Introduction

Dementia is a disorder characterized by two or more cognitive impairments that can seriously affect daily life. Currently, 47 million people worldwide suffer from dementia, and approximately 25% of them live in China, posing a huge burden for families and policy-makers [1]. The cost of Alzheimer's disease in China is 1.47% of the gross domestic product (GDP), in contrast to the cost of 1.09% of the global GDP worldwide. In 2015, the annual socioeconomic cost per dementia patient in China was US $19,144.36, with a total cost of US $167.74 billion. In detail, direct medical costs accounted for 32.5%, and direct nonmedical costs accounted for 15.6% [2]. Resources for dementia care in China include expensive private institutions for long-term care, community-based day-care centers, and nursing homes. Community-based day-care centers and nursing homes that are funded by the government are free for dementia patients, especially for those elderly who live alone. However, due to poor medical resources, most patients with dementia usually receive informal care at home [2]. A national survey of 1,335 dementia patients found that only 27 (2%) with dementia could access formal care in hospitals or nursing homes, while the remaining 1308 (98%) were cared for by family members at home [3].

Numerous studies have shown that comorbidities, such as cerebral vascular disease, depression, epilepsy, metabolic syndrome, chronic obstructive pulmonary disease, and anemia, not only affect the progression of diseases, reduce quality of life, and increase the economic burden of families but also reveal potential linkages between diseases [4,5,6,7,8,9,10]. Therefore, evaluating comorbidities for dementia is critical to disease management.

The comorbidities index can summarize comorbidities and efficiently predict prognosis [11, 12], which has been verified in several studies in the field of epilepsy, ischemic stroke, COVID-19, hip fracture, and cardiovascular disease [13,14,15,16,17]. The two most commonly used comorbidity indices are the Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI). The CCI includes 17 diseases published in 1987 by Charlson et al., which was originally used to predict one-year mortality [12]. ECI contains 31 comorbidities developed by Elixhauser et al. in 1998 for use with large administrative inpatient datasets [11, 18,19,20,21,22], which has demonstrated its effectiveness in predicting death and hospital cost [15, 23, 24]. Elixhauser A et al. concluded that "comorbidities have an independent impact on outcomes and should probably not be reduced to one indicator, as different patient groups have different effects on outcomes" and encouraged researchers to add or drop several comorbidities as appropriate [19]. Comorbidities included in CCI and ECI have been strictly defined and confirmed to be associated with hospitalization prognosis or death, so it is speculated that these diseases may be more important. On this basis, epilepsy has been confirmed in previous studies may be associated with dementia and thus remained in our study [6]. We noted that the CCI and ECI were used in studies of health care and cost as well as some other cross-sectional studies [10, 25,26,27]. For example, de Lima JD et al. investigated comorbid conditions in older adults with a clinical diagnosis of Alzheimer’s disease (AD), mild cognitive impairment (MCI) or major depressive disorder (MDD) in a cross-sectional study [26]. Kaczynski A et al. described the prevalence of comorbidities in people with dementia and analyzed the association between comorbidities and health care costs based on the CCI [10]. Index as a summative measure to include comorbidities may generate more concise and clear conclusions to understand the outcome. In contrast, using the International Classification of Diseases (ICD) coding directly may provide more detailed information on comorbidities.

Studies have shown that patients with dementia have 2–8 more comorbidities than those without dementia [25]. However, the comorbidities included in studies are usually 8–17 diseases [26,27,28,29,30]. The present study, the first study in western China, included 24 comorbidities derived from CCI and ECI based on the 10th revision of the International Classification of Diseases (ICD-10) and 1 comorbid epilepsy, aiming to demonstrate a more comprehensive relationship between comorbidities and dementia.

Methods

Data source and study participants

Data use for this study were approved by the Institutional Ethics Committee of our hospital. The IRB protocol (No. Res-2020-308). The data were obtained from the ICD-10-based discharge records from May 14, 2018, to August 29, 2021, at our hospital, which is one of the largest tertiary hospitals in West China. The ICD-10 codes (F00-F03, F05.1, G30, G31.1) were used to search inpatients diagnosed with dementia (including but not limited to Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, etc.). Furthermore, supplementary retrieval was performed based on medical records when necessary. Classification and diagnosis of dementia were performed according to the Chinese guidelines [31]. For patients with multiple admissions, the latest record was selected for analysis. In addition, a cohort of age- and gender-matched nondementia patients were randomly selected from the same database as controls.

Comorbidity selection

Discharge diagnosis based on ICD-10 was used to identify comorbid conditions. We preferred Quan's coding algorithms of ICD-10, the newest version of nosology [32]. We selected comorbidities from the CCI and ECI and made minor adjustments. Comorbidities with low diagnosis rates in our dataset (such as mental illness, obesity, and low weight) were excluded. Hemorrhagic anemia and iron deficiency anemia were merged into one category, namely, anemia. Considering the close relationship between dementia and epilepsy [6, 33], epilepsy was added. Finally, 25 comorbidities were selected in this study. They were myocardial infarction, congestive heart failure, cerebral vascular disease, peripheral vascular disease, chronic pulmonary disease (COPD), rheumatoid arthritis collagen, peptic ulcer disease, diabetes uncomplicated, moderate or severe renal disease, diabetes complicated, paraplegia, solid tumor without metastasis, moderate or severe liver disease, mild liver disease, metastatic cancer, HIV, alcohol abuse, coagulopathy, anemia, depression, fluid and electrolyte disorders, hypothyroidism, hypertension, lymphoma, and epilepsy (see Appendix A: Comorbidities and ICD-10 coding in Supplementary material).

Data processing and statistical analysis

We programmed the package in MATLAB (R2016b) to process the discharge data. In detail, the diagnosis of each patient was automatically assigned to a comorbidity category (binary variable) by matching the ICD-10 code of the diagnosis in the discharge abstract with the proposed coding system of the comorbidity category.

SPSS 17.0 (Chicago, IL, U.S.A.) was used for the following statistical procedure, and a 5% level of significance was assumed (two-sided p value). Demographic information and the prevalence of comorbidities were described. Before undertaking t tests, data skewness and kurtosis were assessed for continuous variables. If the data were not normally distributed, Mann–Whitney tests were applied. For example, data “hospital stay” and “Number of comorbidities” were not normally distributed, and the Mann‒Whitney U test was therefore used for comparison. A chi-square test was conducted to compare categorical variables (percentage of the comorbidities). Binary logistic regression was implemented to determine the contribution of comorbidities to dementia. In-hospital dementia use as an outcome was set as the dependent variable, and comorbidities were set as the independent variable. Model coefficients were tested by Omnibus tests, and model fitness was evaluated using Hosmer and Lemeshow tests.

Results

Basic demographic information

A total of 3,355 dementia patients (57.7% males), with a mean age of 80.8 ± 10.7 years, from our hospital (May 2018 to August 2021) were included in the study. The distribution of patients from different departments was as follows: 1312 (39.1%) from the neurology department, 1282 (38.2%) from the geriatrics department, 206 (6.1%) from the internal medicine department, 130 (3.9%) from the psychosomatic department, 126 (3.8%) from the emergency department, and 299 (8.9%) from others.

The prevalence of comorbidities in dementia and nondementia

A total of 93.5% of the dementias suffered from at least one comorbidity. A longer hospital stay (17.6 ± 15.9 vs. 12.4 ± 10.7, P < 0.001) and a higher number of comorbidities (3.8 ± 1.9 vs. 2.9 ± 2.1, p < 0.001) were observed in patients with dementia than in those without dementia. The distribution of the following comorbidities was significantly different between dementia and nondementia (Table 1): cerebral vascular disease (73.0% vs. 35.9%), hypertension (62.8% vs. 56.2%), peripheral vascular disease (53.7% vs. 31.2%), uncomplicated diabetes (25.3% vs. 17.6%), fluid and electrolyte disorders (22.2% vs. 18.6%), mild liver disease (20.2% vs. 15.4%), chronic pulmonary disease (19.0% vs. 23.4%), anemia (18.8% vs. 16.1%), moderate or severe renal disease (14.8% vs. 13.4%), diabetes complicated (10.5% vs. 8.9%), depression (10.3% vs. 2.0%), hypothyroidism (5.5% vs. 3.8%), epilepsy (4.8% vs. 0.8%), rheumatoid arthritis collagen vascular disease (3.2% vs. 1.6%), solid tumor without metastasis (3.2% vs. 10%), metastatic cancer (1.6% vs. 4.0%), and paraplegia (0.4% vs. 1.1%).

Table 1 Prevalence of comorbidities in cohorts with dementia and without dementia
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The prevalence of comorbidities in Alzheimer's disease and vascular dementia

Our dementia cohort included 1503 (44.8%) patients with Alzheimer's disease, 395 (11.8%) with vascular dementia, 441 (13.1%) with mixed dementia, 36 (1.1%) with Parkinson's dementia, 14 (0.4%) with Lewy body dementia (DLB), 8 (0.3%) with frontotemporal dementia (FTD), 26 (0.8%) with dementia paralytica, 2 (0.05%) with HIV-associated dementia, and 930 (27.7%) as unclassified. The mean number of comorbidities in Alzheimer's disease and vascular dementia were 3.4 and 4.0, respectively. The distribution of the following comorbidities was significantly different between patients with Alzheimer's disease and vascular dementia (Table 2): cerebral vascular disease (68.7% vs. 80.3%), hypertension (58% vs. 71.6%), peripheral vascular disease (48.6% vs. 54.9%), uncomplicated diabetes (26.1% vs. 32.9%), congestive heart failure (16.7% vs. 21.3%), fluid and electrolyte disorders (20.9% vs. 27.1%), complicated diabetes (6.9% vs. 11.1%), solid tumor without metastasis (2.1% vs. 4.1%), myocardial infarction (0.9% vs. 3.8%), and paraplegia (0.2% vs. 1.0%).

Table 2 Comorbidity distribution of Alzheimer's disease and vascular dementia
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Comorbidities associated with dementia

Ten comorbidities were determined to be associated with dementia (Table 3). They were epilepsy (OR 4.8, 95% CI 3.5–6.8), cerebral vascular disease (OR 4.1, 95% CI 3.7–4.5), depression (OR 4.0, 95% CI 3.2–5.0), diabetes uncomplicated (OR 1.5, 95% CI 1.4–1.7), peripheral vascular disease (OR 1.8, 95% 1.6–2.0), rheumatoid arthritis collagen vascular disease (OR 1.7, 95% CI 1.3–2.3), anemia (OR 1.2, 95% CI 1.04–1.3), hypertension (OR 0.8, 95% CI 0.7–0.9), COPD (OR 0.6, 95% CI 0.5–0.6), and solid tumor without metastasis (OR 0.4, 95% CI 0.3–0.4) (all p < 0.001).

Table 3 Effects of risk factors on in-hospital dementia
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Discussion

In our study, the proportions of Alzheimer's disease (44.8% vs. 50–70%), vascular dementia (11.8% vs. 15–20%), FTD (0.3% vs. 5–10%) and DLB (0.4% vs. 5–10%) in this study were lower than those in other studies [34]. This may be related to the fact that nearly 60% of the patients were hospitalized out of the Neurology department, where classification of dementia was not preferred since dementia was not the principle diagnosis at admission. In addition, some techniques, such as positron emission tomography-computed tomography (PET-CT), dementia-associated biomarkers in cerebrospinal fluid or brain pathological examinations, are not widely available because of their high cost [1], which leads to unclear diagnoses. Compared with nondementia patients, the dementia group had longer hospital stays and more comorbidities, indicating that more medical resources were needed for dementia patents.

An epidemiological survey showed an almost twofold increased risk of Alzheimer's disease in women versus men. However, a greater incidence was found in males than females regarding vascular dementia, dementia with Lewy bodies, mixed dementia, normal pressure hydrocephalus, and frontotemporal degeneration [35]. In our hospital, the prevalence of dementia in males outnumbered that in females. One reason is that some other type of dementia accounted for 55.2%, which might screw the overall distribution of gender. The other reason might rely on the number of male patients in the hospital (elderly male vs. female = 53.2% vs. 46.8% in database), which might be because male elderly inpatients were more likely to have more chronic diseases and needed hospitalization.

The prevalence of comorbidities in patients with dementia (93.5%) was significantly higher than that in patients without dementia (86.9%) in our study, which was in line with studies by Barnett et al. (94.7%) [36] and Jorge Brown’s study (91.7%) [28]. Our study found that cerebral vascular disease was the most prevalent comorbidity, followed by hypertension, peripheral vascular disease and diabetes, which is partly consistent with previously published studies [4, 26, 27, 37]. For example, a study of 132,405 hospitalized Alzheimer's patients found that hypertension was the most common comorbidity, followed by diabetes [38]. One population-based study found that the prevalence of cerebral vascular disease and diabetes in people with cognitive impairment was 34% and 26%, respectively [39]. One reason to explain the discrepancy is that comorbidities in dementia vary with the subtype of dementia, the severity of the cognitive impairment, and the population studied. For example, vascular dementia has more cardiovascular and cerebrovascular diseases and metabolic morbid conditions.

With respect to the comorbidities associated with dementia, our results suggested cerebrovascular disease, peripheral vascular disease, and diabetes increased the risk of dementia, which was in line with previous studies [5, 40]. In addition, depression, epilepsy, rheumatoid arthritis collagen vascular disease, and anemia were found to increase the risk of dementia in our study, which is in accordance with various studies. For example, people with epilepsy are more likely to develop dementia and vice versa [6, 33, 41]. A study of 4906 patients found a two-way link between epilepsy and dementia, with either condition nearly doubling the risk of developing the other compared to the control group [42]. A systematic review and meta-analysis demonstrated that depression showed strong positive associations with all types of dementia (OR 1.6, 95% CI 1.5–1.8) [43]. However, there is little evidence on the relationship between rheumatoid arthritis collagen vasculature and dementia. Genetic predisposition and inflammatory mechanisms in both diseases are thought to be the possible mechanisms of interaction in a review [44]. A significant positive association was shown between anemia and global cognitive decline as well as the incidence of dementia [8, 45]. Frank J. Wolters found that anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease [46].

Hypertension was shown to be a protective factor for dementia in our study, which is contrary to other studies [4, 47]. This phenomenon is possibly due to the collinearity in the model, which is affected by the interaction between some variables. After excluding the influence of cerebrovascular disease and peripheral vascular diseases, hypertension was found to be a risk factor for dementia. An inverse relationship between dementia and cancer was proven in our study, which is similar to other studies [48, 49]. A study demonstrated an inverse relationship between Alzheimer’s disease and 10 cancer types (e.g., prostate cancer, ovarian cancer, and lung cancer) [50]. However, the clear underlying mechanism is unknown. The relationship between COPD and dementia is controversial. A study demonstrated that the risk of dementia was significantly increased in patients with COPD (HR 1.8, 95% CI 1.6–2.0) compared with individuals in the general population [9]. Other studies suggested that COPD only increased the risk of cognitive impairment (HR 1.13, 95% CI 1.09–1.18) but was not significant in dementia [51]. In a population-based study with more than 25 years of follow-up, midlife COPD was associated with an almost twofold risk of mild cognitive impairment and dementia later in life (HR 1.85, 95% CI 1.05–3.28). However, pulmonary diseases diagnosed later in life seemed to have a protective effect on cognitive impairment (HR 0.42, 95% CI 0.19–0.93) [52]. We surmise that the protective effect may be due to the relatively high occurrence of pulmonary disease among patients in controls adjusted by age and the relatively low occurrence in dementia patients because of the deceased survival rate complicated with this condition in old age. In addition, hyperlipidemia, atrial fibrillation, hearing loss, glaucoma, schizophrenia, osteoporosis, Huntington and Parkinson's disease are also believed to be associated with dementia [4]. Since the selection of comorbidities in this study was based on CCI and ECI, these diseases were not included.

It is acknowledged that Alzheimer's disease is more inclined to degeneration, while vascular dementia is more likely to be related to the vascular system in the traditional definition. However, the contribution of vascular factors to Alzheimer's disease also deserves attention. A study of cardiovascular medication burden in dementia has found that up to 84% of vascular dementias used cardiovascular medication, significantly higher than in Alzheimer's disease patients (59%) [53], which indicates management of vascular risk is equally important for Alzheimer's disease patients.

The study found that the prevalence of comorbidities in dementia was up to 93.5%, indicating that most dementia patients may have polypharmacy. It was reported that the frequency of polypharmacy (greater than or equal to five unique medications) in patients with dementia ranged from 50 to 71.2% [54,55,56]. Lau et al. found that there were an average of 5–10 drugs taken by dementia patients, of which only 1–2 drugs were taken for dementia [57]. For patients with dementia, the most commonly used drugs included cardiovascular disease and diabetes drugs, followed by antipsychotics, antiepileptics, and anticholinergic drugs [58, 59]. An increased risk of cognitive impairment associated with polypharmacy has been observed in multiple studies [60,61,62,63]. For example, a Japanese survey found that multiple medications can cause cognitive impairment after excluding confounding factors [60]. A South Korean study found that the OR for dementia increased significantly as the number of prescribed drugs increased (1–4 drugs, OR = 1.72, 95%: 1.56–1.88; 5–9 drugs, OR-3.35, 95% CI 2.38–4.71, with 1 drug as reference) [61]. Different drugs may exert beneficial or detrimental effects on cognition; for example, anticholinergics, antiepileptic drugs, benzodiazepines and antipsychotics may increase the risk of dementia; in contrast, statins, antihypertensive medications, and antidiabetics could potentially protect against cognitive impairment [59, 63].

Limitations

Some limitations of this study include the following. First, diagnostic bias was inevitable because the samples of this study were all from a single center. Population bias should also be considered, as the population is in-hospital patients from different departments. Second, we did not include patients from clinics. Although inpatient data have merits (for example, it is more likely to have comprehensive diagnosis for a patient due to target and thorough examination, which was suitable for our study purpose). Inclusion of outpatient data would provide an overview of dementia patients in our areas. Unlike inpatients, outpatients with dementia might have fewer comorbidities and mild dementia symptoms, which is important for clinical investigation. Third, in the present study, all patients were from the same hospital database, and we did not specifically select corresponding controls from the same department. Instead, we randomly selected those controls from the database, which would definitely cause some bias. Finally, since this study focused on the overall situation of dementia and comorbidities, the comorbidities for various subtypes of dementia were not detailed.

Conclusion

Compared with those without dementia, patients with dementia had more comorbidities. Comorbidities (esp. cardio-cerebral vascular risks) in patients with vascular dementia were more than those in patients with AD. Specifically, vascular and circulatory diseases, epilepsy, diabetes and depression increase the risk of dementia.