Mortality Risks and Causes of Death by Dementia Types in a Japanese Cohort with Dementia: NCGG-STORIES

INTRODUCTION

Due to decreasing fertility rates and increasing longevity, the global population is experiencing a structural age shift, especially in developed countries [1]. Of the global burden of serious age-associated health-related conditions, dementia is expected to have the highest proportional increase (264% increase between 2016 and 2060) [2]. Among serious health-related conditions, dementia not only significantly affects individuals but also their families and the entire society. Furthermore, most cases of dementia are incurable and progressive, gradually leading to the loss of cognitive function and ultimately to death. Thus, understanding the prognosis of dementia is important for health policymakers to formulate policies and plans for national resources needed in the management of dementia along with provision of advanced care planning for patients, caregivers, and health professionals.

Previous studies have shown that the median survival time after a diagnosis of dementia varies from 3 to 6 years [3–5], and life expectancy in those with dementia is shorter than that in the general population [6–8]. The dementia type also affects life expectancy. A recent meta-analysis reported that survival time differed between dementia types, with those with dementia with Lewy bodies (DLB) having a shorter survival time than those with Alzheimer’s disease (AD) [9]. Of the dementia types, patients with vascular dementia (VaD) or DLB have been shown to have the shortest survival, followed by patients with AD [7]. Additionally, it has been reported that patients with mild cognitive impairments (MCI) also have shorter survival times than individuals with normal cognition [7, 10, 11]. Prognostic factors of patients with dementia have been reported, including age, sex, number of comorbid conditions, low socioeconomic status, functional disability, and low cognitive function [4, 12–16]. However, few studies have considered prognostic factors or causes of death based on the type of dementia. As mortality rates differ among dementia types, it is necessary to investigate the specific death-related information according to dementia type.

Additionally, previous studies in Asia on prognosis of dementia [17, 18] are limited, and those studies were conducted about a decade ago. The incidence and prevalence trend of dementia varies across countries, decreasing over the last two or three decades in America and Europe [19–21], but increasing in Eastern Asia [17, 22]. However, it is unclear whether this variation is due to differences in race/ethnicity, national systems, and/or maturity levels in countries. As more countries implement dementia-related measures, we have observed progressive improvements in its treatment and diagnosis over the past decade. In Japan, the long-term care insurance system—a welfare system started in 2000 for older people with disability—contributes to supporting people in their late life. Since 2010, all anti-dementia drugs have been available for dementia treatment. Considering changes in these medical and long-term care environments over the last two decades, prognosis of dementia may be improving, and prognosis-related information regarding dementia in Japan needs to be updated.

This study aimed to investigate mortality, cause of death, and prognostic factors according to the type of dementia diagnosis in a Japanese clinic-based cohort (2010–2018). Japan has the highest aging population rate and a well-developed dementia control and care system; therefore, providing evidence from the latest large-scale clinical cohort studies in Japan will have important implications for the trajectory toward dealing with the challenges in dementia.

METHODS

RESULTS

Finally, 3,731 participants in our cohort were identified as providing valid responses to the questionnaire (Fig. 1). Clinical features of valid respondents compared with non-respondents and invalid respondents are shown in Supplementary Table 1. Valid respondents were more frequently female, lived with others, and had better cognitive function and ADL than did non-respondents and invalid respondents.

Fig. 1

Flow chart in this study.

Among the valid respondents, 3,229 participants were analyzed (NC = 483, MCI = 865, AD = 1,587, VaD = 76, DLB = 173, and FTLD = 45). Baseline characteristics at diagnosis are shown in Table 1. A total of 564 deaths were recorded (Table 2). The diagnosis with the highest percentage of deaths was DLB (37.6%, 101.80 per 1,000 person-years), followed by VaD (35.5%, 87.28 per 1,000 person-years) and FTLD (31.1%, 85.10 per 1,000 person-years). The causes of death by diagnosis are shown in Table 3. Pneumonia was the leading cause of death in all the diagnoses, MCI and NC, followed by cancer in patients with MCI, AD, and DLB. However, heart disease was the second leading cause of death in patients with VaD. The causes of death that fell under “other causes of death” are shown in Supplementary Table 2.

In the Cox regression hazard model, using crude and multivariable models, all the types of dementia and MCI were associated with death (adjusted hazard ratios and 95% confidence intervals for MCI: 2.61, 1.37–4.97; AD: 2.70, 1.40–5.22; VaD: 2.84, 1.33–6.05; DLB: 4.57, 2.28–9.14; FTLD: 5.20, 2.21–12.26, respectively) (Table 4). The adjusted hazard ratio of DLB was statistically higher than that of MCI and AD (MCI versus DLB, p = 0.0027; AD versus DLB, p = 0.0002).

To examine death-related factors in MCI, AD, and DLB, we used the Cox proportional hazards model. Regarding the MMSE score, since only a few patients had scores <20 in the MCI group, we re-categorized them from the three classes (<20, 20–23, ≥24) to two classes (<24, ≥24). Since the number of patients in the AD and DLB groups with scores ≥24 was insufficient, we re-categorized them from the three classes (<20, 20–23, ≥24) to two classes (<20, ≥20). In the MCI group, sex, MMSE score, age, and BMI were associated with death. In the AD group, sex, MMSE score, age, education, BMI, and BADL were associated with death. In the DLB group, sex and MMSE scores were associated with death (Table 5).

In the Cox proportional hazards model that included APOE in the MCI, AD, and DLB groups, being an APOE ɛ4 carrier compared with APOE ɛ4 non-carrier was not associated with death (adjusted hazard ratios and 95% confidence intervals for MCI: 0.66, 0.39–1.12; AD: 0.82, 0.65–1.03; and DLB: 1.53, 0.88–2.66, respectively (Table 6).

DISCUSSION

We investigated the prognosis of the types of dementia (AD, VaD, DLB, and FTLD) and MCI by mortality, cause of death, and prognostic factors in a Japanese national center cohort. Compared with NC, all dementia types and MCI were associated with higher mortality rates. The most common causes of death were pneumonia, followed by cancer. In the MCI, AD, and DLB groups, male sex and low cognitive function were common prognostic factors. APOE ɛ4 status in patients with dementia subtype and MCI was not associated with death.

Studies have consistently shown that patients with dementia have lower survival rates than those without dementia. The median survival time after a diagnosis of dementia varies largely between studies (from 3.2 to 6.6 years) [3] and differs by dementia subtypes [15, 35]. In the current results, the median survival times for those with AD, VaD, DLB, and FTLD were greater than 3,000, 2,397, 2,290, and 2,586 days, respectively, which was longer than those reported in previous studies [3–5]. Recent reports on AD, VaD, and DLB [4, 7] showed that median survival rates for AD, VaD, and DLB were 5.1–7.4 years, 3.9–4.7 years, and 3.4–4.8 years, respectively. The current results showed a longer median survival time compared to those in previous studies; moreover, the current results are also supported by those of another Japanese study [17] that reported that the 5-year survival rate of all-cause dementia and AD improved from the 1988 to the 2002 cohort. The improvement over time could be due to improvement of the dementia control and care system in Japan.

It has also been reported that the mortality due to MCI and AD has increased compared to that of the general population [7, 18, 36, 37]. Furthermore, DLB also has shorter survival time than AD [9], though the time in VaD and FTLD was shorter than that in AD [7, 38, 39]. In our study, patients with MCI and AD had higher mortality rates than those with NC, the hazard ratio of VaD was similar to that of AD and MCI after adjustment. In the multiple comparisons among the groups, the adjusted hazard ratio of DLB was statistically higher than those of MCI and AD. As the results of this study are similar to those of previous studies, mortality due to the types of dementia may not be affected by race or ethnicity. The following reasons may explain the shorter survival observed in DLB. Patients with DLB have a history of recurrent falls [40] and disease severity, such as more common neuropsychiatric symptoms (including parkinsonism) [40, 41] and/or more frequent delirium [42], and increased mortality. Although the hazard ratio of FTLD was not significantly higher than MCI or AD in this study, studies with more FTLD will be needed.

The present study showed that pneumonia was the main cause of death for patients with all dementia types, and cancer was the second major reason for MCI, AD, and DLB. One study reported that the two most frequent causes of death in a population with dementia (n = 207) were pneumonia (34.3%) and acute myocardial infarction (30.4%) [43]. Another study reviewed the effects of pneumonia on the mortality rate of patients with dementia [44]. The risk of pneumonia-associated death in patients with dementia was twice as high as that in those without dementia. A third study found that the most common cause of death was pneumonia (38.4%), followed by ischemic heart disease (23.1%) [45]. From previous studies and the current results, pneumonia has an observably high effect on dementia-related deaths. This may be because in the terminal stages of the disease, patient care and feeding are difficult to manage.

Cancer was the second leading cause of death in the present study. The relationship between cancer and dementia has been reported to be inversely associated with relationship between cancer and AD because of the competing risk [46]. However, these relationships mainly observed the incidence of dementia in patients with diagnosed cancer, and not the incidence of cancer in patients with diagnosed dementia. Additionally, death in patients diagnosed with dementia was not observed. Cancer is a leading cause of death in the Japanese population; as most cancer deaths are among older people (76% and 67% among men and women, respectively) [47]; this may reflect an aged society. Physicians need to pay attention to comorbid cancer in advanced care when planning for dementia in an aged society. Further studies are needed to confirm these results.

In the present study, different prognostic factors affected two types of dementia (AD and DLB) and MCI. Some studies have reported that male sex and older age were prognostic factors [3, 7, 12]. The effect of low cognitive function as measured by the MMSE was not consistently associated with mortality [7, 14]. The current results showed that male sex and low cognitive function were associated with mortality regardless of the type of dementia. Male patients with low cognitive function may require more care or support.

In addition, a low BMI was associated with mortality in patients with MCI and AD. Low nutritional status (malnutrition and underweight) has been reported to be associated with mortality in AD [48]. However, only a few studies have focused on this relationship. Furthermore, the present results can be considered acceptable if a low BMI is considered representative of impaired physical function or sarcopenia.

Moreover, APOE ɛ4 carrier status was not associated with mortality in MCI, AD, and DLB. APOE ɛ4 carrier status has been shown to lead to a high incidence of AD [49] and DLB [50], but the effect of APOE ɛ4 on the risk of dementia and mortality diminishes or disappears with advanced age [51, 52].

This study has several strengths. We were able to investigate various uniform scales for dementia types at baseline and establish a comparison group (NC). As the world’s population ages and the survival rates of patients with dementia along with advances in diagnostic and medical technologies improve, mortality rates and causes of death are expected to change over time. The present results are the latest study findings from Japan, the most aged society in the world.

However, the study also has a few limitations. First, as we collected death-related information via a postal survey, information bias may exist. However, the accuracy of death and the day of death was more than 90%. We believe that the information bias was minimized as much as possible. Second, about one-fourth of the questionnaires were not returned or were invalidated for our survey, suggesting that there may have been a selection bias. Previous studies [53, 54] showed a response rate to mailed epidemiologic questionnaires from 40% to 56%, and the mean response rate in social studies was 67%. Thus, since the response rate of our study exceeds these rates, it is an acceptable rate. Valid respondents were more likely to be female and live with others, exhibit better cognitive function, and have better ADL than non-respondents and invalid respondents. As worsening cognitive function and ADL result in high mortality, our results could be underestimated. As the hazard trends and prognostic factors in this study were similar to those in previous studies, it would indicate the robustness of our results. Third, the cause of death options in our questionnaire was selective. However, the selected cause of death was based on major causes of death in Japan. As the “others” option was freely written by close relatives who might be not well-versed in medical knowledge, that information was not necessarily accurate. Thus, it is necessary to investigate official data, such as death certificates, to determine the cause of death in the future. Fourth, NC group may not be healthy because they sought care at our center with an awareness of cognitive decline. The results compared with NC may be underestimated. Finally, as patients in this study were recruited from a single center and older Japanese patients, the generalizability of their findings would not be guaranteed. Further studies must generalize the results and to capture changes in the progression of dementia care.

In conclusion, in a Japanese national center cohort, we compared mortality rates of patients with various types of dementia and MCI to those of participants with NC. The most common causes of death in patients with dementia and MCI were pneumonia followed by cancer. In the MCI, AD, and DLB, groups, male sex and lower cognitive function were common prognostic factors. APOE ɛ4 status in patients with the subtypes of dementia and MCI was not associated with death. Our findings would be useful to caregivers and health professionals as they provide advanced care planning and would also be useful to health policymakers as they make policies and plans for national resources needed in the management of dementia.