Mortality from Dementia in Advanced Age

J Clin Epidemiol Vol. 52, No. 8, pp. 737–743, 1999 Copyright © 1999 Elsevier Science Inc. All rights reserved.

0895-4356/99/$–see front matter PII S0895-4356(99)00067-0

Mortality from Dementia in Advanced Age: A 5-Year Follow-Up Study of Incident Dementia Cases Hedda Agüero-Torres,1,2,* L. Fratiglioni,1,2 Z. Guo,1,2 M. Viitanen,1,2 and B. Winblad1,2 1Stockholm

Gerontology Research Center, Stockholm, Sweden; and 2Department of Clinical Neuroscience and Family Medicine, Division of Geriatric Medicine, Karolinska Institute, Karolinska, Sweden

ABSTRACT. Five-year follow-up of a community-based, 771 old cohort including incident dementia cases was used to evaluate the impact of dementia on the risk of death, taking into account other chronic conditions potentially related to death, and contrasting Alzheimer’s disease (AD), and vascular dementia (VaD). In this population, 70% of the dementia cases died during the five years after diagnosis, with a mortality rate specific for dementia of 2.4 per 100 person-years. After controlling for sociodemographic variables and comorbidity, 14% of all deaths could be attributed to dementia with a risk of death among demented subjects twice as high as that for non-demented people. Mortality risk ratios were 2.0 (95% confidence interval 1.5–2.7) for AD and 3.3 (95% confidence interval 2.0–5.3) for VaD. This study confirms that dementing disorders are a major risk factor for death. Even in the oldest old (851), dementia shortens life, especially among women. J CLIN EPIDEMIOL 58;8:737– 743, 1999. © 1999 Elsevier Science Inc. KEY WORDS. Mortality, dementia, elderly, Alzheimer’s disease

INTRODUCTION Among the age-related chronic disorders, dementia is a highly prevalent condition [1] which causes progressive and severe disability [2]. In a previous study, we found that dementia was the major determinant for the development of functional dependence over three years, whereas other chronic conditions led more frequently to death [3]. Nevertheless, demential has been also reported to shorten survival [4–17]. Few data are present in the literature concerning mortality rates specific for dementia in the community [18,19]. Death certificates are generally considered to grossly underreport dementia, even when underlying causes of death are taken into account [20]. In 1986, Chandra and coworkers [18] reported a mortality rate of 0.98 per 1,000 person-years in 851 old subjects, which is similar to the rate of 1.1 per 1,000 person-years in 801 old people reported more recently by the Centers for Disease Control in Atlanta [19]. Several community-based studies have investigated mortality in dementia [5,6,8–13,15–17], and all showed an increased risk of death in demented compared to non-demented subjects. However, most of these studies have used prevalent rather than incident cases. The few studies that have investigated the risk of dying in incident dementia cases *Address for correspondence: Hedda Agüero-Torres, MD, PhD, Stockholm Gerontology Research Center, The Kungsholmen Project, Box 6401, S-11382 Stockholm, Sweden. Tel.: 146 8 6905854; fax: 146 8 6905954. Accepted for publication on 30 March 1999.

[9,15,21,22] have focused on pre-senile dementia [21,22], have studied selected populations of elderly [15], or have included patients who came to medical attention. In this last group, very mild cases as well as rapidly progressiving forms of the disease might have been under-represented [9]. The reported relative risk of dying varied between 1.9 to 3.0 for dementia [9–11,16] and 1.4 to 2.9 for Alzheimer’s disease [8,12,13,15,17]. Additionally, some other authors have suggested that dementia may not necessarily cause decreased life-expectancy in very old age [23]. We had the opportunity to evaluate the impact of dementia on mortality using incident dementia cases from a community-based population followed for 5 years after diagnosis. Information on important covariates such as education and co-morbidity were also available, as was the diagnosis of different dementia types. SUBJECTS AND METHODS Study Population The study population consisted of a cohort of subjects aged 75 years or older who were not demented at the beginning of the follow-up. The cohort was identified within the Kungsholmen Project’s population by means of a cross-sectional study that led to the detection of the prevalent dementia cases [24]. All the inhabitants of an area in Stockholm (Kungsholmen) on October 1, 1987, born in 1912 or before, living at home or in institutions were included in the study population. The incident dementia cases were all subjects who had developed dementia during an average

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(6SD) follow-up of 3.4 6 0.6 years. A second cross-sectional study started November 1990 and ended December 1992 to ascertain the new dementia cases. Among the cohort members who were clinically examined at follow-up, 127 individuals were classified as affected by clinically definite dementia, and 72 subjects classified as questionable dementia [25]. Among the definite dementia cases, 80% were Alzheimer’s disease (AD), 17% were vascular dementia (VaD), and 4 subjects were classified as having other dementias. All cases were newly diagnosed as they had developed dementia during the three years prior to follow-up. These are hereby referred to as “incident cases.” Diagnostic Procedure and Diagnostic Criteria for Dementia and Dementia Types The dementia diagnoses were based on data collected during clinical evaluations where a standard protocol was used. Details of the protocol have already been reported [26]. Briefly, it included collection of family and personal history by nurses, clinical examination by physicians, and psychological tests administered by psychologists. When the subject was not able to answer, an informant, usually the next-of kin, was interviewed. The physicians examined the physical and neurological conditions, as well as the cognitive and psychiatric status. Psychological tests included the Mini Mental State Examination (MMSE; [27]), free recall and recognition of random words, and digit span [28]. Finally, to detect secondary dementias, serum vitamin B12 measurements and thyroid function tests were carried out. DSM III-R diagnostic criteria for dementia [29] were used, with the addition of a category of questionable dementia [25,26]. DSM III-R diagnostic criteria were also utilized to differentiate different dementia types. For an AD diagnosis both gradual onset and progressive deterioration of dementia were required and all other specific causes of dementia had to be excluded. The diagnosis of VaD was based on clinical data because neurological investigations were not performed in all cases. A clinical feature of dementia with abrupt onset, stepwise deterioration, history of stroke and/or focal deficits were required for a diagnosis of VaD. As an aid of the clinical data, the Hachinski scale [30] was used: a score greater than 6 indicated VaD; lower than 5 AD; and 5 or 6 mixed dementia. This scale was completed by the physician who made the diagnoses, and who took into account the temporal sequence of events (onset of dementia symptoms and history of stroke reported by relative and/or by clinical records). When data were insufficient to identify the dementing disorder, a category of unspecified type of dementia was used. The final diagnosis was based on the agreement of two independently made diagnoses, one by the examining physician, and the second by a specialist. In case of disagreement, a third opinion was sought and the concordant diagnosis accepted [26].

Data Collection The whole cohort was followed for 5 years or in some cases until death, if they died before the end of this time period. Information on vital status was obtained every month from official registers for all subjects. Data on demographic variables, including age, gender, and educational attainment were collected at the inception of the cohort. Information on educational level was missing for four subjects. Data concerning common diseases potentially related to death, such as cancer, heart disease, stroke not followed by dementia, and hip fracture were obtained from the Computerized Stockholm Inpatient Register System. The hospital discharge diagnoses from 1969 to the data of follow-up examination were reviewed for the entire population. Disease diagnoses were based on the International Classification of Diseases, Eighth revision (ICD-8; [31]): cancer (ICD-8: 140 to 208 and 230 to 239); heart disease including coronary disease (ICD-8: 410-414), dysrrhythmia (ICD-8: 427), and heart failure, (ICD-8: 428); hip fracture (ICD-8: 820); and cerebrovascular disease (ICD-8: 430-438) without dementia. The new variable of comorbidity was created when history of at least one of these disease was present. Statistical Analyses To describe the impact of dementia on mortality, KaplanMeier survival curves were created for demented and nondemented subpopulations and for different dementia types. Log rank tests were used to evaluate the equality of survival distributions for dementia. The following measurements were used to quantify the impact of dementia on 5-years mortality: 1. Mortality rates specific for dementia stratified by age and gender, in the total population were calculated by dividing number of dead demented subjects by person-years at risk during the five year follow-up. Person-years for decreased subjects were calculated as the time between follow-up examination and death. 2. The possible interaction between dementia and gender was explored by stratified analysis. Mortality rates for demented and non-demented subjects were calculated separately after stratification by age (77–84 and 851) and gender. Additionally, relative risks of death comparing demented and non-demented were calculated for men and women in the two different age strata. 3. Relative risks of deaths from dementia, and different types of dementia, were derived from Cox proportional hazard models [32], with controlling for sociodemographic factors and comorbidity. The variables included in the models were age and the following dichotomous variables: gender (male vs. female), educational level (elementary school vs. high school/university), AD (yes vs. no), VaD (yes vs. no), OD (yes vs. no), and comorbidity (yes vs. no).

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739

TABLE 1. Sociodemographic characteristics and comorbidity (percentages) for non-demented subjects and for clinically definite demented elderly

Non-demented n 5 790

Clinically definite dementia n 5 127

61.0 39.0 74.6

34.6 65.4 87.4

53.7 46.3 34.1

74.6 25.4 41.7

Age (years) 77–84 851 Female gender Educationa Low (,8 years) High (8 years) Comorbidity aThis

variable has some missing values, as explained in Materials and Methods.

4. The population attributable risk (PAR%) of dementia on the 5-year mortality was calculated as follows [33]: ( Mortality rate in the total population – Mortality rate among non-demented ) ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Mortality rate in the total population

When PAR% was estimated taking into account the effect of other variables, the corresponding mathematical formula using relative risk derived from the Cox model was used [33]. RESULTS The cohort of 989 subjects included 77% women, and 43% highly education subjects. The average age 6 SD was 84.3 6

4.3 years, the mean MMSE score 6 SD was 25.2 6 5.3 points. Thirty-eight percent had a history of at least one of the following conditions, either cancer, heart disease, hip fracture, or stroke without dementia. Those affected by only one of these conditions amounted to 30%, and those affected by more than one condition to 8%. One hundred ninety-nine (20%) subjects developed dementia in the previous 3 years, of whom 127 were classified as clinically definite dementia. These subjects together with the 790 nondemented people are shown in Table 1. The group of clinically definite dementia cases were older (P , 0.001), had a higher proportion of women (P , 0.001), and low educated people (P , 0.001) than the non-demented elderly. The proportion of subjects affected by a co-morbid condition was similar in the non-demented and demented groups. After 5 years, 35% of the non-demented and 70% of the demented persons had died. Mortality rates specific for dementia and AD stratified by age and gender were calculated. In our population 2.4 per 100 person-years and 1.9 per 100 person-years, died with dementia or AD, respectively. Older women had the highest mortality rates specific for both dementia and AD (Table 2). The mean survival time from follow-up examination was 3.0 years (95% CI 5 2.7–3.4) for demented subjects, and 4.2 years (95% CI 5 4.1–4.3) for the non-demented elderly. Kaplan-Meier curves were used to compare survival between non-demented and clinically definite dementia cases (Figure 1A). Demented subjects had significantly shorter survival than non-demented (log-rank test: P , .001). Both AD and VaD showed shorter survival in com-

TABLE 2. Mortality Rates and 95% confidence intervals (95%CI) specific for dementia and Alzheimer’s disease per 100 person-years, by age and gender; number of deaths (n) and person years (p-y) are also reported

Dementia Age group (years)

n

p-y

Male 77–84

5

398.4

851

8

456.6

Total

13

Female 77–84

Alzheimer’s disease

Mortality rate per 100 p-y (95%CI)

Mortality rate per 100 p-y (95%CI)

n

p-y

1.3 (0.4–2.9) 1.8 (0.8–3.5)

3

398.4

5

456.6

855.0

1.5 (0.8–2.6)

8

855.0

0.9 (0.4–1.8)

10

1096.4

5

1096.4

851

66

1740.7

0.9 (0.4–1.7) 3.8 (2.9–4.8)

56

1740.7

0.5 (0.1–1.1) 3.2 (2.4–4.1)

Total

76

2837.1

2.7 (2.1–3.4)

61

2837.1

2.2 (1.6–2.8)

89

3692.1

2.4 (1.9–3.0)

69

3692.1

1.9 (1.5–2.4)

Total

0.8 (0.2–2.2) 1.1 (0.4–2.6)

H. Agüero-Torres et al.

740

demented men and women were 2.5, and 2.4, respectively, in comparison to the risk of death for non-demented women. Dementia increased the risk of death 120%, independent of age, gender, education and comorbidity. The PAR% of death due to dementia was 14.3%, when the RR from this model was used. Table 4 shows results from the Cox proportional hazard model, where AD and VaD vs. non-demented were studied. Both AD and VaD increased the risk of death, but although the RR was higher in VaD than in AD, this difference was not statistically significant. The risk of death increased of 10% for 1-year increase in age, and of 40% when a co-morbid condition was present. In contrast, RRs lower than one were found for female gender and high education. After stratification by age (77–84 years and 851 years), the same risk factors for death were found in the two age groups for all dementias together and for AD and VaD separately. However, the adjusted RR for dementia decreased from 2.7 (95% CI 5 1.7–4.2) to 1.9 (95% CI 5 1.4–2.7) from the youngest to the oldest age group. For AD the RRs in the two age groups were almost the same (RR 5 1.8, CI 5 1.0–3.3, for 77–84 years old; and RR 5 2.0, 95% CI 5 1.4– 2.8 for 851 years old).

COMMENT

FIGURE 1. Kaplan-Meier survival functions comparing de-

mented vs. non-demented subjects (A), and AD and VaD vs. non-demented subjects (B)

parison to non-demented (Figure 1B). The mean survival times for AD and VaD subjects were 3.1 years (95% CI 5 2.8–3.5), and 2.8 years (95% CI 5 2.2–3.4), respectively. Age- and gender-specific mortality rates were calculated among demented and non-demented subjects, separately (Table 3). The highest mortality rate was found among demented men, 77–84 years old. Despite dementia diagnosis, mortality rates in men were higher than in women for both age strata. However, the highest RR of death was found among 77–84-year-old females. The PARs% were dramatically higher among women than men in both age groups. We also studied the possible interaction between male gender and presence of dementia on mortality, for the two separate age strata. In the age group 77–84 years, demented men and women had increased risk of death of 7.4, and 4.5, respectively, in comparison to non-demented women. In the age group 851 years, the increased risk of death for demented men and women was very close. The risk of death for

This is one of the few population-based studies where mortality specific for dementia has been investigated by following incident dementia cases identified from a community of elderly subjects, and also where the mortality rate ratio associated with dementia has been estimated after controlling for other chronic medical conditions potentially related to death. The main findings from the present study can be summarized in two points: 1. The impact of dementia on mortality is extraordinarily high, compared to previous reports. In this very old population, 70% of incident dementia cases died during the five years after diagnosis, with a mortality rate specific for dementia of 2.4 per 100 person-years. The risk of death among demented subjects was twice that among non-demented people, after controlling for sociodemographic variables and comorbidity. Fourteen percent of all deaths could be attributed to dementia. Both AD and VaD increased the risk of death in comparison to non-demented subjects. There was also a tendency, although not statistically significant, of a worse prognosis among VaD compared to AD. 2. There are differential mortality patterns due to dementia that vary by age and gender. Although demented men aged 77–84 years, experienced the highest mortality, the RR for death associated with dementia was much higher in women than in men, as well in the younger than 851 age group. In addition, the attributable population risks (accounting for 17–18%) were much higher among women than men in both age groups. Finally, we found that in very old age demented men and women had a

Mortality from Incident Dementia

741

TABLE 3. Number of dead subjects (n), mortality rates, and 95% confidence intervals

(95%CI) by age and gender among demented and non-demented elderly; relative risk of death comparing demented and non-demented (RR), and population attributable risk of death (PAR%) for each age and gender strata are also presented Non-demented

Demented

Dead subjects n

Mortality rate per 100 p-y (95% CI)

Dead subjects n

Mortality rate per 100 p-y (95%CI)

RR (95%CI)

PAR%

Male 77–84

31

5

851

62

8.1 (5.5–11.1) 14.6 (11.2–18.7)

28.8 (9.2–67.3) 24.8 (10.8–48.9)

3.6 (1.4–9.1) 1.7 (0.8–3.5)

10 (8–13) 5 (4–7)

Female 77–84

41

3.9 (2.8–5.3) 10.0 (8.4–11.8) 8.5 (7.5–9.5)

10

17.5 (8.4–32.3) 23.6 (18.2–30.0) 23.0 (18.5–28.3)

4.5 (2.2–8.9) 2.4 (1.8–3.2) 2.7 (2.1–3.4)

17 (13–20) 18 (14–20) 15 (12–15)

Age group (years)

851 Total

146 280

similar risk of death when compared to non-demented women. In other words, the protective effect against death linked to female gender that was present in the non-demented population, was eliminated by the presence of dementia in very old subjects. It is known that mortality rates specific for dementia as derived from death certificates are largely underestimated [34]. The underreporting of dementia on death certificates has been measured in several studies. The percentage of underreporting varied from a minimum of 11.5% reported in Rochester [20], to a maximum of 65% in an English study [35] where presenile dementia was studied. Our mortality rate of 2 per 100 person-years is far from the 1 per 1,000 person-years reported in studies based on death certificates [18,19]. We corrected this last figure taking into account the estimation of the underreporting in death certificates

TABLE 4. Relative risk (RR) and 95% confidence intervals

(95% CI) derived from proportional hazard model relating Alzheimer’s disease and vascular dementia to 5-year mortality; sociodemographic characteristics and comorbidity were also included.

Alzheimer’s disease Vascular dementia Age (1-year increase) Female gender High education Comorbiditya

RR

(95% CI)

2.0 3.3 1.1 0.6 0.8 1.4

(1.5–2.7) (2.0–5.3) (1.1–1.2) (0.5–0.8) (0.6–0.9) (1.2–1.8)

aHistory of at least one comorbid condition, as explained in Materials and Methods.

8

66 89

derived from a study in Rochester, Minnesota, in a situation close to the routine certification in the general population. We obtained a “corrected mortality rate” specific for dementia of 1 per 100 person-years, which is still lower, but of the same magnitude as our finding. Among the few studies based on incident dementia cases, only one investigation [9] included a population with comparable age structure. In this study the reported RR of 3.0 is close to our unadjusted RR of 2.7. A similar result was reported from Norway [16], based on prevalent dementia cases. In addition, the RR of death associated with dementia among 851 year old subjects found in our study was perfectly in agreement with the report from Heeren and collaborators [11]. Finally, the mortality risk ratio due to AD was slightly higher than two previous reports based on prevalent cases [8,12], but was similar to the findings reported from, an investigation of younger incident cases [15]. Few data are available in the literature concerning mortality patterns due to dementia in different ages and gender. Aronson et al. [9] in a cohort of volunteers reported agespecific mortality rates that were in general lower than ours for non-demented subjects, but in particular for demented subjects. This may be due to the exclusion criteria used at the cohort inception. In spite of this, the risks of death due to dementia, and mortality patterns in old age between men and women were similar to our findings. Katzman et al. [13] found a RR of death of 2.8 (95% CI 5 2.1–3.6) for AD subjects and 3.5 (95% CI 5 2.4–5.1) in VaD cases, after adjustment for demographic variables and medical conditions. These values are close to those found in our study, when the same covariates were entered in the models. Both studies support the hypothesis that the risk of death is increased by being affected by any type of demen-

H. Agüero-Torres et al.

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tia, and that there is a tendency of a worse prognosis in VaD than in AD. Finally, in addition to dementia, age and comorbidity emerged as independent risk factors for death in the total population, whereas female gender, and high educational attainment were protective factors against death. These findings are in agreement with studies carried out in old populations, where the increasing risk of mortality associated with age, male gender and low educational attainment are well established [36,37]. These results are apparently in contrast with the differential mortality patterns due to dementia in different ages and gender, as discussed in the previous paragraph. The decreased risk of death associated with female gender found in the entire population was probably reflection of the protective effect of female gender among non-demented women. This effect was due to the higher absolute number of non-demented in comparison to demented women. We conclude that even in very old populations, gender is a factor that affects survival, but for demented subjects this is true only for “youngest old.” Regarding the limitations of our study, five aspects deserve discussion. First, we restricted our analyses to those non-demented subjects who underwent follow-up examination after 3 years. In the Kungsholmen Project, new dementia cases were ascertained by means of a cross-sectional study 3 years on average after cohort inception. For those individuals who had died before follow-up examination, dementia diagnosis was retrospectively made using information provided by hospital records and death certificates. These subjects have not been included in this study as the degree of ascertainment for them was less specific than for the examined subjects. In order to preserve a high specificity of our diagnoses more than a high sensitivity, we have accepted this exclusion even though it possibly led to an underestimation of the mortality rate ratio. Second, we have calculated the 5-year mortality from the disease diagnosis and not from disease onset. The disease onset may refer to the appearance of one or more symptoms related to dementia, which would usually reach the diagnostic level some time later. However, we decided to calculate mortality from disease diagnosis for three reasons: (1) any statistical approach to disease onset may give only an approximation of the real onset; (2) even the very early clinical manifestations of dementia might not reflect the neuropathological onset of the disease; and (3) the calculation of mortality rates from disease diagnosis instead of from disease onset is more relevant for public health planning. Third, the dementia diagnosis in population surveys are always less accurate than in a clinical setting [26]. This is due to limited contact with the subject and his/her family, the difficulty of distinguishing mild cases from “normal aging,” the reduction in work and social activities in old populations, and the multimorbidity common in old age. We tried to overcome these difficulties by asking the subject and next of kin about any change in daily activities previously

carried out. Moreover, each diagnosis was made twice, separately [26]. In this way, misinterpretations of the diagnostic criteria were reduced, and the most controversial data were deeply discussed by at least two senior clinicians, with expertise in dementia. Four, the differential diagnosis of dementia type was made clinically, without the aid of neuroimaging or pathological data. In our study, every case presenting some atypical clinical symptomathology was classified in the category of unspecified type. Thus, once more we have chosen high specificity, rather than high sensitivity. Misclassification at the individual level is surely present, but it seems more likely to be present among AD cases than among VaD, due to the fact that some vascular dementia cases with silent, or unrecognized, or unreported strokes may have been classified as AD. This misclassification, if present, affect only the results concerning different mortality patterns in the two dementing disorders. Finally, the use of comorbidity data from the Computerized Stockholm Inpatient Register System needs to be discussed. Comorbidity in the elderly is not a well-established concept. Nevertheless, in order to accurately assess the risk of death in dementia, it is important to control at least for other potentially lethal diseases. Since the included diseases are likely to lead to hospitalization, we consider our data quite accurate. In fact, prevalence figures of these diseases were comparable with those reported by other studies [38–40]. In conclusion, the results of this study confirm that dementing disorders are a major risk factor for death, even after age 75 and in the oldest old (851), with a mortality rate higher than those previously reported. However, the main impact is present among the youngest old and among women. After the age of 85, demential still shortens life, especially among women, but much less so than in younger subjects. Finally, whether this differential survival was due to the disease itself (dementia) or to increased vulnerability of other causes of death, such as infections or falls, needs further investigation. Our findings stress the importance of further studying the “malignancy of the dementias” [13], taking into account different subpopulations and different measures in order to be able to better counsel when prognostic indications are requested both at the individual and community levels. We thank all members of the Kungsholmen Project Study group for their collaboration. We also thank The Swedish Council for Social Research, The Swedish Medical Research Council, The Swedish Society for Medical Research, and the Greta Lindenau-Hansells Foundation.

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