Disease Burden and Risk Factors of Early-Onset Alzheimer’s Disease and other Dementias in China (1990–2021) with 20-Year Projections to 2041: A Global Burden of Disease Study Analysis

Disease Burden and Risk Factors of Early-Onset Alzheimer’s Disease and other Dementias in China (1990–2021) with 20-Year Projections to 2041: A Global Burden of Disease Study Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Disease Burden and Risk Factors of Early-Onset Alzheimer’s Disease and other Dementias in China (1990–2021) with 20-Year Projections to 2041: A Global Burden of Disease Study Analysis Shuai-Yu Zhu, Qiu-Xia Xiao, Zheng-Yuan Duan, Qi-Jun Li, Xiu-Ji Ou-Yang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7495038/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Early-onset Alzheimer’s disease and other Dementias (EOAD) have emerged as a major public-health challenge worldwide and in China. With the rapidly ageing population, especially in China, the burden of EOAD continues to rise. Using 2021 Global Burden of Disease (GBD) data, we analysed the EOAD burden and its principal risk factors among Chinese adults aged 40–64 years from 1990 to 2021, and projected trends for the ensuing 20 years. Methods Data from GBD 2021 were extracted to quantify the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) of EOAD in China from 1990 to 2021, along with corresponding age-standardised rates (ASRs). Temporal trends were evaluated using the annual average percentage change (AAPC), and an autoregressive integrated moving average (ARIMA) model was applied to forecast the EOAD burden over the next 20 years. We also assessed the association between EOAD burden and the Socio-Demographic Index (SDI). Results From 1990 to 2021, the age-standardized prevalence rate (ASPR) of EOAD in China for the 40–64 age group increased from 703.1 to 900.8 per 100,000, with a percentage change (PC) of 28.1% (AAPC = 0.44%, 95% UI: 0.35%, 0.53%), significantly higher than the global increase of 3.2%. The age-standardised incidence rate (ASIR) increased from 100.3 to 126.5 per 100,000 in males and from 135.4 to 171.8 per 100,000 in females, representing rises of 26.2% (AAPC = 0.50%, 95% UI: 0.43%, 0.57%) and 26.9% (AAPC = 0.42%, 95% UI: 0.33%, 0.50%), respectively. The age-standardised mortality rate (ASMR) in males rose modestly from 25.1 to 25.9 per 100,000 (3.1% increase; AAPC = − 0.03%, 95% UI: −0.07%, 0.01%), whereas the female rate remained largely unchanged at 33.8 per 100,000 (AAPC = − 0.20%, 95% UI: −0.24%, − 0.17%). For age-standardized DALYs rate (ASDAR), males increased from 429.9 to 463.7 per 100,000, while females increased from 596.7 to 631.4 per 100,000, with increases of 7.9% (AAPC = 0.09%, 95% UI: 0.05%, 0.13%) and 5.8% (AAPC = -0.02%, 95% UI: -0.06%, 0.03%), respectively. ASRs for incidence and prevalence were positively correlated with SDI. Metabolic risk factors now constitute the principal drivers of EOAD burden, whereas smoking and other behavioural risks continue to exert a pronounced effect among men. Prevalence and incidence are projected to rise further over the next two decades, with the steepest increases anticipated in women. Although male mortality shows a slight decline, female mortality remains stable. Conclusion China’ s EOAD burden has risen markedly over the past three decades, with women disproportionately affected. In the future, public health interventions, early screening and clinical management measures for gender differences and metabolic health will be the key to reducing the burden of EOAD in China. Early-onset Alzheimer's disease and other dementias Global Burden of Disease gender differences metabolic risk factors Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Dementia, especially Alzheimer's disease and other types of dementia, has traditionally been regarded as an age-related disease. However, with the rising prevalence of dementia across all age groups globally, it has become an increasingly severe challenge in the field of global health.In 2019, approximately 57 million people globally were living with dementia, with an associated economic burden of 2.8 trillion USD. It is projected that by 2050, the number of people with dementia will reach 153 million, and the economic burden will rise to 16.9 trillion USD [ 1 – 3 ]. Against this backdrop, China has become the country with the highest number of dementia patients in the world, facing increasingly severe health and economic pressures [ 4 ]. However, Early-Onset Alzheimer's disease and other Dementias (EOAD), defined as dementia that manifests before the age of 65, is increasingly recognized as an important global health challenge [ 5 ]. Studies have shown that EOAD accounts for approximately 6.9% of all dementia cases globally, with an annual incidence rate of 13.4 cases per 100,000 people [ 6 ]. Globally, from 1990 to 2021, the number of EOAD cases in the 40–64 age group nearly doubled, reaching 7.758 million in 2021, with most of this growth occurring in developing countries. This highlights the urgent need for effective prevention, diagnosis, and management strategies in this area [ 7 ]. EOAD patients often present with atypical clinical symptoms, including behavioral, language, and personality changes, as well as executive dysfunction. These symptoms lead to delays in early diagnosis and are often misdiagnosed as mild cognitive impairment or depression, which exacerbates the condition [ 5 , 8 , 9 ]. Despite significant progress in neurodegenerative disease research, the precise causes of Alzheimer's disease and other dementias (ADOD) remain unclear, and existing medications mainly alleviate symptoms without curing these diseases [ 10 – 12 ]. As EOAD patients often lose their ability to work during their prime years, this results in a substantial caregiving burden and economic strain on both the patient's family and society [ 8 , 13 – 15 ]. In China, approximately 15 million patients and their families face long-term caregiving needs [ 16 ]. Although studies have explored the global burden of EOAD, research on the epidemiological patterns and risk factors of EOAD in China remains relatively limited. This study uses data from GBD 2021 to analyze the trends in prevalence, incidence, mortality, and disability-adjusted life years (DALYs) of EOAD in China from 1990 to 2021, aiming to fill this research gap. The results of this study will provide scientific evidence for the development of more targeted prevention and management strategies to alleviate the increasing burden of EOAD in China. 2. Methods 2.1 Data Sources and Disease Definition This study utilized GBD 2021 data, which includes comprehensive estimates of 371 diseases and injuries across 204 countries and regions from 1990 to 2021 [ 17 ]. Considering the relatively few cases of EOAD in populations under 40, this study only analyzed data for individuals aged 40 years and older [ 7 ]. Specifically, we extracted data from the GBD database on the prevalence, incidence, mortality, and DALYs for ADOD in the 40–64 year old population in China from 1990 to 2021, along with their age-standardized rates (ASR) and 95% uncertainty intervals (UI). The data used are comprehensive, sourced from mortality registries, disease surveillance, cohort studies, and hospital records, with the analysis following the health estimation guidelines provided in the GBD study report [ 18 – 20 ]. ADOD include major types such as Alzheimer's disease (AD), vascular dementia, Lewy body dementia, and frontotemporal dementia. In the GBD 2021 study, all dementia types are categorized under "Alzheimer's disease and other dementias," corresponding to the following ICD-10 codes: F00 (Alzheimer's disease dementia), F01 (vascular dementia), F02 (dementia due to other diseases), F03 (unspecified dementia), G30 (Alzheimer's disease), G31 (other neurodegenerative dementias) [ 7 , 21 ]. Therefore, the disease burden addressed in this study encompasses all health losses attributed to various types of dementia. Although the GBD study does not categorize early-onset dementia as a separate disease, it is typically distinguished by age of onset: cases with onset before age 65 are generally defined as EOAD [ 22 ]. 2.2 Study Population, Age Groups, and Regions This study focuses on middle-aged adults aged 40 to 64 years, divided into five age groups: 40–44 years, 45–49 years, 50–54 years, 55–59 years, and 60–64 years. All indicators were analyzed by sex, with separate reporting for male and female data. The study primarily compares the disease burden of EOAD from 1990 to 2021 in China, globally, and across the G20 countries (an international economic forum consisting of 20 major economies, with the European Union excluded from the analysis, thus including only 19 countries). The Socio-Demographic Index (SDI) is a composite indicator of social and economic development, ranging from 0 to 1, considering factors such as education, economy, and fertility rate [ 23 ]. A higher SDI value indicates a higher level of social development in a country or region. Based on SDI values, countries and regions are classified into five levels: low, low-middle, middle, upper-middle, and high. 2.3 Measurement of Disease Burden We compared the prevalence, incidence, mortality, and DALYs of EOAD in different populations stratified by age and sex. The age-standardized incidence rate (ASIR) and prevalence rate (ASPR) per 100,000 people reflect the incidence of new cases and the prevalence of existing cases in the 40–64 age group. The age-standardized mortality rate (ASMR) per 100,000 people reflects the risk of death due to EOAD. DALY is used to measure the health loss caused by the disease, including the years of life lost due to premature death (YLL) and the years of healthy life lost due to disability (YLD), with one year of lost healthy life counting as one DALY. We used percentage change (PC) and average annual percentage change (AAPC) to measure the annual change rates of prevalence, incidence, and other indicators. The calculation of AAPC is derived through regression analysis and applied using the formula AAPC = (exp(β1) − 1) × 100, where β1 is the regression slope that transforms logarithmic values into original scale [ 7 ]. All rate indicators are age-adjusted using the GBD standard population, with units per 100,000 population. 2.4 Risk Factors The selection of risk factors is based on those identified in GBD 2021 as attributable to dementia. This study includes "all risk factors" and several classified risk factors, including behavioral risks (such as smoking and tobacco) and metabolic risks (such as high body-mass index and high fasting plasma glucose). In GBD, high body-mass index (BMI) in adults is defined as individuals with a BMI > 25 kg/m²; high fasting plasma glucose (FPG) is defined as fasting blood glucose levels above the theoretical minimum risk level (4.8–5.4 mmol/L) [ 21 ]. Smoking in GBD is defined as individuals who currently use any tobacco products or have quit smoking within the past six months, while the "tobacco" risk factor includes both active and passive smoking exposure [ 24 ]. For each risk factor, we extracted the attributable DALY counts and their proportions of the total dementia DALY burden, and performed sex-stratified comparisons. 2.5 Statistical Analysis We described the incidence, prevalence, mortality, and DALY counts and trends of EOAD from 1990 to 2021, along with the corresponding ASR. Additionally, we evaluated differences in China across different age groups, sexes, and risk factors. We assessed temporal trends by calculating PC and AAPC, along with their corresponding 95% UI. AAPC and its 95% UI were used to determine whether the indicators were increasing (AAPC > 0), decreasing (AAPC < 0), or stable (when the uncertainty interval includes 0). We also applied the ARIMA model to predict future trends in disease burden over the next 20 years, using data from 1990 to 2021. Furthermore, we used Pearson's correlation coefficient to analyze the relationship between SDI and EOAD disease burden indicators (ASPR, ASIR, ASMR, and ASDAR), with statistical significance set at p < 0.05. Finally, we conducted Frontier analysis to assess the minimum disease burden achievable at different SDI levels. All analyses were performed using R software, with relevant R packages including tidyr, scales, dplyr, broom, ComplexHeatmap, ggplot2, and reshape2. 3. Results 3.1 Disease Burden of EOAD in China From 1990 to 2021, ASPR of EOAD in China increased significantly, especially in 2021, reaching 900.8 per 100,000, ranking first in G20 countries ( Fig. 1 , Table S1 ) . In contrast, developed countries such as France (525.2 per 100,000) and Australia (589.9 per 100,000) have lower prevalence rates and have shown a downward trend since 1990 (5.10% and 16.10%, respectively). The prevalence rate in China increased by 28.10% (AAPC = 0.44%, 95% UI: 0.35%, 0.53%) from 703.1 per 100,000 in 1990, becoming the largest increase among G20 countries, and this increase was significantly higher than the global average of 3.20%. In addition, the number of patients increased more than fourfold from 4.025 million in 1990 to 16.991 million in 2021, further reflecting the severity of the disease burden (Table S1 ) . ASIR of EOAD in China also showed rapid growth and ranked first among G20 countries, with 151.5 per 100,000 in 2021, followed by Germany (142.1 per 100,000). Since 1990, the incidence rate in China has increased by 25.10% (AAPC = 0.41%, 95% UI: 0.33%, 0.49%). In contrast, the incidence of many G20 countries has not increased since 1990, but has declined, such as the United Kingdom fell by about 5.80%, Canada fell by 11.50% and so on. In 1990, China 's incidence rate (121.1 per 100,000) was close to the global average, and by 2021, China 's incidence rate was about 26.5% higher than the global average (119.8 per 100,000) (Table S1 ) . In terms of mortality, China 's ASMR in 2021 is 30.8 per 100,000, ranking first in G20 countries. Nevertheless, the mortality rate was slightly lower than that in 1990 ( 31.4 per 100,000), with a change of only-1.80% (AAPC= -0.19%, 95% UI : -0.23%, -0.15%). This trend is lagging behind that of most high-income countries ( such as France, Australia, and South Korea, which fell by about 5.60%, 5.40%, and 18.70%, respectively ). In addition, the mortality rates of some middle-income countries such as India and Indonesia increased significantly by 27.20% and 30.90%, respectively. Finally, in terms of DALYs, China ranks first among G20 countries. In 2021, ASDAR of dementia in China was 562.4 per 100,000, higher than that in Germany (508.6 per 100,000) and the United States (509.7 per 100,000). Since 1990, China 's ASDAR has increased by 5.20% (AAPC= -0.02%, 95% UI: -0.07%, 0.02%). Compared with most high-income G20 countries (such as South Korea fell by 13.90%, Australia fell by 9.20%, etc.), China 's growth trend is obvious. In 2021, China 's ASDAR was about 24.7% higher than the global average (451.0 / 100,000), and the gap was wider than in 1990 (Table S1 ) . These results suggest that the burden of EOAD in China has continued to increase over the past few decades, especially in terms of prevalence, morbidity and DALYs, indicating a further increase in the burden of disease in the future. This also highlights the urgency of public health policies and disease prevention and control measures. 3.2 Age and Sex Differences in EOAD Burden in China The disease burden of EOAD in China significantly increases with age, and is particularly pronounced in women. In the 40–44 age group, all indicators were relatively low, and no significant gender differences were observed. However, with increasing age, especially after 50, ASPR and ASIR begin to rise significantly, and both ASMR and ASDAR also increase. Despite these increases being lower than incidence and prevalence, they peak in the 60–64 age group ( Fig. 2 ) . In the 60–64 age group, the prevalence and DALYs burden of dementia in women were significantly higher than in men: the number of affected women was approximately 558,000, 1.2 times that of men (479,000); women in this age group had 288,000 DALYs, significantly higher than men ( Fig. 3 A, D ) . The number of female patients and health losses in this age group accounted for the largest share of the total EOAD burden in China. In comparison, although the incidence and DALYs in men in the 60–64 age group were also at high levels, they were lower than in women ( Fig. 3 A, D ) . Additionally, the annual new cases and mortality cases in the 60–64 age group were the highest among all age groups, with women higher than men ( Fig. 3 B, C ) . Overall, the 60–64 age group, especially women, bears the heaviest disease burden from EOAD in China. Over the past 30 years, the dementia burden in China's middle-aged and elderly population has shown a significant upward trend ( Fig. 4 ) . From 1990 to 2021, the number of cases continued to increase, and ASPR steadily rose ( Fig. 4 A ) . The number of affected women increased from 2.513 million in 1990 to 10.829 million in 2021, with ASPR rising from approximately 785.2 per 100,000 to nearly 1025.1 per 100,000; for men, ASPR increased from 574.6 per 100,000 to 731.2 per 100,000 during the same period ( Table 1 ) . ASIR and ASDAR also showed an upward trend ( Fig. 4 B, D ) , with the number of new cases reaching about 2.914 million in 2021. The female incidence rate rose to 171.8 per 100,000, higher than the male rate of 126.5 per 100,000. The female ASDAR were 631.4 per 100,000, while the male rate was 463.7 per 100,000. Regarding ASMR, women reached a peak in the 1990s, then declined, but in 2021, ASMR for women (33.8 per 100,000) remained higher than for men (25.9 per 100,000) ( Fig. 4 C, Table 1 ) . These results indicate that China, especially in the 60–64 age group and particularly among women, faces a severe EOAD disease burden. Although the national disease burden increases year by year, significant gender differences remain, which should be specifically addressed in public health policies and interventions. International comparisons show that in 2021, China had a relatively high level of ASPR, ASIR, ASMR, and ASDAR for EOAD across all age groups among G20 countries (Fig. S1 ) . For the 60–64 age group, China’s ASPR (1421.0 per 100,000) was significantly higher than the global average (1081.5 per 100,000), ranking second in the G20, only behind Canada (1444.1 per 100,000) (Fig. S1 A) ; ASIR was 239.7 per 100,000, ranking first in the G20 (Fig. S1 B) ; ASMR reached 15.8 per 100,000, second only to Brazil (19.7 per 100,000) (Fig. S1 C) ; ASDAR were 732.2 per 100,000, second only to Brazil (833.2 per 100,000) (Fig. S1 D) . Table 1 Trends in key epidemiological indicators of Early-Onset Alzheimer’ s Disease and other Dementias (EOAD) burden in China from 1990 to 2021 by sex. Measure Sex Number_1990 Rate_ 1990 Number_ 2021 Rate_ 2021 PC AAPC_ UI (95%) Prevalence Both 4024536 (3446398, 4623086) 703.14 (608.36, 809.51) 16990827 (14488494, 19672741) 900.82 (770.92, 1043.22) 28.10% 0.44% (0.35%, 0.53%) Prevalence Female 2512934 (2165052, 2892724) 785.19 (681.22, 900.41) 10828630 (9315735, 12515957) 1025.11 (879.04, 1186.81) 30.60% 0.46% (0.36%, 0.55%) Prevalence Male 1511602 (1280688, 1737520) 574.55 (493.64, 666.55) 6162198 (5142286, 7141800) 731.21 (618.54, 851.63) 27.30% 0.51% (0.44%, 0.58%) Incidence Both 703178 (601506, 808633) 121.11 (105.5, 137.99) 2914112 (2504728, 3350743) 151.47 (131.22, 173.34) 25.10% 0.41% (0.33%, 0.49%) Incidence Female 442528 (381567, 507194) 135.42 (118.39, 154.07) 1836815 (1593651, 2101343) 171.81 (150.12, 195.9) 26.90% 0.42% (0.33%, 0.5%) Incidence Male 260650 (222339, 301788) 100.25 (86.5, 115.16) 1077297 (908448, 1248194) 126.48 (107.78, 145.62) 26.20% 0.5% (0.43%, 0.57%) Mortality Both 119809 (28349, 322103) 31.39 (7.6, 83.63) 491774 (124968, 1330182) 30.82 (7.88, 82.43) -1.80% -0.19% (-0.23%, -0.15%) Mortality Female 80212 (19176, 212442) 34.61 (8.32, 90.6) 328431 (83715, 862460) 33.8 (8.6, 87.19) -2.30% -0.2% (-0.24%, -0.17%) Mortality Male 39597 (9247, 113675) 25.12 (6, 70.58) 163343 (40664, 466660) 25.9 (6.51, 73.2) 3.10% -0.03% (-0.07%, 0.01%) DALYs Both 2702484 (1239177, 6085395) 534.47 (236.2, 1190.6) 10072478 (4947154, 22219154) 562.39 (271.16, 1238.81) 5.20% -0.02% (-0.07%, 0.02%) DALYs Female 1729685 (790232, 3750294) 596.71 (265.21, 1288.3) 6500199 (3171765, 13681029) 631.38 (305.95, 1318.24) 5.80% -0.02% (-0.06%, 0.03%) DALYs Male 972799 (434085, 2307848) 429.85 (186.23, 998.45) 3572279 (1694716, 8148478) 463.67 (214.26, 1055.84) 7.90% 0.09% (0.05%, 0.13%) 3.3 Comparison of EOAD Burden Between China and Other Countries Worldwide According to the global disease burden map for the 40–64 age group, China’ s crude prevalence rate (CPR) falls in the second-highest range of 1123.31-1534.35/100,000, the crude incidence rate (CIR) falls in the mid-high range of 196.09-266.37/100,000, only below the highest category; crude mortality rate (CMR) is in the moderate range of 17.5-35.16/100,000, and crude DALY rate (CDR) is between 386.34-707.96/100,000, indicating that the disease burden is at a moderate to high level (Fig. S2) . In global comparison, China’ s ASPR is significantly higher, with the global ASPR for EOAD in the 40–64 age group in 2021 being 589.5/100,000, while China’ s rate reached 731.2/100,000, 1.2 times the global average. Additionally, China’ s ASIR is also higher than the global average (Table S1 ). In regional comparisons, China has a higher CPR, CIR, CMR, and CDR than South Asian countries but lower than developed countries in Europe and North America. For example, South Asian countries like India have much lower CPR and CIR compared to China, whereas high-income Asian countries such as Japan and Korea, as well as the United States, Canada, and most European countries, have a higher EOAD burden (Fig. S2) . Overall, China is considered a high-burden country for EOAD globally, with its prevalence rate exceeding the Asian average but still lower than that of high-SDI European and American countries. Therefore, to address the growing EOAD burden, China needs to enhance public health interventions, improve early diagnosis and treatment levels, and reduce the disease burden, particularly in the middle-aged and elderly population. 3.4 The Relationship Between EOAD Burden and SDI In this study, a scatter plot was used to analyze the correlation between ASPR, ASIR, ASMR, and ASDAR with SDI. Pearson correlation analysis revealed a significant positive correlation between EOAD ASPR and SDI (r = 0.309, p < 0.001) ( Fig. 5 A ) , and a similarly significant correlation between ASIR and SDI (r = 0.357, p < 0.001) ( Fig. 5 B ) , indicating that countries with higher SDI typically have higher ASIR and ASPR. However, no significant correlation was found between ASMR and ASDAR with SDI (ASMR: p = 0.63, ASDAR: p = 0.503) ( Fig. 5 C, D ) , suggesting that the relationship between mortality and DALYs loss with socio-economic development level is weak. From 1990 to 2021, China’ s SDI significantly improved, and ASDAR showed an increasing trend. This trend suggests that as China’ s SDI increases, it faces an increasing burden of dementia cases. In 2021, China’ s DALYs value was higher than the global expected value for its corresponding SDI level, and compared to other high-SDI countries (e.g., the United States and Germany), China’ s overall DALYs level is relatively higher (Fig. S3) . This difference may reflect China’s potential for improvement and capacity in EOAD prevention, early diagnosis, and management, although its socio-economic level is increasing, the investment in healthcare resources and disease prevention still needs strengthening. 3.5 Risk Factors for EOAD Burden in China In 2021, the DALYs associated with EOAD in the Chinese population aged 40–64 were mainly attributed to modifiable risk factors. Overall, metabolic risk factors (such as high FPG and high BMI) and behavioral risk factors (especially smoking) contributed the most. High FPG is considered the primary risk factor for EOAD in China and globally; smoking in males, as a behavioral risk factor, significantly contributes to the disease burden. In the male population, the main risk factors, in order, are metabolic factors and behavioral factors such as smoking: metabolic risk accounts for 14.8%, with high FPG contributing 12.1% and high BMI contributing 3.3%; smoking contributes 14%. High FPG and smoking are the primary driving factors of EOAD burden in males (Fig. S4A) . In the female population, the main risk factors are still metabolic: metabolic risk accounts for 16%, with high FPG contributing 11.8% and high BMI contributing 5.0%; smoking’ s contribution is relatively low, at only 1.6%. This indicates that the EOAD burden in females is mainly driven by metabolic risks, with high FPG being the most significant factor, while behavioral risks such as smoking hardly contribute (Fig. S4B) . A comparison between sexes shows that the proportion of metabolic risks (mainly high FPG and high BMI) is similar in both sexes (14.8% for males vs. 16% for females), while the difference in behavioral risks is very evident: the smoking rate in males is much higher than in females, leading to a 14% contribution to DALYs related to smoking in males, whereas it is only 1.6% in females. In males, the contribution of behavioral factors such as smoking to the EOAD burden is significantly higher than in females, whereas metabolic abnormalities are a major issue faced by both sexes. 3.6 Future Projections of EOAD Burden in China Over the Next 20 Years A quantitative analysis of the trends in ASPR, ASIR, and ASMR of EOAD over the next 20 years was conducted using the ARIMA model. The projection shows that ASPR of EOAD will continue to rise. The male ASPR is expected to rise from 731.2 per 100,000 in 2021 to 876.7 per 100,000 by 2041; the female ASPR is expected to increase from 1025.1 per 100,000 to 1345.7 per 100,000, with the female prevalence rate consistently higher than that of males ( Fig. 6 A, B, Table S2) . Similarly, ASIR is also projected to rise, with the male ASIR increasing from 126.5 per 100,000 to 150.7 per 100,000, and the female ASIR rising from 171.8 per 100,000 to 219.3 per 100,000 ( Fig. 6 C, D, Table S2) . In comparison, ASMR for EOAD shows a significant gender difference: although the male ASMR is projected to slowly decrease from 25.9 per 100,000 in 2021 to 24.8 per 100,000 by 2041, the female ASMR is expected to remain relatively stable, with only a slight decrease to 33.7 per 100,000 ( Fig. 6 E, F, Table S2) . This trend suggests that the male EOAD mortality rate may improve, while the female mortality rate will change little, indicating that further attention is needed in managing clinical outcomes in the female population. 4. Discussion Overall, ASPR and ASIR of EOAD in Chinese population aged 40–64 years have increased significantly over the past three decades, with an increase significantly higher than that of the global and most G20 countries (except the European Union), while ASMR has remained stable. Compared with 1990, China 's EOAD ASDAR showed a slight upward trend, and ranked top among G20 countries (except the European Union), and this gap has widened. The burden of disease increases sharply with age, especially in the 60–64 age group (especially women), which contributes the most; women continued to have higher ASPR, ASIR, ASMR, and ASDAR than men. Metabolic risk factors (such as high FPG, high BMI) have replaced smoking as the main driving factor, and men are still more affected by smoking. ARIMA prediction shows that ASPR and ASIR will continue to rise in the next 20 years, and ASMR of men will decrease slightly, while that of women will remain almost unchanged, indicating that there is an imbalance in the improvement of clinical outcomes between genders. Taken together, these findings highlight the increasing burden of EOAD in China and call for more robust public health interventions and policy responses. 4.1 The age group difference of EOAD burden in China Our study found that the EOAD burden of Chinese adults aged 40–64 increased significantly with age, especially in the 60–64 age group, which was consistent with the natural progression of neurodegenerative diseases. Aging is the most important demographic risk factor for ADOD. Since the late 1970s, China’ s population aging process has accelerated and continued to grow at an annual rate of about 3.2%. By the end of 2023, the elderly population aged 60 years and over has reached 297 million, accounting for 21.1% of the total population of the country [ 25 ]. This trend is expected to continue for a long time and further promote the increase of the disease burden of EOAD. In addition, multiple factors such as diabetes, hypertension, smoking and obesity have been shown to be associated with the risk of AD, and these factors are particularly common in the middle-aged and elderly population [ 26 ]. Rapid urbanization and lifestyle changes in China have led to a continuous increase in the proportion of middle-aged people exposed to risk factors such as metabolic syndrome, smoking and diabetes. Especially in 2021, the prevalence of obesity among people over 60 years of age has reached 18% [ 16 , 25 , 27 ]. These changes may accelerate the clinical manifestations of EOAD in late middle age. In addition, the prevalence of sleep deprivation and mental health problems in middle age has been shown to be associated with cognitive decline [ 28 , 29 ]. With the acceleration of social modernization, the incidence of sleep disorders has increased significantly, and the global prevalence rate has reached 27%. About 300 million people in China face sleep disorders, of which the incidence of insomnia in adults is as high as 38.2% [ 30 – 32 ]. This problem may be another reason for the significant increase in the prevalence of EOAD in China. 4.2 Gender-related differences in EOAD burden in China In this study, we observed significant differences in EOAD burden between Chinese men and women. From 1990 to 2021, women were significantly higher than men in ASPR, ASIR, ASMR, and ASDAR, a trend consistent with related studies worldwide [ 7 , 33 ]. This gender difference may be caused by a variety of biological and social factors. Studies have shown that women are more susceptible to ADOD in old age. When women suffer from neurodegenerative diseases, they usually show faster hippocampal atrophy and more severe behavioral disorders [ 33 ]. In addition, women are more likely than men to carry AD-related genes, such as APOE ε4, and when they carry these genes, women are more likely to develop dementia [ 34 ]. It is worth noting that the Met66 allele of the BDNF gene only increases the risk of AD in women, while the 219K allele of the ABCA1 gene increases the risk in women but has a protective effect in men [ 35 , 36 ]. Estrogen has a significant protective effect on hippocampal synapse formation, brain glucose metabolism and β-amyloid clearance [ 37 ]. However, women experience a dramatic loss of estrogen after menopause, a physiological change that significantly increases the risk of AD ; in contrast, men 's testosterone levels can be converted into estrogen, and its decline is slower, so men in their later years did not experience the sharp estrogen loss faced by women after menopause [ 37 , 38 ]. In addition, low education level and poor career history are also associated with higher prevalence and incidence of AD [ 39 – 41 ]. According to the 2004 data of China Education Statistics Yearbook, the enrollment rate of rural women in higher education is only 0.64%, which is much lower than that of rural men (1.34%) and urban women (0.85%) [ 42 ]. This educational gap has caused the cognitive reserve level of elderly women to be generally lower than that of men of the same age, making them more likely to show clinical symptoms under the same pathological load. In addition, women face a higher risk of metabolic diseases in middle age, including high BMI, high FPG, and high blood pressure, which may accelerate their cognitive decline [ 43 – 47 ]. In China, the risk of AD in women with FPG levels ≥ 7.0 mmol/L is 41% higher than that in men, which may be related to the increased sensitivity of women to insulin resistance in the absence of estrogen [ 48 ]. In addition, women generally live longer, which means that they are exposed to the risk of cognitive decline for a long time, which further aggravates the disease burden of EOAD [ 49 , 50 ]. Therefore, improving the metabolic health management of the female population and providing targeted cognitive function interventions may help reduce the EOAD burden of Chinese women. 4.3 Analysis of the main risk factors of EOAD burden in China This study shows that metabolic risk factors (such as high BMI, high FPG) and behavioral risk factors (mainly smoking) are the main risk factors for EOAD burden in China. With the improvement of material living standards and quality of life, metabolic diseases such as metabolic syndrome, hypertension, diabetes and obesity are gradually increasing in China [ 46 , 51 ]. These factors are closely related to the occurrence of EOAD. In particular, high FPG, high blood pressure and high BMI have been confirmed as independent risk factors for ADOD by multiple studies [ 52 , 53 ]. In 2021, 45.1% of the world’ s adults are overweight and obese, and more than half of them live in countries such as China, India, and the United States. China has the largest number of overweight and obese adults, reaching 402 million [ 54 ]. Studies have shown that the number of adults aged 18–69 with hypertension in China was 274 million in 2018.Although the prevalence of hypertension has decreased since 2010, the treatment and control rates are still low [ 55 ]. In addition, the average annual concentration of PM2.5 in some areas of China has reached 50 µg/m³, which is several times the standard of the World Health Organization [ 16 ].Long-term exposure to such pollution may induce neuroinflammation and oxidative stress, and increase the risk of EOAD. Smoking is one of the major risk factors for many chronic diseases known worldwide. Studies have shown that smoking is closely related to cognitive decline and the occurrence of dementia [ 56 ]. China has the largest smoking population in the world. More than 300 million smokers and 740 million non-smokers are exposed to second-hand smoke, which not only leads to cognitive impairment, but also brings huge economic pressure to families and society [ 57 , 58 ]. In addition, lifestyle factors, such as lack of exercise, are significantly associated with the incidence of cognitive impairment and AD [ 59 – 62 ]. However, in the past 30 years, the proportion of Chinese adults who regularly exercise has decreased from 60% in 1990 to 35% in 2021, which may increase the risk of illness in the Chinese population [ 16 ]. Studies have shown that the Chinese Healthy Diet Index can not only directly affect the cognitive health of rural elderly people, but also improve cognitive function by improving mental health and reducing depressive symptoms [ 63 ]. However, with the acceleration of urbanization in China, lifestyle changes, especially the popularity of sedentary and high-calorie diets, may promote the prevalence of EOAD to some extent. Mental health problems such as sleep disorders and depression are also considered to be important risk factors for EOAD [ 64 – 66 ]. China’ s middle-aged and elderly people, especially urban residents, generally face higher work pressure and poor sleep quality, which to some extent aggravate the burden of EOAD [ 32 ]. In addition, the level of socio-economic development in some parts of China is low, especially in rural areas. Insufficient medical resources and inadequate early screening may lead to delays in the early diagnosis and treatment of dementia, which in turn increases the burden of disease. Therefore, the analysis of the risk factors of EOAD burden in China reveals the potential of public health policies, lifestyle interventions and socio-economic factors in the prevention of EOAD. Strengthening early intervention of metabolic diseases, improving the lifestyle of middle-aged and elderly people, and promoting health education and public health measures in the whole society will be the key steps to reduce the burden of EOAD in the future. 4.4 Future trends of China’ s EOAD burden The burden of EOAD in China will continue to rise in the next 20 years: ASPR and ASIR will increase significantly, and the burden of women will be higher than that of men. It is predicted that ASMR of men will decrease slowly, while the ASMR of women will be basically stable.In order to cope with the increasingly severe burden of EOAD, the Chinese government has taken a number of positive measures. According to the "Work Program on Exploring Special Services for the Prevention and Treatment of Alzheimer' s Disease", China plans to implement a national prevention and treatment promotion between 2023 and 2025, aiming to increase public awareness of dementia and community screening rates to 80%. In addition, the "Guiding Opinions on Promoting the Development of Aging during the 14th Five-Year Plan" issued by the State Council further strengthened early diagnosis and screening, and established the National Center for Geriatric Disease Research [ 48 ]. On the other hand, the "Healthy China 2030 Action Plan" tobacco control initiative proposes the creation of smoke-free families, advocates that family members do not smoke or actively quit smoking, and educates minors to avoid smoking, so as to reduce the risk of second-hand smoke harm to family members [ 68 ]. Since the implementation of the National Fitness Program (2021–2025) in China, the level of public services for national fitness has been significantly improved, fitness venues and facilities have been increasing, and the proportion of people regularly participating in physical exercise has reached 37.2% [ 69 ]. These policies may reduce the EOAD burden in China in the future. In recent years, with the development of diagnostic tools such as biomarkers and imaging techniques, the early diagnosis rate has gradually increased, especially in young and middle-aged people. These advances not only enable more cases to be detected in time, but also may affect the rising trend of prevalence in the next few years. 4.5 Advantages and limitations Based on GBD 2021 data, this study systematically assessed the burden of EOAD in Chinese population aged 40–64 years, focused on the analysis of metabolic and behavioral risk factors, and conducted age and gender differences. Analysis and future trend prediction provide valuable data support for public health interventions. However, this study also has some limitations. First, the data relies on existing public health records and death registrations, which may lead to deficiencies in disease diagnosis and screening in some areas. Secondly, although 12 dementia-related risk factors have been reported, only the metabolic and behavioral risk factors covered in GBD 2021 were used in this study [ 67 ]. Although other risk factors were mentioned in the discussion, all potential risk factors were not fully considered. In addition, the lack of a unified dementia registration system has led to heterogeneity in the definition and case identification of EOAD, and diagnostic criteria, biomarkers and ICD codes have changed over the past three decades, further exacerbating the heterogeneity of the data. Finally, although the ARIMA model provides useful predictive information, its prediction is essentially an extension of historical trends and may fail to capture future inflection points due to factors such as breakthroughs in diagnostic technologies, the launch of new therapeutic drugs, or major public health policy interventions. Therefore, the prediction results should be considered as the baseline scenario under the existing trend. 5. Conclusion From 1990 to 2021, the burden of EOAD in China increased significantly, especially among women. Metabolic risk factors, such as high FPG and high BMI, play a key role in increasing the burden of EOAD, and behavioral risk factors such as smoking can not be ignored. In the next 20 years, the prevalence and incidence of EOAD in China are expected to continue to rise, especially among women. The study emphasizes the urgency of strengthening public health interventions and improving early screening and treatment to cope with the increasingly severe disease burden. Declarations Consent The authors have nothing to report. Clinical trial number Not applicable. Ethics Statement The authors have nothing to report. Conflicts of Interest : The authors declare no conflict of interest. Funding: Not applicable. Author Contribution Data curation, Shuai Zhu, Zheng Duan, Ou Yang and Qi Li; Supervision, Liu Xiong; Visualization, Shuai Zhu; Writing – original draft, Shuai Zhu; Writing – review & editing, Qiu Xiao; All authors have read and agreed to the published version of the manuscript. Acknowledgments: The authors sincerely express their gratitude for the GBD data provided by the team members of the Global Burden of Diseases, Injuries, and Risk Factors (GBD) study. 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The red line represents ASIR, the green line represents ASMR, the blue line represents ASPR, and the purple line represents ASDAR. EOAD: Early-Onset Alzheimer’ s Disease and other Dementias; ASIR: Age-standardized incidence rate; ASMR: Age-standardized mortality rate; ASPR: Age-standardized prevalence rate; ASDAR: Age-standardized disability-adjusted life years rate\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/2953f5bbd0755208345f2de1.png"},{"id":92541993,"identity":"42c1d7dc-d447-47a9-8a77-30d80d4f6c9f","added_by":"auto","created_at":"2025-09-30 19:08:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1097775,"visible":true,"origin":"","legend":"\u003cp\u003eGender distribution of EOAD in different age groups of the 40-64 age group in China: Age-Standardized Rates. \u003cstrong\u003e(A)\u003c/strong\u003e ASPR, \u003cstrong\u003e(B)\u003c/strong\u003e ASIR, \u003cstrong\u003e(C)\u003c/strong\u003e ASMR,\u003cstrong\u003e (D)\u003c/strong\u003e ASDAR. The curves represent different gender populations (red for females, blue for males), and the shaded areas indicate the 95% UI. EOAD: Early-Onset Alzheimer’ s Disease and other Dementias; ASPR: Age-standardized prevalence rate; ASIR: Age-standardized incidence rate; ASMR: Age-standardized mortality rate; ASDAR: Age-standardized disability-adjusted life years rate\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/f4ec26789ca5f7958243204b.png"},{"id":92542559,"identity":"614cb99a-c02b-44c8-b8d8-779db843a442","added_by":"auto","created_at":"2025-09-30 19:24:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1275013,"visible":true,"origin":"","legend":"\u003cp\u003eGender and age distribution of prevalence, incidence, mortality, and DALYs of EOAD in China’s 40-64 age group in 2021. \u003cstrong\u003e(A)\u003c/strong\u003ePrevalence,\u003cstrong\u003e (B)\u003c/strong\u003e Incidence, \u003cstrong\u003e(C)\u003c/strong\u003e Mortality, \u003cstrong\u003e(D)\u003c/strong\u003e DALYs. The red bars represent females, blue bars represent males, with the x-axis representing the number of cases and the y-axis representing age groups (in 5-year intervals). EOAD: Early-Onset Alzheimer’s Disease and other Dementias\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/8f3d33255a0406d2278f77fd.png"},{"id":92542145,"identity":"ebd53e1d-d673-470c-9feb-dd74b0d2d227","added_by":"auto","created_at":"2025-09-30 19:16:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1525033,"visible":true,"origin":"","legend":"\u003cp\u003eTime trends of EOAD in China’s 40-64 age group (1990-2021). \u003cstrong\u003e(A)\u003c/strong\u003eNumber of Cases and ASPR; \u003cstrong\u003e(B)\u003c/strong\u003e Number of Cases and ASIR; \u003cstrong\u003e(C)\u003c/strong\u003eNumber of Mortality and ASMR; \u003cstrong\u003e(D)\u003c/strong\u003e DALYs and ASDAR. The bars represent the number of EOAD cases (left axis), and the solid lines represent age-standardized rates (right axis). Red indicates females, blue indicates males, and the shaded area represents the 95% UI. EOAD: Early-Onset Alzheimer’ s Disease and other Dementias; ASPR: Age-standardized prevalence rate; ASIR: Age-standardized incidence rate; ASMR: Age-standardized mortality rate; ASDAR: Age-standardized disability-adjusted life years rate\u003c/p\u003e","description":"","filename":"Fig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/b1e906d746cd819cc7e486a6.png"},{"id":92541961,"identity":"999cef4b-13be-4ff9-8390-a35979dbc6f9","added_by":"auto","created_at":"2025-09-30 19:08:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2569510,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation analysis between EOAD disease burden and SDI in 2021. \u003cstrong\u003e(A)\u003c/strong\u003eCorrelation between ASPR and SDI;\u003cstrong\u003e (B)\u003c/strong\u003e Correlation between ASIR and SDI; \u003cstrong\u003e(C) \u003c/strong\u003eCorrelation between ASMR and SDI; \u003cstrong\u003e(D)\u003c/strong\u003e Correlation between ASDAR and SDI. Each point represents a country, and the color of the points distinguishes the geographical regions. The black curve represents the fitted trend line, which shows the overall correlation trend of each indicator with SDI. EOAD: Early-Onset Alzheimer’ s Disease and other Dementias; ASPR: Age-standardized prevalence rate; ASIR: Age-standardized incidence rate; ASMR: Age-standardized mortality rate; ASDAR: Age-standardized disability-adjusted life years rate; SDI: Socio-Demographic Index\u003c/p\u003e","description":"","filename":"Fig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/a7c370f308dcd81223e1138d.png"},{"id":92542008,"identity":"3b099123-907c-4b33-8aae-4fb9c1b4822c","added_by":"auto","created_at":"2025-09-30 19:08:36","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":358086,"visible":true,"origin":"","legend":"\u003cp\u003eGender distribution and future trend projections of key EOAD indicators in China (1990–2041). \u003cstrong\u003e(A-B)\u003c/strong\u003e ASPR for males and females; \u003cstrong\u003e(C-D)\u003c/strong\u003eASIR for males and females; \u003cstrong\u003e(E-F)\u003c/strong\u003e ASMR for males and females. The red line represents the actual observed values from 1990 to 2021, while the blue line and shaded area represent the predicted values for 2022-2041 and their 95% UI. EOAD: Early-Onset Alzheimer’ s Disease and other Dementias; ASPR: Age-standardized prevalence rate; ASIR: Age-standardized incidence rate; ASMR: Age-standardized mortality rate\u003c/p\u003e","description":"","filename":"Fig.6.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/95385f37c1e54cf8595a9286.png"},{"id":99315459,"identity":"5724efc8-1e32-4242-b2bc-5f4a621e2a9a","added_by":"auto","created_at":"2025-12-31 16:26:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8510040,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/8ee88392-1840-410d-86f2-234e7e7994ac.pdf"},{"id":92541956,"identity":"a30cac61-132d-4dd4-90c2-cb8670358841","added_by":"auto","created_at":"2025-09-30 19:08:34","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2028435,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/c671795a893884ab8344fffb.docx"},{"id":92542138,"identity":"c5e42628-387e-48f7-a217-a9fb3d9666ee","added_by":"auto","created_at":"2025-09-30 19:16:35","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":349941,"visible":true,"origin":"","legend":"","description":"","filename":"Fig.S4.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/79a9c5f26ad845bc787d21d0.png"},{"id":92541968,"identity":"f1d41ac1-2d10-4259-b4a3-f7ca8758a4c0","added_by":"auto","created_at":"2025-09-30 19:08:35","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":519753,"visible":true,"origin":"","legend":"","description":"","filename":"Fig.S3.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/2f74456844de9075ac796483.png"},{"id":92541985,"identity":"cce7bee9-dd07-4817-9bf2-549598faae3f","added_by":"auto","created_at":"2025-09-30 19:08:35","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":729056,"visible":true,"origin":"","legend":"","description":"","filename":"Fig.S1.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/19e8142575bd0a42f12da418.png"},{"id":92542146,"identity":"bf223eac-7a0f-4f56-9ee4-0222def6b526","added_by":"auto","created_at":"2025-09-30 19:16:36","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":779047,"visible":true,"origin":"","legend":"","description":"","filename":"Fig.S2.png","url":"https://assets-eu.researchsquare.com/files/rs-7495038/v1/8e1f31bb3a57b737e89dea71.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Disease Burden and Risk Factors of Early-Onset Alzheimer’s Disease and other Dementias in China (1990–2021) with 20-Year Projections to 2041: A Global Burden of Disease Study Analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eDementia, especially Alzheimer's disease and other types of dementia, has traditionally been regarded as an age-related disease. However, with the rising prevalence of dementia across all age groups globally, it has become an increasingly severe challenge in the field of global health.In 2019, approximately 57\u0026nbsp;million people globally were living with dementia, with an associated economic burden of 2.8 trillion USD. It is projected that by 2050, the number of people with dementia will reach 153\u0026nbsp;million, and the economic burden will rise to 16.9 trillion USD [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Against this backdrop, China has become the country with the highest number of dementia patients in the world, facing increasingly severe health and economic pressures [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, Early-Onset Alzheimer's disease and other Dementias (EOAD), defined as dementia that manifests before the age of 65, is increasingly recognized as an important global health challenge [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Studies have shown that EOAD accounts for approximately 6.9% of all dementia cases globally, with an annual incidence rate of 13.4 cases per 100,000 people [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Globally, from 1990 to 2021, the number of EOAD cases in the 40\u0026ndash;64 age group nearly doubled, reaching 7.758\u0026nbsp;million in 2021, with most of this growth occurring in developing countries. This highlights the urgent need for effective prevention, diagnosis, and management strategies in this area [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEOAD patients often present with atypical clinical symptoms, including behavioral, language, and personality changes, as well as executive dysfunction. These symptoms lead to delays in early diagnosis and are often misdiagnosed as mild cognitive impairment or depression, which exacerbates the condition [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Despite significant progress in neurodegenerative disease research, the precise causes of Alzheimer's disease and other dementias (ADOD) remain unclear, and existing medications mainly alleviate symptoms without curing these diseases [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. As EOAD patients often lose their ability to work during their prime years, this results in a substantial caregiving burden and economic strain on both the patient's family and society [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In China, approximately 15\u0026nbsp;million patients and their families face long-term caregiving needs [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough studies have explored the global burden of EOAD, research on the epidemiological patterns and risk factors of EOAD in China remains relatively limited. This study uses data from GBD 2021 to analyze the trends in prevalence, incidence, mortality, and disability-adjusted life years (DALYs) of EOAD in China from 1990 to 2021, aiming to fill this research gap. The results of this study will provide scientific evidence for the development of more targeted prevention and management strategies to alleviate the increasing burden of EOAD in China.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Data Sources and Disease Definition\u003c/h2\u003e\u003cp\u003eThis study utilized GBD 2021 data, which includes comprehensive estimates of 371 diseases and injuries across 204 countries and regions from 1990 to 2021 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Considering the relatively few cases of EOAD in populations under 40, this study only analyzed data for individuals aged 40 years and older [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Specifically, we extracted data from the GBD database on the prevalence, incidence, mortality, and DALYs for ADOD in the 40\u0026ndash;64 year old population in China from 1990 to 2021, along with their age-standardized rates (ASR) and 95% uncertainty intervals (UI). The data used are comprehensive, sourced from mortality registries, disease surveillance, cohort studies, and hospital records, with the analysis following the health estimation guidelines provided in the GBD study report [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eADOD include major types such as Alzheimer's disease (AD), vascular dementia, Lewy body dementia, and frontotemporal dementia. In the GBD 2021 study, all dementia types are categorized under \"Alzheimer's disease and other dementias,\" corresponding to the following ICD-10 codes: F00 (Alzheimer's disease dementia), F01 (vascular dementia), F02 (dementia due to other diseases), F03 (unspecified dementia), G30 (Alzheimer's disease), G31 (other neurodegenerative dementias) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, the disease burden addressed in this study encompasses all health losses attributed to various types of dementia. Although the GBD study does not categorize early-onset dementia as a separate disease, it is typically distinguished by age of onset: cases with onset before age 65 are generally defined as EOAD [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Study Population, Age Groups, and Regions\u003c/h2\u003e\u003cp\u003eThis study focuses on middle-aged adults aged 40 to 64 years, divided into five age groups: 40\u0026ndash;44 years, 45\u0026ndash;49 years, 50\u0026ndash;54 years, 55\u0026ndash;59 years, and 60\u0026ndash;64 years. All indicators were analyzed by sex, with separate reporting for male and female data. The study primarily compares the disease burden of EOAD from 1990 to 2021 in China, globally, and across the G20 countries (an international economic forum consisting of 20 major economies, with the European Union excluded from the analysis, thus including only 19 countries). The Socio-Demographic Index (SDI) is a composite indicator of social and economic development, ranging from 0 to 1, considering factors such as education, economy, and fertility rate [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A higher SDI value indicates a higher level of social development in a country or region. Based on SDI values, countries and regions are classified into five levels: low, low-middle, middle, upper-middle, and high.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Measurement of Disease Burden\u003c/h2\u003e\u003cp\u003eWe compared the prevalence, incidence, mortality, and DALYs of EOAD in different populations stratified by age and sex. The age-standardized incidence rate (ASIR) and prevalence rate (ASPR) per 100,000 people reflect the incidence of new cases and the prevalence of existing cases in the 40\u0026ndash;64 age group. The age-standardized mortality rate (ASMR) per 100,000 people reflects the risk of death due to EOAD. DALY is used to measure the health loss caused by the disease, including the years of life lost due to premature death (YLL) and the years of healthy life lost due to disability (YLD), with one year of lost healthy life counting as one DALY. We used percentage change (PC) and average annual percentage change (AAPC) to measure the annual change rates of prevalence, incidence, and other indicators. The calculation of AAPC is derived through regression analysis and applied using the formula AAPC = (exp(β1)\u0026thinsp;\u0026minus;\u0026thinsp;1) \u0026times; 100, where β1 is the regression slope that transforms logarithmic values into original scale [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. All rate indicators are age-adjusted using the GBD standard population, with units per 100,000 population.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Risk Factors\u003c/h2\u003e\u003cp\u003eThe selection of risk factors is based on those identified in GBD 2021 as attributable to dementia. This study includes \"all risk factors\" and several classified risk factors, including behavioral risks (such as smoking and tobacco) and metabolic risks (such as high body-mass index and high fasting plasma glucose). In GBD, high body-mass index (BMI) in adults is defined as individuals with a BMI\u0026thinsp;\u0026gt;\u0026thinsp;25 kg/m\u0026sup2;; high fasting plasma glucose (FPG) is defined as fasting blood glucose levels above the theoretical minimum risk level (4.8\u0026ndash;5.4 mmol/L) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Smoking in GBD is defined as individuals who currently use any tobacco products or have quit smoking within the past six months, while the \"tobacco\" risk factor includes both active and passive smoking exposure [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. For each risk factor, we extracted the attributable DALY counts and their proportions of the total dementia DALY burden, and performed sex-stratified comparisons.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Statistical Analysis\u003c/h2\u003e\u003cp\u003eWe described the incidence, prevalence, mortality, and DALY counts and trends of EOAD from 1990 to 2021, along with the corresponding ASR. Additionally, we evaluated differences in China across different age groups, sexes, and risk factors. We assessed temporal trends by calculating PC and AAPC, along with their corresponding 95% UI. AAPC and its 95% UI were used to determine whether the indicators were increasing (AAPC\u0026thinsp;\u0026gt;\u0026thinsp;0), decreasing (AAPC\u0026thinsp;\u0026lt;\u0026thinsp;0), or stable (when the uncertainty interval includes 0). We also applied the ARIMA model to predict future trends in disease burden over the next 20 years, using data from 1990 to 2021. Furthermore, we used Pearson's correlation coefficient to analyze the relationship between SDI and EOAD disease burden indicators (ASPR, ASIR, ASMR, and ASDAR), with statistical significance set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Finally, we conducted Frontier analysis to assess the minimum disease burden achievable at different SDI levels. All analyses were performed using R software, with relevant R packages including tidyr, scales, dplyr, broom, ComplexHeatmap, ggplot2, and reshape2.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Disease Burden of EOAD in China\u003c/h2\u003e\u003cp\u003eFrom 1990 to 2021, ASPR of EOAD in China increased significantly, especially in 2021, reaching 900.8 per 100,000, ranking first in G20 countries \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/b\u003e. In contrast, developed countries such as France (525.2 per 100,000) and Australia (589.9 per 100,000) have lower prevalence rates and have shown a downward trend since 1990 (5.10% and 16.10%, respectively). The prevalence rate in China increased by 28.10% (AAPC\u0026thinsp;=\u0026thinsp;0.44%, 95% UI: 0.35%, 0.53%) from 703.1 per 100,000 in 1990, becoming the largest increase among G20 countries, and this increase was significantly higher than the global average of 3.20%. In addition, the number of patients increased more than fourfold from 4.025\u0026nbsp;million in 1990 to 16.991\u0026nbsp;million in 2021, further reflecting the severity of the disease burden \u003cb\u003e(Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/b\u003e. ASIR of EOAD in China also showed rapid growth and ranked first among G20 countries, with 151.5 per 100,000 in 2021, followed by Germany (142.1 per 100,000). Since 1990, the incidence rate in China has increased by 25.10% (AAPC\u0026thinsp;=\u0026thinsp;0.41%, 95% UI: 0.33%, 0.49%). In contrast, the incidence of many G20 countries has not increased since 1990, but has declined, such as the United Kingdom fell by about 5.80%, Canada fell by 11.50% and so on. In 1990, China 's incidence rate (121.1 per 100,000) was close to the global average, and by 2021, China 's incidence rate was about 26.5% higher than the global average (119.8 per 100,000) \u003cb\u003e(Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/b\u003e. In terms of mortality, China 's ASMR in 2021 is 30.8 per 100,000, ranking first in G20 countries. Nevertheless, the mortality rate was slightly lower than that in 1990 ( 31.4 per 100,000), with a change of only-1.80% (AAPC= -0.19%, 95% UI : -0.23%, -0.15%). This trend is lagging behind that of most high-income countries ( such as France, Australia, and South Korea, which fell by about 5.60%, 5.40%, and 18.70%, respectively ). In addition, the mortality rates of some middle-income countries such as India and Indonesia increased significantly by 27.20% and 30.90%, respectively. Finally, in terms of DALYs, China ranks first among G20 countries. In 2021, ASDAR of dementia in China was 562.4 per 100,000, higher than that in Germany (508.6 per 100,000) and the United States (509.7 per 100,000). Since 1990, China 's ASDAR has increased by 5.20% (AAPC= -0.02%, 95% UI: -0.07%, 0.02%). Compared with most high-income G20 countries (such as South Korea fell by 13.90%, Australia fell by 9.20%, etc.), China 's growth trend is obvious. In 2021, China 's ASDAR was about 24.7% higher than the global average (451.0 / 100,000), and the gap was wider than in 1990 \u003cb\u003e(Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/b\u003e. These results suggest that the burden of EOAD in China has continued to increase over the past few decades, especially in terms of prevalence, morbidity and DALYs, indicating a further increase in the burden of disease in the future. This also highlights the urgency of public health policies and disease prevention and control measures.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Age and Sex Differences in EOAD Burden in China\u003c/h2\u003e\u003cp\u003eThe disease burden of EOAD in China significantly increases with age, and is particularly pronounced in women. In the 40\u0026ndash;44 age group, all indicators were relatively low, and no significant gender differences were observed. However, with increasing age, especially after 50, ASPR and ASIR begin to rise significantly, and both ASMR and ASDAR also increase. Despite these increases being lower than incidence and prevalence, they peak in the 60\u0026ndash;64 age group \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. In the 60\u0026ndash;64 age group, the prevalence and DALYs burden of dementia in women were significantly higher than in men: the number of affected women was approximately 558,000, 1.2 times that of men (479,000); women in this age group had 288,000 DALYs, significantly higher than men \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, D\u003cb\u003e)\u003c/b\u003e. The number of female patients and health losses in this age group accounted for the largest share of the total EOAD burden in China. In comparison, although the incidence and DALYs in men in the 60\u0026ndash;64 age group were also at high levels, they were lower than in women \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, D\u003cb\u003e)\u003c/b\u003e. Additionally, the annual new cases and mortality cases in the 60\u0026ndash;64 age group were the highest among all age groups, with women higher than men \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, C\u003cb\u003e)\u003c/b\u003e. Overall, the 60\u0026ndash;64 age group, especially women, bears the heaviest disease burden from EOAD in China. Over the past 30 years, the dementia burden in China's middle-aged and elderly population has shown a significant upward trend \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. From 1990 to 2021, the number of cases continued to increase, and ASPR steadily rose \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003eA\u003cb\u003e)\u003c/b\u003e. The number of affected women increased from 2.513\u0026nbsp;million in 1990 to 10.829\u0026nbsp;million in 2021, with ASPR rising from approximately 785.2 per 100,000 to nearly 1025.1 per 100,000; for men, ASPR increased from 574.6 per 100,000 to 731.2 per 100,000 during the same period \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. ASIR and ASDAR also showed an upward trend \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003eB, D\u003cb\u003e)\u003c/b\u003e, with the number of new cases reaching about 2.914\u0026nbsp;million in 2021. The female incidence rate rose to 171.8 per 100,000, higher than the male rate of 126.5 per 100,000. The female ASDAR were 631.4 per 100,000, while the male rate was 463.7 per 100,000. Regarding ASMR, women reached a peak in the 1990s, then declined, but in 2021, ASMR for women (33.8 per 100,000) remained higher than for men (25.9 per 100,000) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003eC, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. These results indicate that China, especially in the 60\u0026ndash;64 age group and particularly among women, faces a severe EOAD disease burden. Although the national disease burden increases year by year, significant gender differences remain, which should be specifically addressed in public health policies and interventions.\u003c/p\u003e\u003cp\u003eInternational comparisons show that in 2021, China had a relatively high level of ASPR, ASIR, ASMR, and ASDAR for EOAD across all age groups among G20 countries \u003cb\u003e(Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/b\u003e. For the 60\u0026ndash;64 age group, China\u0026rsquo;s ASPR (1421.0 per 100,000) was significantly higher than the global average (1081.5 per 100,000), ranking second in the G20, only behind Canada (1444.1 per 100,000) \u003cb\u003e(Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eA)\u003c/b\u003e; ASIR was 239.7 per 100,000, ranking first in the G20 \u003cb\u003e(Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eB)\u003c/b\u003e; ASMR reached 15.8 per 100,000, second only to Brazil (19.7 per 100,000) \u003cb\u003e(Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eC)\u003c/b\u003e; ASDAR were 732.2 per 100,000, second only to Brazil (833.2 per 100,000) \u003cb\u003e(Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eD)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTrends in key epidemiological indicators of Early-Onset Alzheimer\u0026rsquo; s Disease and other Dementias (EOAD) burden in China from 1990 to 2021 by sex.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMeasure\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNumber_1990\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRate_\u003c/p\u003e\u003cp\u003e1990\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNumber_\u003c/p\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eRate_\u003c/p\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePC\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAAPC_\u003c/p\u003e\u003cp\u003eUI (95%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevalence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBoth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4024536 (3446398, 4623086)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e703.14 (608.36, 809.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16990827 (14488494, 19672741)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e900.82 (770.92, 1043.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e28.10%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.44% (0.35%, 0.53%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevalence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2512934 (2165052, 2892724)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e785.19 (681.22, 900.41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10828630 (9315735, 12515957)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1025.11 (879.04, 1186.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e30.60%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.46% (0.36%, 0.55%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevalence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1511602 (1280688, 1737520)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e574.55 (493.64, 666.55)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6162198 (5142286, 7141800)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e731.21 (618.54, 851.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e27.30%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.51% (0.44%, 0.58%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIncidence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBoth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e703178 (601506, 808633)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e121.11 (105.5, 137.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2914112 (2504728, 3350743)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e151.47 (131.22, 173.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e25.10%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.41% (0.33%, 0.49%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIncidence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e442528 (381567, 507194)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e135.42 (118.39, 154.07)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1836815 (1593651, 2101343)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e171.81 (150.12, 195.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e26.90%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.42% (0.33%, 0.5%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIncidence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e260650 (222339, 301788)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e100.25 (86.5, 115.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1077297 (908448, 1248194)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e126.48 (107.78, 145.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e26.20%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.5% (0.43%, 0.57%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMortality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBoth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e119809 (28349, 322103)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e31.39 (7.6, 83.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e491774 (124968, 1330182)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e30.82 (7.88, 82.43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e-1.80%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e-0.19% (-0.23%, -0.15%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMortality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e80212 (19176, 212442)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e34.61 (8.32, 90.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e328431 (83715, 862460)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e33.8 (8.6, 87.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e-2.30%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e-0.2% (-0.24%, -0.17%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMortality\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39597 (9247, 113675)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e25.12 (6, 70.58)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e163343 (40664, 466660)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e25.9 (6.51, 73.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3.10%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e-0.03% (-0.07%, 0.01%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDALYs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBoth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2702484 (1239177, 6085395)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e534.47 (236.2, 1190.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10072478 (4947154, 22219154)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e562.39 (271.16, 1238.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e5.20%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e-0.02% (-0.07%, 0.02%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDALYs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1729685 (790232, 3750294)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e596.71 (265.21, 1288.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6500199 (3171765, 13681029)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e631.38 (305.95, 1318.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e5.80%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e-0.02% (-0.06%, 0.03%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDALYs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e972799 (434085, 2307848)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e429.85 (186.23, 998.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3572279 (1694716, 8148478)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e463.67 (214.26, 1055.84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e7.90%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.09% (0.05%, 0.13%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Comparison of EOAD Burden Between China and Other Countries\u003c/h2\u003e\u003cp\u003eWorldwide According to the global disease burden map for the 40\u0026ndash;64 age group, China\u0026rsquo; s crude prevalence rate (CPR) falls in the second-highest range of 1123.31-1534.35/100,000, the crude incidence rate (CIR) falls in the mid-high range of 196.09-266.37/100,000, only below the highest category; crude mortality rate (CMR) is in the moderate range of 17.5-35.16/100,000, and crude DALY rate (CDR) is between 386.34-707.96/100,000, indicating that the disease burden is at a moderate to high level \u003cb\u003e(Fig. S2)\u003c/b\u003e. In global comparison, China\u0026rsquo; s ASPR is significantly higher, with the global ASPR for EOAD in the 40\u0026ndash;64 age group in 2021 being 589.5/100,000, while China\u0026rsquo; s rate reached 731.2/100,000, 1.2 times the global average. Additionally, China\u0026rsquo; s ASIR is also higher than the global average \u003cb\u003e(Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e). In regional comparisons, China has a higher CPR, CIR, CMR, and CDR than South Asian countries but lower than developed countries in Europe and North America. For example, South Asian countries like India have much lower CPR and CIR compared to China, whereas high-income Asian countries such as Japan and Korea, as well as the United States, Canada, and most European countries, have a higher EOAD burden \u003cb\u003e(Fig. S2)\u003c/b\u003e. Overall, China is considered a high-burden country for EOAD globally, with its prevalence rate exceeding the Asian average but still lower than that of high-SDI European and American countries. Therefore, to address the growing EOAD burden, China needs to enhance public health interventions, improve early diagnosis and treatment levels, and reduce the disease burden, particularly in the middle-aged and elderly population.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.4 The Relationship Between EOAD Burden and SDI\u003c/h2\u003e\u003cp\u003eIn this study, a scatter plot was used to analyze the correlation between ASPR, ASIR, ASMR, and ASDAR with SDI. Pearson correlation analysis revealed a significant positive correlation between EOAD ASPR and SDI (r\u0026thinsp;=\u0026thinsp;0.309, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e5\u003c/span\u003eA\u003cb\u003e)\u003c/b\u003e, and a similarly significant correlation between ASIR and SDI (r\u0026thinsp;=\u0026thinsp;0.357, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e5\u003c/span\u003eB\u003cb\u003e)\u003c/b\u003e, indicating that countries with higher SDI typically have higher ASIR and ASPR. However, no significant correlation was found between ASMR and ASDAR with SDI (ASMR: p\u0026thinsp;=\u0026thinsp;0.63, ASDAR: p\u0026thinsp;=\u0026thinsp;0.503) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e5\u003c/span\u003eC, D\u003cb\u003e)\u003c/b\u003e, suggesting that the relationship between mortality and DALYs loss with socio-economic development level is weak. From 1990 to 2021, China\u0026rsquo; s SDI significantly improved, and ASDAR showed an increasing trend. This trend suggests that as China\u0026rsquo; s SDI increases, it faces an increasing burden of dementia cases. In 2021, China\u0026rsquo; s DALYs value was higher than the global expected value for its corresponding SDI level, and compared to other high-SDI countries (e.g., the United States and Germany), China\u0026rsquo; s overall DALYs level is relatively higher \u003cb\u003e(Fig. S3)\u003c/b\u003e. This difference may reflect China\u0026rsquo;s potential for improvement and capacity in EOAD prevention, early diagnosis, and management, although its socio-economic level is increasing, the investment in healthcare resources and disease prevention still needs strengthening.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Risk Factors for EOAD Burden in China\u003c/h2\u003e\u003cp\u003eIn 2021, the DALYs associated with EOAD in the Chinese population aged 40\u0026ndash;64 were mainly attributed to modifiable risk factors. Overall, metabolic risk factors (such as high FPG and high BMI) and behavioral risk factors (especially smoking) contributed the most. High FPG is considered the primary risk factor for EOAD in China and globally; smoking in males, as a behavioral risk factor, significantly contributes to the disease burden. In the male population, the main risk factors, in order, are metabolic factors and behavioral factors such as smoking: metabolic risk accounts for 14.8%, with high FPG contributing 12.1% and high BMI contributing 3.3%; smoking contributes 14%. High FPG and smoking are the primary driving factors of EOAD burden in males \u003cb\u003e(Fig. S4A)\u003c/b\u003e. In the female population, the main risk factors are still metabolic: metabolic risk accounts for 16%, with high FPG contributing 11.8% and high BMI contributing 5.0%; smoking\u0026rsquo; s contribution is relatively low, at only 1.6%. This indicates that the EOAD burden in females is mainly driven by metabolic risks, with high FPG being the most significant factor, while behavioral risks such as smoking hardly contribute \u003cb\u003e(Fig. S4B)\u003c/b\u003e. A comparison between sexes shows that the proportion of metabolic risks (mainly high FPG and high BMI) is similar in both sexes (14.8% for males vs. 16% for females), while the difference in behavioral risks is very evident: the smoking rate in males is much higher than in females, leading to a 14% contribution to DALYs related to smoking in males, whereas it is only 1.6% in females. In males, the contribution of behavioral factors such as smoking to the EOAD burden is significantly higher than in females, whereas metabolic abnormalities are a major issue faced by both sexes.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.6 Future Projections of EOAD Burden in China Over the Next 20 Years\u003c/h2\u003e\u003cp\u003eA quantitative analysis of the trends in ASPR, ASIR, and ASMR of EOAD over the next 20 years was conducted using the ARIMA model. The projection shows that ASPR of EOAD will continue to rise. The male ASPR is expected to rise from 731.2 per 100,000 in 2021 to 876.7 per 100,000 by 2041; the female ASPR is expected to increase from 1025.1 per 100,000 to 1345.7 per 100,000, with the female prevalence rate consistently higher than that of males \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e6\u003c/span\u003eA, B, \u003cb\u003eTable S2)\u003c/b\u003e. Similarly, ASIR is also projected to rise, with the male ASIR increasing from 126.5 per 100,000 to 150.7 per 100,000, and the female ASIR rising from 171.8 per 100,000 to 219.3 per 100,000 \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e6\u003c/span\u003eC, D, \u003cb\u003eTable S2)\u003c/b\u003e. In comparison, ASMR for EOAD shows a significant gender difference: although the male ASMR is projected to slowly decrease from 25.9 per 100,000 in 2021 to 24.8 per 100,000 by 2041, the female ASMR is expected to remain relatively stable, with only a slight decrease to 33.7 per 100,000 \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e6\u003c/span\u003eE, F, \u003cb\u003eTable S2)\u003c/b\u003e. This trend suggests that the male EOAD mortality rate may improve, while the female mortality rate will change little, indicating that further attention is needed in managing clinical outcomes in the female population.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eOverall, ASPR and ASIR of EOAD in Chinese population aged 40\u0026ndash;64 years have increased significantly over the past three decades, with an increase significantly higher than that of the global and most G20 countries (except the European Union), while ASMR has remained stable. Compared with 1990, China 's EOAD ASDAR showed a slight upward trend, and ranked top among G20 countries (except the European Union), and this gap has widened. The burden of disease increases sharply with age, especially in the 60\u0026ndash;64 age group (especially women), which contributes the most; women continued to have higher ASPR, ASIR, ASMR, and ASDAR than men. Metabolic risk factors (such as high FPG, high BMI) have replaced smoking as the main driving factor, and men are still more affected by smoking. ARIMA prediction shows that ASPR and ASIR will continue to rise in the next 20 years, and ASMR of men will decrease slightly, while that of women will remain almost unchanged, indicating that there is an imbalance in the improvement of clinical outcomes between genders. Taken together, these findings highlight the increasing burden of EOAD in China and call for more robust public health interventions and policy responses.\u003c/p\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e4.1 The age group difference of EOAD burden in China\u003c/h2\u003e\u003cp\u003eOur study found that the EOAD burden of Chinese adults aged 40\u0026ndash;64 increased significantly with age, especially in the 60\u0026ndash;64 age group, which was consistent with the natural progression of neurodegenerative diseases. Aging is the most important demographic risk factor for ADOD. Since the late 1970s, China\u0026rsquo; s population aging process has accelerated and continued to grow at an annual rate of about 3.2%. By the end of 2023, the elderly population aged 60 years and over has reached 297\u0026nbsp;million, accounting for 21.1% of the total population of the country [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. This trend is expected to continue for a long time and further promote the increase of the disease burden of EOAD. In addition, multiple factors such as diabetes, hypertension, smoking and obesity have been shown to be associated with the risk of AD, and these factors are particularly common in the middle-aged and elderly population [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Rapid urbanization and lifestyle changes in China have led to a continuous increase in the proportion of middle-aged people exposed to risk factors such as metabolic syndrome, smoking and diabetes. Especially in 2021, the prevalence of obesity among people over 60 years of age has reached 18% [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. These changes may accelerate the clinical manifestations of EOAD in late middle age. In addition, the prevalence of sleep deprivation and mental health problems in middle age has been shown to be associated with cognitive decline [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. With the acceleration of social modernization, the incidence of sleep disorders has increased significantly, and the global prevalence rate has reached 27%. About 300\u0026nbsp;million people in China face sleep disorders, of which the incidence of insomnia in adults is as high as 38.2% [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. This problem may be another reason for the significant increase in the prevalence of EOAD in China.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Gender-related differences in EOAD burden in China\u003c/h2\u003e\u003cp\u003eIn this study, we observed significant differences in EOAD burden between Chinese men and women. From 1990 to 2021, women were significantly higher than men in ASPR, ASIR, ASMR, and ASDAR, a trend consistent with related studies worldwide [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This gender difference may be caused by a variety of biological and social factors. Studies have shown that women are more susceptible to ADOD in old age. When women suffer from neurodegenerative diseases, they usually show faster hippocampal atrophy and more severe behavioral disorders [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In addition, women are more likely than men to carry AD-related genes, such as APOE ε4, and when they carry these genes, women are more likely to develop dementia [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. It is worth noting that the Met66 allele of the BDNF gene only increases the risk of AD in women, while the 219K allele of the ABCA1 gene increases the risk in women but has a protective effect in men [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Estrogen has a significant protective effect on hippocampal synapse formation, brain glucose metabolism and β-amyloid clearance [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. However, women experience a dramatic loss of estrogen after menopause, a physiological change that significantly increases the risk of AD ; in contrast, men 's testosterone levels can be converted into estrogen, and its decline is slower, so men in their later years did not experience the sharp estrogen loss faced by women after menopause [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In addition, low education level and poor career history are also associated with higher prevalence and incidence of AD [\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. According to the 2004 data of China Education Statistics Yearbook, the enrollment rate of rural women in higher education is only 0.64%, which is much lower than that of rural men (1.34%) and urban women (0.85%) [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. This educational gap has caused the cognitive reserve level of elderly women to be generally lower than that of men of the same age, making them more likely to show clinical symptoms under the same pathological load. In addition, women face a higher risk of metabolic diseases in middle age, including high BMI, high FPG, and high blood pressure, which may accelerate their cognitive decline [\u003cspan additionalcitationids=\"CR44 CR45 CR46\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. In China, the risk of AD in women with FPG levels\u0026thinsp;\u0026ge;\u0026thinsp;7.0 mmol/L is 41% higher than that in men, which may be related to the increased sensitivity of women to insulin resistance in the absence of estrogen [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. In addition, women generally live longer, which means that they are exposed to the risk of cognitive decline for a long time, which further aggravates the disease burden of EOAD [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Therefore, improving the metabolic health management of the female population and providing targeted cognitive function interventions may help reduce the EOAD burden of Chinese women.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e4.3 Analysis of the main risk factors of EOAD burden in China\u003c/h2\u003e\u003cp\u003eThis study shows that metabolic risk factors (such as high BMI, high FPG) and behavioral risk factors (mainly smoking) are the main risk factors for EOAD burden in China. With the improvement of material living standards and quality of life, metabolic diseases such as metabolic syndrome, hypertension, diabetes and obesity are gradually increasing in China [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. These factors are closely related to the occurrence of EOAD. In particular, high FPG, high blood pressure and high BMI have been confirmed as independent risk factors for ADOD by multiple studies [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. In 2021, 45.1% of the world\u0026rsquo; s adults are overweight and obese, and more than half of them live in countries such as China, India, and the United States. China has the largest number of overweight and obese adults, reaching 402\u0026nbsp;million [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Studies have shown that the number of adults aged 18\u0026ndash;69 with hypertension in China was 274\u0026nbsp;million in 2018.Although the prevalence of hypertension has decreased since 2010, the treatment and control rates are still low [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. In addition, the average annual concentration of PM2.5 in some areas of China has reached 50 \u0026micro;g/m\u0026sup3;, which is several times the standard of the World Health Organization [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].Long-term exposure to such pollution may induce neuroinflammation and oxidative stress, and increase the risk of EOAD.\u003c/p\u003e\u003cp\u003eSmoking is one of the major risk factors for many chronic diseases known worldwide. Studies have shown that smoking is closely related to cognitive decline and the occurrence of dementia [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. China has the largest smoking population in the world. More than 300\u0026nbsp;million smokers and 740\u0026nbsp;million non-smokers are exposed to second-hand smoke, which not only leads to cognitive impairment, but also brings huge economic pressure to families and society [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. In addition, lifestyle factors, such as lack of exercise, are significantly associated with the incidence of cognitive impairment and AD [\u003cspan additionalcitationids=\"CR60 CR61\" citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. However, in the past 30 years, the proportion of Chinese adults who regularly exercise has decreased from 60% in 1990 to 35% in 2021, which may increase the risk of illness in the Chinese population [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Studies have shown that the Chinese Healthy Diet Index can not only directly affect the cognitive health of rural elderly people, but also improve cognitive function by improving mental health and reducing depressive symptoms [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. However, with the acceleration of urbanization in China, lifestyle changes, especially the popularity of sedentary and high-calorie diets, may promote the prevalence of EOAD to some extent.\u003c/p\u003e\u003cp\u003eMental health problems such as sleep disorders and depression are also considered to be important risk factors for EOAD [\u003cspan additionalcitationids=\"CR65\" citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. China\u0026rsquo; s middle-aged and elderly people, especially urban residents, generally face higher work pressure and poor sleep quality, which to some extent aggravate the burden of EOAD [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn addition, the level of socio-economic development in some parts of China is low, especially in rural areas. Insufficient medical resources and inadequate early screening may lead to delays in the early diagnosis and treatment of dementia, which in turn increases the burden of disease. Therefore, the analysis of the risk factors of EOAD burden in China reveals the potential of public health policies, lifestyle interventions and socio-economic factors in the prevention of EOAD. Strengthening early intervention of metabolic diseases, improving the lifestyle of middle-aged and elderly people, and promoting health education and public health measures in the whole society will be the key steps to reduce the burden of EOAD in the future.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e4.4 Future trends of China\u0026rsquo; s EOAD burden\u003c/h2\u003e\u003cp\u003eThe burden of EOAD in China will continue to rise in the next 20 years: ASPR and ASIR will increase significantly, and the burden of women will be higher than that of men. It is predicted that ASMR of men will decrease slowly, while the ASMR of women will be basically stable.In order to cope with the increasingly severe burden of EOAD, the Chinese government has taken a number of positive measures. According to the \"Work Program on Exploring Special Services for the Prevention and Treatment of Alzheimer' s Disease\", China plans to implement a national prevention and treatment promotion between 2023 and 2025, aiming to increase public awareness of dementia and community screening rates to 80%. In addition, the \"Guiding Opinions on Promoting the Development of Aging during the 14th Five-Year Plan\" issued by the State Council further strengthened early diagnosis and screening, and established the National Center for Geriatric Disease Research [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. On the other hand, the \"Healthy China 2030 Action Plan\" tobacco control initiative proposes the creation of smoke-free families, advocates that family members do not smoke or actively quit smoking, and educates minors to avoid smoking, so as to reduce the risk of second-hand smoke harm to family members [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e]. Since the implementation of the National Fitness Program (2021\u0026ndash;2025) in China, the level of public services for national fitness has been significantly improved, fitness venues and facilities have been increasing, and the proportion of people regularly participating in physical exercise has reached 37.2% [\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]. These policies may reduce the EOAD burden in China in the future. In recent years, with the development of diagnostic tools such as biomarkers and imaging techniques, the early diagnosis rate has gradually increased, especially in young and middle-aged people. These advances not only enable more cases to be detected in time, but also may affect the rising trend of prevalence in the next few years.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003e4.5 Advantages and limitations\u003c/h2\u003e\u003cp\u003eBased on GBD 2021 data, this study systematically assessed the burden of EOAD in Chinese population aged 40\u0026ndash;64 years, focused on the analysis of metabolic and behavioral risk factors, and conducted age and gender differences. Analysis and future trend prediction provide valuable data support for public health interventions. However, this study also has some limitations. First, the data relies on existing public health records and death registrations, which may lead to deficiencies in disease diagnosis and screening in some areas. Secondly, although 12 dementia-related risk factors have been reported, only the metabolic and behavioral risk factors covered in GBD 2021 were used in this study [\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. Although other risk factors were mentioned in the discussion, all potential risk factors were not fully considered. In addition, the lack of a unified dementia registration system has led to heterogeneity in the definition and case identification of EOAD, and diagnostic criteria, biomarkers and ICD codes have changed over the past three decades, further exacerbating the heterogeneity of the data. Finally, although the ARIMA model provides useful predictive information, its prediction is essentially an extension of historical trends and may fail to capture future inflection points due to factors such as breakthroughs in diagnostic technologies, the launch of new therapeutic drugs, or major public health policy interventions. Therefore, the prediction results should be considered as the baseline scenario under the existing trend.\u003c/p\u003e\u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eFrom 1990 to 2021, the burden of EOAD in China increased significantly, especially among women. Metabolic risk factors, such as high FPG and high BMI, play a key role in increasing the burden of EOAD, and behavioral risk factors such as smoking can not be ignored. In the next 20 years, the prevalence and incidence of EOAD in China are expected to continue to rise, especially among women. The study emphasizes the urgency of strengthening public health interventions and improving early screening and treatment to cope with the increasingly severe disease burden.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003e\u003cb\u003eConsent\u003c/b\u003e\u003c/h2\u003e\u003cp\u003eThe authors have nothing to report.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cb\u003eClinical trial number\u003c/b\u003e\u003c/strong\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cb\u003eEthics Statement\u003c/b\u003e\u003c/strong\u003e\u003cp\u003eThe authors have nothing to report.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003e\u003cb\u003eConflicts of Interest\u003c/b\u003e:\u003c/h2\u003e\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eData curation, Shuai Zhu, Zheng Duan, Ou Yang and Qi Li; Supervision, Liu Xiong; Visualization, Shuai Zhu; Writing \u0026ndash; original draft, Shuai Zhu; Writing \u0026ndash; review \u0026amp; editing, Qiu Xiao; All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e\u003cp\u003eThe authors sincerely express their gratitude for the GBD data provided by the team members of the Global Burden of Diseases, Injuries, and Risk Factors (GBD) study.\u003c/p\u003e\u003ch2\u003eData Availability Statement:\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the website \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://vizhub.healthdata.org/gbd-results/\u003c/span\u003e\u003cspan address=\"https://vizhub.healthdata.org/gbd-results/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 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Website: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.gov.cn/zhengce/zhengceku/2020-11/27/content_5565378.htm\u003c/span\u003e\u003cspan address=\"https://www.gov.cn/zhengce/zhengceku/2020-11/27/content_5565378.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eThe State Council. 'Notice of the State Council on the issuance of the National Fitness Program (2021\u0026ndash;2025) '. Website: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.gov.cn/zhengce/content/2021-08/03/content_5629218.htm\u003c/span\u003e\u003cspan address=\"https://www.gov.cn/zhengce/content/2021-08/03/content_5629218.htm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Early-onset Alzheimer's disease and other dementias, Global Burden of Disease, gender differences, metabolic risk factors","lastPublishedDoi":"10.21203/rs.3.rs-7495038/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7495038/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eEarly-onset Alzheimer\u0026rsquo;s disease and other Dementias (EOAD) have emerged as a major public-health challenge worldwide and in China. With the rapidly ageing population, especially in China, the burden of EOAD continues to rise. Using 2021 Global Burden of Disease (GBD) data, we analysed the EOAD burden and its principal risk factors among Chinese adults aged 40\u0026ndash;64 years from 1990 to 2021, and projected trends for the ensuing 20 years.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eData from GBD 2021 were extracted to quantify the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) of EOAD in China from 1990 to 2021, along with corresponding age-standardised rates (ASRs). Temporal trends were evaluated using the annual average percentage change (AAPC), and an autoregressive integrated moving average (ARIMA) model was applied to forecast the EOAD burden over the next 20 years. We also assessed the association between EOAD burden and the Socio-Demographic Index (SDI).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eFrom 1990 to 2021, the age-standardized prevalence rate (ASPR) of EOAD in China for the 40\u0026ndash;64 age group increased from 703.1 to 900.8 per 100,000, with a percentage change (PC) of 28.1% (AAPC\u0026thinsp;=\u0026thinsp;0.44%, 95% UI: 0.35%, 0.53%), significantly higher than the global increase of 3.2%. The age-standardised incidence rate (ASIR) increased from 100.3 to 126.5 per 100,000 in males and from 135.4 to 171.8 per 100,000 in females, representing rises of 26.2% (AAPC\u0026thinsp;=\u0026thinsp;0.50%, 95% UI: 0.43%, 0.57%) and 26.9% (AAPC\u0026thinsp;=\u0026thinsp;0.42%, 95% UI: 0.33%, 0.50%), respectively. The age-standardised mortality rate (ASMR) in males rose modestly from 25.1 to 25.9 per 100,000 (3.1% increase; AAPC\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.03%, 95% UI: \u0026minus;0.07%, 0.01%), whereas the female rate remained largely unchanged at 33.8 per 100,000 (AAPC\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.20%, 95% UI: \u0026minus;0.24%, \u0026minus;\u0026thinsp;0.17%). For age-standardized DALYs rate (ASDAR), males increased from 429.9 to 463.7 per 100,000, while females increased from 596.7 to 631.4 per 100,000, with increases of 7.9% (AAPC\u0026thinsp;=\u0026thinsp;0.09%, 95% UI: 0.05%, 0.13%) and 5.8% (AAPC = -0.02%, 95% UI: -0.06%, 0.03%), respectively. ASRs for incidence and prevalence were positively correlated with SDI. Metabolic risk factors now constitute the principal drivers of EOAD burden, whereas smoking and other behavioural risks continue to exert a pronounced effect among men. Prevalence and incidence are projected to rise further over the next two decades, with the steepest increases anticipated in women. Although male mortality shows a slight decline, female mortality remains stable.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eChina\u0026rsquo; s EOAD burden has risen markedly over the past three decades, with women disproportionately affected. In the future, public health interventions, early screening and clinical management measures for gender differences and metabolic health will be the key to reducing the burden of EOAD in China.\u003c/p\u003e","manuscriptTitle":"Disease Burden and Risk Factors of Early-Onset Alzheimer’s Disease and other Dementias in China (1990–2021) with 20-Year Projections to 2041: A Global Burden of Disease Study Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-30 19:08:25","doi":"10.21203/rs.3.rs-7495038/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3c36794f-d4d4-48cc-81e3-98a744bced61","owner":[],"postedDate":"September 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-29T07:09:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-30 19:08:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7495038","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7495038","identity":"rs-7495038","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}