Ten-year trends in hospitalizations due to Alzheimer’s disease in Brazil: a national-based study

Brazil has the second highest age-standardized prevalence of Alzheimer’s disease worldwide. However, information about Alzheimer’s disease-related hospitalizations in Brazil is scarce despite its economic and social impact. We described temporal trends in hospitalizations related to Alzheimer’s disease in Brazil from 2010 to 2019. We conducted a time-series, retrospective, descriptive, national-based study using data from the DATASUS database of the Brazilian Ministry of Health. Hospitalizations, mean days hospitalized, and economic costs from those hospitalizations were extracted from 2010 to 2019. Hospitalizations by Alzheimer’s disease increased 87.7% from 2010 to 2019, with greater increase among men (97.4%), mixed ethnicity (224%), 80 years or older (115.1%), and in the Northeast (172.1%) and Central West (144.2%) regions. Although mean days hospitalized decreased in all subgroups, an increasing time trend in hospital admission was observed in the Central West Region. Costs per hospitalization increased for patients aged 50 years or younger and in admissions related to emergency services. Compared with other non-communicable chronic diseases, Alzheimer’s disease had the highest increase in absolute number and rate of hospitalizations in Brazil from 2010 to 2019. AD is a public health problem in Brazil. Strategies to reduce its burden are necessary but only if accompanied by greater equality and awareness of this disease. Alzheimer Disease; Hospitalization; Time Series Studies Correspondence N. Feter Rua Luís de Camões 625, Pelotas, RS 96055-630, Brasil. natanfeter@hotmail.com 1 Universidade Federal de Pelotas, Pelotas, Brasil. 2 The University of Queensland, St. Lucia, Australia 3 Universidade Federal do Rio Grande, Rio Grande, Brasil. This article is published in Open Access under the Creative Commons Attribution license, which allows use, distribution, and reproduction in any medium, without restrictions, as long as the original work is correctly cited.


Introduction
In 2016, Brazil had the second highest age-standardized prevalence of dementia in the world, affecting about 1.7 million people 1 . Alzheimer's disease, which accounts for up to 80% of all cases of dementia, is a neurodegenerative disease characterized by deterioration of cognitive function, such as memory and physical capacity 2 . While in Argentina, Chile, and Uruguay the number of deaths attributable to dementia has decreased by up to 5.3% 1 , the mortality rate in Brazil increased annually by 12.5% from 2000 to 2008 3 . Likewise, the annual total cost per individual living with dementia in Brazil is greater than the global average regardless of disease stage 4 .
According to the Scientific Department for Cognitive Neurology and Aging of the Brazilian Academy of Neurology 5 , the diagnosis of Alzheimer's disease occurs when cognitive or behavioral symptoms affects at least two of the following domains: memory, executive functions, visual and spatial skills, language, and personality or behavior. Usually together with loss of functional capacity, these problems increased the frequency of hospitalizations in Alzheimer's disease patients 6,7,8 . This is particularly concerning since these patients may have an irreversible cognitive and functional decline during hospitalization 9 .
About 40% of all annual hospitalizations from 2000 to 2008 in the United States were people 85 years or older living with dementia 8 . Feng et al. 6 showed that patients with Alzheimer's disease living in community residences are more likely to have any avoidable hospitalization and emergency visit than non-demented older people. Data from the United States 7 revealed that sensitive conditions of ambulatory care, which are related to problems in continuity of care, inefficient resource use, and poor patient outcomes, costed USD 4.7 billion in 2013 and were responsible for 25% of all Alzheimer's disease-related hospitalizations 10 .
Although information about hospitalization due to ischemic heart disease 11 , overweight, and obesity 12 is available, the information concerning Alzheimer's disease-related hospitalizations in Brazil is scarce despite its economic and social impact 1,3,4 . As such, this study describes the trend of number, duration, and economic cost from hospitalizations related to Alzheimer's disease in Brazil from 2010 to 2019.

Methods
For this time-series, retrospective, descriptive study, we collected data from Brazilian Informatics Department of SUS (DATASUS. http://www.datasus.gov.br). We extracted the number of hospital admissions, total days hospitalized, and total costs of hospitalizations from 2010 to 2019, which was the latest year with available data.
Total hospitalizations were considered as any new authorized hospitalization form, transferences, and re-hospitalization related to Alzheimer's disease. To account for population size and growth, we divided the number of hospital admissions by the total population size. For stratified analysis, we divided the number of hospitalizations by the population size in each subgroup (i.e., sex, age group, ethnicity, and region) for each year. The number of inhabitants was obtained using the 2010 National Census (Instituto Brasileiro de Geografia e Estatística. http://www.ibge.gov.br) and the Continuous Brazilian National Household Survey (PNAD Contínua, in Portuguese. https://www.ibge.gov.br/en/ statistics/social/labor/16833-monthly-dissemination-pnadc1.html?=&t=o-que-e, accessed on 10/ Mar/2020).
Mean days hospitalized was calculated by dividing the total in-hospital days of all hospitalizations by the number of hospital admissions during the 10-year period. Hospitalization duration was calculated based on admission and discharge. For example, if the patient was admitted on January 15st and discharged on January 18th, that would be a 3-days hospitalization.
Total costs was considered as the value referred to all hospitalizations during a specific period. Values from each year were adjusted to the inflation rate based on the Extended National Consumer Price Index (IPCA) (Banco Central do Brasil. Correção de valores. https://www3.bcb.gov.br/CAL CIDADAO/publico/exibirFormCorrecaoValores.do?method=exibirFormCorrecaoValores&aba=1, accessed on 13/Oct/2020), enabling direct comparison among the years.
Cad. Saúde Pública 2021; 37(8):e00073320 The cause of hospitalizations was informed as the main diagnosis, defined as what caused the hospitalization. For Alzheimer's disease, we considered all hospitalizations from which the main diagnose were Alzheimer's Disease defined as G30.0 to G30.9 according to the International Classification of Disease, 10th revision (ICD-10) 13 .
We also stratified these outcomes by sex (male/female), age groups based on birth and admission days (less than 50, 50-59, 60-69, 70-79, 80 or older), ethnicity (white, black, mixed, yellow, and indigenous), type of admission (emergency or elective), and region (South, Southeast, North, Northeast, and Central West). After data collection, we calculated the percent changes in our outcomes from 2010 to 2015 and then from 2015 to 2019. Values from Asian and indigenous people were not shown due to missing data in most of the years for all outcomes.
To test time trend in number, duration, and cost of hospitalizations due to Alzheimer's disease from 2010 to 2019 in Brazil, the Prais-Winsten regression method was used, with Corchrane-Orcutt transformation and search for rho to minimize the sum-of-squared errors of the transformed equation. This test corrects the first-order autocorrelation effect and quantifies the annual variation in number, rate (per 100,000 inhabitants), duration (days), and cost (BRL) of hospitalization due to Alzheimer's disease in Brazil throughout that period 14 . Regression coefficients classified time trend as increased or decreased if p < 0.05 and coefficient higher or lower than 0, respectively. If p > 0.05, trend was classified as stationary. Since public data were available in DATASUS and in Brazilian Institute of Geography ansd Statistics (IBGE, in Portuguese) website, approval by the Ethics Research Committee was not needed.

Results
We observed an increase of 87.7% in hospitalizations due to Alzheimer's disease in Brazil from 2010 to 2019 (Table 1). This increase was even greater among men (97.4%), mixed ethnicity (224%), those aged 80 years or older (115.1%), and in Northeast (172.1%), Central West (144.2%), and Southeast (91.6%) regions of Brazil. Further, the time trend of the number of hospital admissions during that 10-year period did not achieve statistical significance only in patients aged 50 years or younger (p = 0.105), admitted as elective (p = 0.099), and in the Southeast (p = 0.057) and North (p = 0.097) regions.
Even though there was a decrease in hospitalizations due to Alzheimer's disease among black individuals from 2010 to 2015 (-20.4%), this ethnicity was more hospitalized from 2015 to 2019 (105.1%). On the other hand, women, subjects aged 79 or less, admission on hospital by elective, and patients from the Southeast and North regions had an increase in hospitalizations from 2010 to 2015, followed by decrease from 2015 to 2019.
Furthermore, Table 2 summarizes the hospitalization rate attributable to Alzheimer's disease from 2010 to 2019 in Brazil. Our findings showed that, in this 10-year period, the hospitalization rate increased 75.3% in the country, with higher values in patients self-declared white (76.7%) and mixed ethnicity (192.8%), from Southeast (91.6%), Central West (119.2%), and Northeast (158.9%). Nevertheless, only patients aged 50 years or younger presented a decrease in this indicator (-43.6%).

Hospitalization
Difference per (0.03; 95%CI: 0.02; 0.04), and Central West (0.07; 95%CI: 0.05; 0.09) regions. This trend was also identified in all sex and ethnic groups. On the other hand, no trend in hospitalization rate was identified by different age groups. Table 3  The economic cost from hospitalizations due to Alzheimer's disease in Brazil increased 41.6% from 2010 to 2019, as shown in Table 4. In hospitalizations whose patients were from the South Region (43%), men (51.9%), aged 80 years or older (87.3%), admitted by emergency services (98.9%), and from the Central West Region (793.4%), the increase was higher than the average.   Compared to the top-5 non-communicable chronic diseases that serve as cause of death in Brazil, Alzheimer's disease showed the highest and third-highest increase in disease-related hospitalization rate per 100,000 inhabitants (Figure 1a; 75%) and total costs from hospitalizations (Figure 1c; 42%), respectively. On the other hand, the greatest reduction in mean days hospitalized and costs per admission were from patients with Alzheimer's disease (Figure 1b; 41%; Figure 1d; 25%).

Discussion
This was the first national-based, time-series study that described hospital admissions from Alzheimer's disease in Brazil. We reported that total (87.7%) and rate (75.3%) of hospitalizations and total cost from hospitalization (41.6%) due to Alzheimer's disease increased from 2010 to 2019 in Brazil, indicating an increase in hospitalizations over this 10-year interval in Brazil. On the other hand, mean days hospitalized (-37%) and costs per hospitalization (-24.5%) decreased during the same period.
Although 66% of all hospitalization from Alzheimer's disease in 2019 were among females, the increase in hospital admission rate was higher in men (84.2%) than women (71.9%). Also, the annual variation coefficient indicates a time trend of increase in the absolute number and rate of hospitalization in both sexes from 2010 to 2019. In Brazil, prevalence and morbidity attributable to Alzheimer's Cad. Saúde Pública 2021; 37(8):e00073320 Table 4 Trend from 2010 to 2019 in economic cost of hospitalizations a due to Alzheimer's disease in Brazil. disease and other dementia were, respectively, 69% and 68% higher among women in 2017 (Institute for Health Metrics and Evaluation. GBD results tool. http://ghdx.healthdata.org/gbd-results-tool%20, accessed on Oct/2020). On the other hand, women tend to present longer survival time but more affective symptoms and disability 15 , while men reported more comorbidity, decline in behavior control, and higher mortality rates 16 , which may led to an increasing need of hospital admissions. Regarding ethnicity, white subjects accounted for 66.1% of hospitalizations due to Alzheimer's disease in 2019 at Brazil. Moreover, this ethnic group had a hospitalization rate 2.2 and 2.7 times higher than black and mixed ethnicity patients, respectively. However, we observed an increase of about 105.1% and 208.6% of hospitalization in black subjects from 2015 to 2019 and in mixed ethnicity from 2010 to 2019. This relative change was corroborated by the positive and significant annual percentage change in those ethnic groups. Husaini et al. 17 reported that besides a gender disparity in prevalence of dementia, there is also an ethnic disparity, with higher prevalence among black women and men compared to whites. According to the IBGE 18 , the self-declared black population increased 7.4% from 2012 to 2015, and 23.1% from 2015 to 2018, and mixed ethnicity became the most prevalent ethnicity in Brazil (46.5%).

Figure 1
Percentage changes in hospitalization rate per 100,000 inhabitants, mean days hospitalized, and total and mean cost from hospitalization due to top-5 cause of death non-communicable chronic disease in Brazil, 2010-2019.
Cad. Saúde Pública 2021; 37(8):e00073320 Death by cerebrovascular disease, hypertension and diabetes contributed for the "white-black" gap in life expectancy in Brazil, with black and mixed ethnicity individuals dying earlier by those chronic conditions 19 . Previous researchers have suggested that the elevated prevalence and incidence of cognitive impairment and dementia in these groups are associated with increased vascular risk induced by health disparities-related stress 20 . Cumulative stress throughout life affects neural mechanisms contributing to cognitive impairment 21 . Also, disparities in stressful events are associated with building environment, employment status, access to health care services, and social support. As a result, patients might present the first signals of dementia when the disease is at more advanced stages, ultimately increasing the number of admissions from emergency services 20 . In this vein, strategies to increase awareness about prevention, diagnoses, and treatment of dementia must be promoted at population level, especially in these ethnic groups.
The Brazilian population is ageing. From 2000 to 2050, the prevalence of people living with at least 60 years will increase by 280% 22 . The most important risk factor for Alzheimer's disease is age, with the prevalence of the disease doubling every 5 years after age 65 2 . This fact could explain the 115.1% increase in hospitalization for patients aged 80 or older. Although the youngest age group (< 50 years-old) had a decrescent trend from 2010 to 2019 in hospitalization rate, the mean economic cost changed in the opposite direction. Early-onset Alzheimer's disease included cases of Alzheimer's disease onset before age 65 23 and is associated in most cases with genetic mutations 2,24 . People with this condition are more likely to present more brain changes related to Alzheimer's disease 25,26 , which could be associated with the increased cost per admission. Although it is estimated to represent about 5% of all Alzheimer's disease cases in the world 27 , no data about the prevalence of this type of Alzheimer's disease in the Brazilian population is available 28 . Early-onset Alzheimer's disease is poorly understood, underdiagnosed, and inadequately treated, leading to underestimation of the impact of this condition on the healthcare system 28,29 . Future population-based studies that aim to describe the people with Alzheimer's disease and its sub-types in Brazil are encouraged.
The prevalence of Alzheimer's disease and other dementia in 2017 were higher in subjects aged from 60 to 74 years old in Brazil compared to United States, Canada, and Australia (Institute for Health Metrics and Evaluation. GBD results tool. http://ghdx.healthdata.org/gbd-results-tool%20, accessed on Oct/2020), which could be related to earlier onset of disease in most prevalent ethnicities 19 . Also, the country has made progress in the public health agenda concerning dementia control, especially in providing high cost medication free of charge for patients with dementia 30 . However, the difficult diagnosis for Alzheimer's disease and related disorders may lead to longer hospital stays and more screenings to possible diagnoses. Then, more training and resources for diagnosis of dementia, better long-term management provide by health professionals, and improved knowledge about risk factors for dementia and how to control them need to be done to reduce the hospital-related burden of Alzheimer in all age groups 31 .
Also related to disease management is the major type of admission switch from elective to emergency from 2010 to 2019. Indeed, the cost of emergency-related admissions due to Alzheimer's disease increased annually about BRL 122,744.60 (95%CI: 97,079.92; 148,409.40), whereas the cost from elective admission decreased by on average BRL 722,290.40 (95%CI: -1,190,403.00; -254,177.30) during this 10-year period. A similar pattern was observed in the United Kingdom, where admissions from emergency services increased from 2008 to 2016 32 . In the United States, the average emergency department visit is 1,471 per 1,000 older people with Alzheimer's disease 33 . Moreover, Alzheimer's disease patients are more likely to have a potentially avoidable emergency visit that resulted in hospitalization 33 . LaMantia et al. 34 explained that age, ethnicity, number of comorbidities and hospitalization were predictors of emergency department visits in the United States. As mentioned, the Brazilian population is ageing and more self-declared black 18 , and Alzheimer's disease is strictly related to higher prevalence of comorbidities 3 . Likewise, the underdiagnoses of dementia led to an increase in use of emergency settings. While the national underdetection rate in United Kingdom is about 52%, in Brazil this number may reach 77% 31 . Attached to low awareness and attitudes towards dementia and its care, these factors may result in failure to seek help and treatment 35 , leading to an increase in emergency setting admission from Alzheimer's disease patients.
Our findings indicate an annual rise in hospitalization rate from 2010 to 2019 in the South, Northeast, Central West, and Southeast regions. Regarding hospitalization duration, we observed an Cad. Saúde Pública 2021; 37(8):e00073320 annual reduction in four of the five Brazilian regions, with the only crescent trend being observed in the Central West Region. Similarly, the morbidity associated with Alzheimer's disease increased by 153% from 2010 to 2019 in Central West Region while it decreased by 6% in the Southeast in the same period (Institute for Health Metrics and Evaluation. GBD results tool. http://ghdx.healthdata.org/ gbd-results-tool%20, accessed on Oct/2020). Indeed, older population in the Central West Region increased 42% from 2010 to 2017 primarily due to migration of people from other Brazilian regions 18 . Together, those facts may explain the change of hospitalizations due to Alzheimer's disease in those regions.
From 2010 to 2019, Alzheimer's disease had the highest increase in number and rate of hospitalizations among the top-5 causes of death by non-communicable disease in Brazil. For example, the observed increase in hospitalization per 100,00 inhabitants attributable to Alzheimer's disease was 330% and 263% higher than for cerebrovascular and ischemic heart diseases, respectively. Based on annual rate change, we projected that in 2050, more people will be hospitalized in Brazil due to Alzheimer's disease than chronic obstructive pulmonary disease. At Central West and Northeast regions, Alzheimer's disease will overcome diabetes in number of hospital admissions in 2048 and 2035, respectively.
Similarly, the growth in costs of Alzheimer's disease in hospital settings from 2010 to 2019 was 785% higher than chronic obstructive pulmonary disease and 53% higher than diabetes mellitus. Although mortality rate by Alzheimer's disease decreased from 19.1 to 13.7 between 2010 to 2015, it increased throughout the following years by up to 24.2 in 2019, the highest increase in mortality rate from 2015 to 2019 (DATASUS. http://www.datasus.gov.br). That made Alzheimer's disease the disease with the third-highest all-cause mortality rate in Brazil in 2019 (24.1%), followed by septicemia (44.7%) and malignant neoplasia in the trachea, lungs, and bronchus (26.8%). In the United States, the percentage of death by Alzheimer's disease increased by 145% from 2000 to 2017 33 , killing more than breast and prostate cancer combined 36 .
Alzheimer's disease already costs USD 1 trillion worldwide, and it is estimated that this value will double in the next 30 years 37 . Just in the United States, early and accurate diagnosis could save up to USD 7.9 trillion 36 . In Brazil, about 32.3% of Alzheimer's disease prevalence is due to modifiable risk factors such as diabetes mellitus, midlife hypertension and obesity, physical inactivity, depression, smoking, and low educational attainment 38 . Considering a 20% reduction per decade among those aforementioned risk factors by 2050, there would be 604,000 less cases of dementia in Brazil and USD 10.3 million in disease-related costs could be saved 38 . Although our findings revealed a decrease in the mean costs per hospitalization, this indicator increased annually in young patients and patients admitted by emergency services. For most people worldwide, Alzheimer's disease is still perceived as a non-preventable condition that is a normal part of ageing 39 . Health policies to increased awareness of Alzheimer's disease and preventive strategies need to be stimulated.
The main limitation of this study is its descriptive design. Nevertheless, this type of investigation is relevant in Brazil as it led to a broader view of the current situation of Alzheimer's disease in Brazil. This is the first time-series national-based study that descripted total number of hospitalizations, hospitalized days and the related costs attributable to Alzheimer's disease in Brazil. The prevalence of this disease will triple by 2050 38 , affecting more than 3 million people, and only 1 in 4 cases of dementia are diagnosed 30 . As a result, public health policies, such as high-cost medication available free-ofcharge, have been delineated to reduce the burden of Alzheimer's disease in the country. Nevertheless, much more needs to be done. Alzheimer's disease in underdiagnosed, undertreated, and much of these come from under-recognition and undermanagement 40 .
In conclusion, Alzheimer's disease is already a public health problem in Brazil. The number, duration, and the costs of hospitalizations due to this disease increased more than other top-5 causes of death by non-communicable chronic diseases from 2010 to 2019. Strategies to reduce the burden of Alzheimer's disease in Brazil are necessary but only if followed by greater equality and awareness of this disease.