients without apathy [12], whereas others have found no differences [13‐15]. In studies that also included a small number of patients with DLB, no associations were found between apathy and MMSE scores [16, 17]. In neuropsychological tests, patients with AD and apathy have demonstrated more impairment in impulse control [18, 19], attention [18], visual memory [15], verbal memory [13, 18], naming, phonological verbal fluency [13], and semantic verbal fluency [14] than patients with AD without apathy. For patients with DLB, there were no associations between apathy and verbal memory, phonemic verbal fluency, and naming, except for a negative correlation between apathy and an executive task of sorting [17]. Patients with AD that, during a period of 1–4 years, developed apathy showed a faster cognitive and ADL decline than patients who did not develop apathy [7]. Even though an apathy-executive function syndrome has been described in different dementias, and although apathy rather than depression influences executive skills [20], the results of previous research are internally contradictory and inconclusive.

In extreme cases, apathy can be seen as a way of dying, because adequate response to changes in the environment is necessary for survival. The association between apathy and higher mortality is well documented in patients with AD [10, 21]. Apathy may also lead to faster nursing home admission for patients with AD [22].

There are few studies regarding apathy in AD and particularly few in DLB. We therefore investigated whether apathy was associated with shorter survival and higher risk of nursing home admission, as well as if apathy was associated with cognitive impairment at baseline. Finally, we examined if apathy was associated with faster global cognitive decline over 4 years as measured by MMSE. All analyses were performed in the total sample and stratified in AD and DLB.

Patients with dementia and apathy had reduced executive function as measured in neuropsychological domains and in the Stroop color test, even after controlling for depression, which was moderately correlated with apathy. When comparing AD and DLB separately, the only significant difference was found in the DLB group, where patients with apathy had more verbal learning deficits than the nonapathy group. This could be explained by patients with AD having temporal lobe deficits and difficulties with learning in general, regardless of frontal lobe function/apathy. In DLB where temporal lobe pathology is not advanced, patients with apathy and frontal lobe dysfunction/apathy have deficits in using learning strategies that are controlled by the frontal lobes and have scores at the same level as patients with AD. However, we found no significant differences in the executive domain in the DLB group, which then would have been expected. In the executive domain, we included a test typically associated with attention. The relationship between attention and executive functions is still debated. It has been suggested that they are interrelated but have different anatomical components [36], so the use of a too-wide concept for the executive domain and too few or suboptimal executive tests (i.e., semantic fluency instead of phonological fluency) could explain the internal contradictory result. There was also more use of dementia medication in the nonapathy DLB group, which could have a positive effect on apathy and cognition. In addition, multiple analyses were performed, so there is a risk of committing family-wise statistical errors (inflated risk of type I errors). It should also be noted, as previously mentioned, that other studies have found worse cognitive performance in AD patients with apathy than in patients without apathy [13‐15, 18, 19].

In sum, the results are not as expected, because in general we found few significant associations with apathy for neuropsychological tests at baseline. On the basis of previous studies, including studies by our group, there is a lack of strong support for the apathy-dysexecutive-frontal syndrome in cognitive tests, whereas it is clearly supported in brain function studies with different approaches [37]. There are only a few studies regarding apathy and neuropsychological tests, and the numbers of patients are often small; therefore, unexpected nonsignificant results could be due to low statistical power. To the best of our knowledge of this literature, we have included the largest number of patients with DLB and the third largest number of patients with AD.

In patients with DLB, we found that apathy was associated with a faster progression in MMSE over 4 years, and it was not explained by depression. Neither is it likely to be caused by the use of dementia medication, because the same number of patients used these drugs after the day of inclusion. The observation may be a result of more negative interactions between apathy and other Behavioral and Psychological Symptoms of Dementia (BPSD), such as visual hallucinations, that are more prevalent in DLB than in AD, which also are correlated with executive dysfunction [38]. It could also be due to differences in genetic profiles and cortical pathology. If dementia medication had a hypothetical positive effect on apathy and progression, this effect would have had its origin from before the patients were included in the study.

Patients with DLB had shorter survival time than patients with AD, but this was not associated with apathy. Several previous studies have also indicated a shorter survival in DLB than in AD [39, 40]. On one hand, time until nursing home admission was more than 1 year shorter for DLB with apathy than for those without, but on the other hand, we found the same rate of survival for the two groups. If we put forward the premise that patients, at group levels, are expected to live approximately the same period of time after nursing home admission, we could hypothetically explain the equal time of survival by better caregiving, more activity, and treatment at the nursing home. This counteracts apathy and helps patients with DLB and apathy live as long as patients with DLB without apathy. There were no statistical differences in health status for patients with and without apathy in DLB, and therefore this could not explain the observation. We do not have information about the quality of caregiver support, but caregiver stress did not influence the results.

Some caution should be taken when interpreting the results. There were some missing data, because a natural consequence of studying patients who are elderly and have a progressing disease. GLMM analyses are an appropriate approach that can compensate to some degree for missing data at random.

As anyone who has performed neuropsychological testing of apathetic patients knows, these patients’ lack of motivation to perform on tests is an obvious problem. We do not have information about the patients’ test effort and therefore could not control for it in the analyses. We have not discussed different types of apathy or the concept of apathy and differential symptoms/diagnosis, but we have operationalized it as what is measured by the apathy subscale on the NPI, rated by the caregivers. Neither did we include information from the patients, because apathy and insight are negatively correlated and will affect validity [4]. Some have asked for a unified assessment tool for apathy in the dementia population. The NPI is one of the most often used instruments for assessing BPSD in patients with dementia and should adequately assess apathy and depression independently [41], but it should be noted that only few studies have investigated the psychometric properties of the NPI in the DLB population.

The MMSE, which was used in the longitudinal analyses, is also often criticized for not having high sensitivity for changes in cognition in pure DLB [42]. However, the test has been found to be valid in patients with Parkinson’s disease, who share similar pathology to patients with DLB [43].

In this study, we performed multiple analyses at baseline, and there is a legitimate possibility of observing significant results simply due to chance. However, by using methods such as the Bonferroni correction, we could risk rejecting H1 even if it were true (type II error). Because we mainly had negative results, and because the consequence of falsely stating that apathy has no negative associations could be worse than the opposite, we chose not to adjust the alpha-level. Nevertheless, we acknowledge that an analytic approach defined purely a priori would have yielded more robust results.

A strength of the study is that it provides knowledge about apathy in DLB, which is an issue that has not been addressed before and can offer useful information to patients, their caregivers, clinicians, and the community. It provides information on prognosis and focuses on apathy in dementia, which should be assessed and intervened when necessary. The study also has a relatively large number of patients with DLB, and they were followed over 4 years with regard to cognition, and longer for nursing home admission and survival. Patients were thoroughly evaluated and diagnosed (i.e., the majority of patients with DLB had undergone ¹²³I-FP-CIT SPECT [DaTSCAN]), including brain autopsy. We have previously reported that in our sample, autopsy in 43 cases showed 92% sensitivity and 83% specificity for the clinical diagnoses [44].

Apathy seems to be associated with more serious consequences in DLB than in AD. Although there were only few differences in neuropsychological tests at baseline, apathy in patients with DLB was associated with faster cognitive decline in MMSE over 4 years and shorter time until nursing home admission. It is important to focus on apathy in dementia because it is one of the most prevalent BPSD symptoms, and interventions are required when apathy is present. More research is needed (i.e., studies with more patients with DLB) that differentiates apathy into subcategories and includes genetic information and pathologically confirmed diagnosis.