Global, regional, and national trends in prevalence and disability-adjusted life years (DALYs) for early-onset dementias, 1990-2021: Insights from the Global Burden of Disease Study 2021

doi:10.21203/rs.3.rs-4896125/v1

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Global, regional, and national trends in prevalence and disability-adjusted life years (DALYs) for early-onset dementias, 1990-2021: Insights from the Global Burden of Disease Study 2021

https://doi.org/10.21203/rs.3.rs-4896125/v1

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Background This study aims to analyze temporal trends in the prevalence and disability-adjusted life year (DALY) burden of early-onset dementia (EOD) globally from 1990 to 2021 and assess the attributable burdens of modifiable risk factors.

Methods Data from the Global Burden of Disease Study (GBD) 2021 were used. EOD was defined as dementia in individuals aged 40-64. The analysis included case numbers with 95% uncertainty intervals (UIs), age-standardized prevalence rates (ASPRs), and DALY rates (ASDRs) with 95% confidence intervals (CIs), stratified by global, regional, and national levels, sociodemographic index (SDI), and sex. Joinpoint regression analysis evaluated the average annual percent change (AAPC). Population attributable fractions (PAFs) estimated the proportion of DALYs attributable to risk factors.

Results The global number of EOD cases and DALYs nearly doubled from 1990 to 2021, reaching 7.758 million cases (95% UI 5.827 to 10.081) and 3.774 million DALYs (95% UI 1.696 to 8.881) in 2021. ASPR and ASDR increased slightly to 355.9 (95% CI 267.2 to 462.8) and 173.3 (95% CI 77.9 to 407.7) per 100,000 in 2021. In 2021, the highest ASPR was in high-middle SDI countries at 387.6 per 100,000 (95% CI 291.1 to 506.8), while the highest ASDR was in middle SDI at 182.9 per 100,000 (95% CI 82.2 to 431). The fastest ASDR increase was in low and low-middle SDI countries from 2010 to 2021, with AAPCs of 0.42% (95% CI 0.34 to 0.50) and 0.36% (95% CI 0.33 to 0.39), respectively. A significant negative correlation was found between SDI and ASDR. During the COVID-19 pandemic (2019-2021), ASPR and ASDR in high-SDI countries declined, while other SDI regions saw an accelerated increase. In 2021, high fasting plasma glucose (FPG) was the most significant attributable risk factor for EOD-related DALYs globally, with PAFs for high body mass index and high FPG increasing in nearly all regions since 1990, while the PAF for smoking decreased.

Conclusions In 2021, EOD burden was highest in high-middle and middle SDI countries, particularly rising during the COVID-19 pandemic. The growing influence of metabolic risk factors underscores the need for targeted public health policies and resource allocation to mitigate the EOD burden.

Health sciences/Neurology

Health sciences/Diseases/Neurological disorders

Health sciences/Medical research/Epidemiology

Dementia

Alzheimer’s disease

Early-onset dementia

Global burden

Prevalence

In 2019, there were 57.4 million individuals with dementia globally, with an associated economic burden of $2.8 trillion. By 2050, the number of dementia patients is projected to rise to 152.8 million, with the economic burden escalating to $16.9 trillion^1,2. Dementia has become an increasingly severe public health issue. It is typically regarded as a disease of older adults, while early-onset dementia (EOD), which is diagnosed in individuals under 65 years of age, often goes unnoticed^3–6. EOD presents more diverse symptoms compared to late-onset dementia (LOD), including cognitive dysfunction, psychiatric symptoms, and behavioral changes, leading to diagnostic delays and frequent misdiagnoses as mild cognitive impairment or depression^5–8.

Similar to LOD, the primary cause of EOD is Alzheimer's disease (AD), followed by vascular dementia (VaD) and frontotemporal dementia (FTD)^6,8–10. Research indicates that early-onset AD has a higher genetic predisposition compared to older patients. Moreover, early-onset AD progresses more rapidly, with quicker cognitive decline, broader lesion distribution, and more typical pathological features of AD, along with a heavier burden of key AD biomarkers^3,4,6. EOD has profound impacts on individuals, families, and society. For the patients, the disease progression results in loss of cognitive and functional abilities, severely affecting daily life and independence. Additionally, EOD patients are often at the peak of their careers, and premature loss of labor contributes to significant economic and caregiving burdens on families, adversely affecting the psychological and social development of family caregivers and their children^3,6,8.

Current analyses of the global burden of EOD are limited and often lack population representativeness. Two systematic reviews by Stevie et al. estimated EOD prevalence and incidence, but these studies primarily drew from data in Europe, Asia, North America, and Oceania, resulting in incomplete global coverage. Methodological heterogeneity further impacted the consistency of the results, and the studies focused only on the average burden over the past 30 years without thoroughly examining trends from 1990 to 2021^9,10. Additionally, while EOD significantly affects patients' quality of life, functional abilities, and lifespan, no studies to date have evaluated the disability-adjusted life years (DALYs) or attributable risk factors associated with EOD. Assessing these factors is essential for a comprehensive understanding of the impact of EOD on individuals and society.

This study aims to use the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 database to analyze temporal trends in the prevalence and DALY burden of EOD globally, regionally, and nationally from 1990 to 2021, stratified by sociodemographic index (SDI) and sex. It will also assess the attributable risk factors on EOD-related DALYs. The findings will inform effective public health strategies to reduce the EOD burden worldwide and in specific regions.

Data source

The GBD 2021 study estimated the global burden of 371 diseases and injuries, along with 88 attributable risk factors, from 1990 to 2021. In GBD 2021, dementia was categorized as "Alzheimer's disease and other dementias" without subtype differentiation. The definition of dementia was based on criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD), including DSM-III, DSM-III-R, DSM-IV, DSM-5, and ICD-8, ICD-9, and ICD-10^11–13. EOD was defined as dementia diagnosed in individuals under the age of 65^3–6. Due to the scarcity of epidemiological data for populations under 40 years old, GBD 2021 assessed the burden of dementia only in individuals aged 40 and above¹³. Consequently, in this study, EOD is defined as dementia diagnosed in individuals aged 40–64.

This study aims to assess the temporal trends in prevalence and disability-adjusted life years (DALYs) of EOD from 1990 to 2021. DALYs comprise years of life lost (YLL) due to premature mortality and years lived with disability (YLD). YLD is calculated by multiplying the number of prevalent cases (P) by the corresponding disability weight (DW), using the formula: YLD = P × DW. GBD 2021 defined disability weights for varying severities of dementia. Mild dementia is characterized by occasional memory loss, difficulty concentrating, and making decisions, with a disability weight of 0.069 (95% uncertainty interval [UI]: 0.046–0.099). Moderate dementia involves memory issues, confusion, disorientation, occasional auditory hallucinations, and the need for some assistance with daily activities, with a disability weight of 0.377 (95% UI: 0.252–0.508). Severe dementia entails complete memory loss, inability to recognize close relatives, and the need for assistance with all daily activities, with a disability weight of 0.449 (95% UI: 0.304–0.595)¹³.

Furthermore, we calculated the population attributable fraction (PAF) to estimate the proportion of DALYs related to EOD that could be attributed to three main risk factors—high fasting plasma glucose (FPG), high body mass index (BMI), and smoking—across different regions and genders from 1990 to 2021. PAF estimates the proportion of disease burden that could be reduced if current exposure levels were lowered to the theoretical minimum risk exposure level (TMREL). For adults aged 20 and above, the TMREL for BMI ranges from 20–23 kg/m²; for fasting plasma glucose, the TMREL is 4.9–5.3 mmol/L; and for smoking, the TMREL is complete non-smoking. The detailed PAF calculation process is documented in previous studies¹⁴.

In GBD 2021, the burden of dementia was assessed not only by country, region, gender, and age but also stratified by the sociodemographic index (SDI). The SDI is a composite measure that reflects the development status of a location and is based on per capita income, average educational attainment among those aged 15 and older, and total fertility rate among women under 25. The SDI ranges from 0 to 1, with higher values indicating higher levels of social development. GBD 2021 categorized countries and regions into five SDI quintiles: low SDI (0.00–0.47), low-middle SDI (0.47–0.62), middle SDI (0.62–0.71), high-middle SDI (0.71–0.81), and high SDI (0.81–1.00). In this study, the burden of dementia estimates was based on repeated cross-sectional data from 1990 to 2021, sourced from the Global Health Data Exchange (GHDx)¹⁵. This study adheres to the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER)¹⁶.

Statistical analysis

We calculated the age-standardized prevalence rate (ASPR) and the age-standardized DALY rate (ASDR) for EOD to ensure comparability across regions and account for age structure differences, using the standard world population from the GBD 2021 report¹⁷. This involved multiplying the age-specific rate by the standard population weight for each 5-year age group between 40 and 64 years, summing these weighted rates, and dividing by the total standard population weight to obtain the ASR. The calculation formula is as follows:

$$\:ASR=\left(\frac{{\sum\:}_{i=1}^{A}{a}_{i}{w}_{i}}{{\sum\:}_{i=1}^{A}{w}_{i}}\right)$$

where: 𝑎ᵢ is the age-specific rate for the i-th age group (per 100,000 population), 𝑤ᵢ is the weight proportion of the i-th age group in the world standard population, and A is the total number of age groups.

In this study, we primarily employed Joinpoint regression analysis to compare temporal trends in ASPR and ASDR of EOD from 1990 to 2021 across different regions, countries, SDI, and sexes. Joinpoint regression analysis is a statistical method used to analyze changes in trends within time series data. This method uses segmented linear regression models to identify significant points of inflection over time. It calculates the annual percent change (APC) for each linear segment and derives the average annual percent change (AAPC) by taking a weighted average of the APCs to reflect the overall trend. Positive or negative APC and AAPC values indicate increasing or decreasing trends, respectively, while an AAPC with a 95% confidence interval (CI) that does not include zero signifies statistical significance. Joinpoint locations were determined using maximum likelihood estimation (MLE), and the optimal number of joinpoints was selected by comparing Bayesian Information Criterion (BIC) values for different models. In this study, we dynamically compared trends in ASPR and ASDR across different regions, countries, sexes, and SDI strata by calculating the AAPC for the decades 1990–2000, 2000–2010, and 2010–2021. Detailed Joinpoint regression analysis results for global and various SDI levels are presented in Supplementary file 1.

All statistical analyses were performed using the Joinpoint Regression Program (version 5.0.2) and R software (version 4.3.2). A two-sided P-value of less than 0.05 was considered statistically significant.

Global trends

Over the past 30 years, the global number of EOD cases has nearly doubled, increasing from 3.675 million (95% UI 2.756 million to 4.769 million) in 1990 to 7.758 million (95% UI 5.827 million to 10.081 million) in 2021 (Supplementary file 1: Table S1). However, the ASPR showed only a slight increase from 345.9 per 100,000 (95% CI 259.5 to 448.9) in 1990 to 355.9 per 100,000 (95% CI 267.2 to 462.8) in 2021, an increase of just 10 per 100,000. The annual percentage change in ASPR varied over the decades: from 1990 to 2000, it increased by an AAPC of 0.13% (95% CI 0.1–0.16%, P < 0.001); from 2000 to 2010, there was no significant change (AAPC 0.01% [95% CI -0.01–0.02%], P = 0.369); and from 2010 to 2021, it increased again with an AAPC of 0.12% (95% CI 0.09–0.16%, P < 0.001) (Fig. 1; Supplementary file 1: Table S1). Notably, in the past decade, the ASPR fluctuated significantly, with a temporary decrease from 2015 to 2019 (APC − 0.25%, P < 0.05), followed by a marked increase from 2019 to 2021 (APC 0.66%, P < 0.05) (Fig. 1; Supplementary file 1: Fig. S1).

In 2021, the global number of DALYs due to EOD reached 3.774 million (95% UI 1.696 million to 8.881 million), nearly doubling from 1.796 million (95% UI 0.814 million to 4.150 million) in 1990 (Supplementary file 1: Table S2). The ASDR also increased over this period, from 168.9 per 100,000 (95% CI 76.6 to 390.2) in 1990 to 173.3 per 100,000 (95% CI 77.9 to 407.7) in 2021, with AAPCs between 0.06% and 0.10% (all P < 0.05) (Fig. 2; Supplementary file 1: Table S2). Similar to ASPR, ASDR exhibited fluctuations in the past decade: a temporary decrease from 2016 to 2019 (APC − 0.17%, P < 0.05), followed by a more pronounced increase from 2019 to 2021 (APC 0.30%, P < 0.05) (Supplementary file 1: Fig. S1).

Sex and SDI stratification

From 1990 to 2021, the global ASPR and ASDR for EOD were consistently higher in females than males. In 2021, females had an ASPR of 386.8 (95% CI 292.3 to 502.1) and an ASDR of 191.5 (95% CI 86.0 to 440.0), while males had an ASPR of 323.9 (95% CI 240.6 to 422.0) and an ASDR of 154.4 (95% CI 67.9 to 367.6) (Supplementary file 1: Table S1; Table S2). As the SDI decreased, the proportion of EOD cases and related DALYs in the 40–64 age group increased across the entire population. In low SDI countries, approximately 25% of dementia cases occurred in the 40–64 age group for EOD (Supplementary file 1: Fig. S2).

In 2021, the highest ASPR of EOD was observed in High-middle SDI countries at 387.6 per 100,000 (95% CI 291.1 to 506.8). This was followed by middle and high SDI countries, with ASPRs of 374.5 per 100,000 (95% CI 280.4 to 491.2) and 370.2 per 100,000 (95% CI 278.8 to 479.9), respectively. From 1990 to 2021, EOD ASPR trends varied significantly across SDI quintiles, with notable inflection points between 2018 and 2021. In low and low-middle SDI countries, ASPR declined overall from 1990 to 2019, with APCs of -0.16% and − 0.09% (both P < 0.05). However, ASPR increased significantly from 2019 to 2021, with APCs of 0.48% and 1.14% (both P < 0.05). In middle and high-middle SDI regions, ASPR increased from 1990 to 2021, especially after 2019, with APCs of 0.92% and 1.06% (both P < 0.05). In high SDI regions, the overall ASPR showed an increasing trend from 1990 to 2021, rising to 370.2 per 100,000 (95% CI 278.8 to 479.9) in 2021, up from 356.6 per 100,000 (95% CI 267.6 to 462.1) in 1990. However, after 2018, there was a significant reversal, with ASPR showing a declining trend, with an APC of -0.25% (P < 0.05) (Fig. 1; Supplementary file 1: Fig. S1; Table S1). Correlation analysis showed no significant relationship between SDI and EOD ASPR (R = 0.1, P = 0.14) (Fig. 3).

Regarding the DALYs burden, middle SDI countries had the highest ASDR in both 2021 and 1990. In 2021, the ASDR was 182.9 per 100,000 (95% CI 82.2 to 431), slightly lower than 184.3 per 100,000 (95% CI 82.5 to 426.9) in 1990. In contrast, the ASDR in other SDI countries increased from 1990 to 2021. In the past decade, ASDR in low and low-middle SDI countries rose significantly, with AAPCs of 0.42% (95% CI 0.34 to 0.50) and 0.36% (95% CI 0.33 to 0.39) from 2010 to 2021 (Fig. 2; Supplementary file 1: Table S2). Middle and high-middle SDI countries also saw significant increases in ASDR from 2019 to 2021, with APCs of 0.40% and 0.58% (both P < 0.05). Conversely, high SDI countries experienced a significant decline in ASDR after 2017, with an AAPC of -0.28% (P < 0.05) (Supplementary file 1: Fig. S1). Further correlation analysis revealed a significant negative correlation between SDI and ASDR (R = -0.31, P < 0.001) (Fig. 3).

Regional trends

In 1990, the highest ASPR of EOD were observed in High-income North America, Tropical Latin America, Southeast Asia, North Africa and the Middle East, and East Asia. Over the past two decades, ASPR in High-income North America and Tropical Latin America has declined. Specifically, from 2000 to 2010, ASPR in High-income North America consistently decreased with an AAPC of -0.24% (95% CI -0.27 to -0.2). Similarly, in Tropical Latin America, ASPR significantly decreased from 2010 to 2021, with an AAPC of -0.4% (95% CI -0.49 to -0.31). Despite these declines, these two regions still had the highest ASPR in 2021, with 461.3 per 100,000 (95% CI 349.9 to 593) and 441 per 100,000 (95% CI 331.2 to 575.4), respectively. Additionally, Southeast Asia and North Africa and the Middle East showed a consistent decline in ASPR from 1990 to 2021 (Fig. 1; Supplementary file 1: Table S1).

In contrast, East Asia's ASPR for EOD increased between 1990 and 2000, with an AAPC of 0.4% (95% CI 0.36 to 0.44), remained stable from 2000 to 2010 (AAPC 0.01% [95% CI -0.04 to 0.06]), and then accelerated from 2010 to 2021 with an AAPC of 0.67% (95% CI 0.52 to 0.81), surpassing other regions. By 2021, East Asia's ASPR was 437.7 per 100,000 (95% CI 326.9 to 573.8), second only to High-income North America and Tropical Latin America, and significantly higher than 388.5 per 100,000 (95% CI 289.4 to 507.8) in 1990. Furthermore, East Asia accounted for the highest proportion of global EOD cases from 1990 to 2021, comprising about a quarter of the global total (Supplementary file 1: Fig. S3). South Asia had the lowest ASPR in both 1990 and 2021, with a gradual decline from 1990 to 2019, followed by a rapid increase from 2019 to 2021 (Fig. 1; Supplementary file 1: Table S1).

In 1990, the highest ASDR for EOD were in Tropical Latin America, East Asia, and Central Sub-Saharan Africa. By 2021, the ASDRs in Tropical Latin America and East Asia remained relatively unchanged at 227.3 per 100,000 (95% CI 100.6 to 532.9) and 205.5 per 100,000 (95% CI 92.7 to 477.5), respectively. However, ASDR in Central Sub-Saharan Africa increased significantly to 217.2 per 100,000 (95% CI 86.5 to 517.4), surpassing East Asia. Notably, South Asia had the fastest increase in EOD-related ASDR over the past decade, with an AAPC of 0.54% (95% CI 0.48 to 0.61) from 2010 to 2021, significantly higher than other regions (Fig. 2; Supplementary file 1: Table S2).

National trends

In 2021, the highest ASPR of EOD were observed in Canada, the United States, and China, with ASPRs of 503 per 100,000 (95% CI 401.7 to 612.6), 456.4 per 100,000 (95% CI 342.4 to 593.3), and 443.3 per 100,000 (95% CI 330.9 to 581.3), respectively. Between 2010 and 2021, the countries with the fastest ASPR increases were Singapore, China, and India, with AAPC of 0.72% (95% CI 0.61 to 0.83), 0.69% (95% CI 0.54 to 0.84), and 0.51% (95% CI 0.23 to 0.78), respectively (Fig. 4; Supplementary file 1: Table S3).

Regarding ASDR for EOD in 2021, the highest rates were in Brazil, Afghanistan, and the Democratic Republic of the Congo, with ASDRs of 227.9 per 100,000 (95% CI 100.9 to 535.1), 226 per 100,000 (95% CI 87.4 to 556.1), and 220.6 per 100,000 (95% CI 84.9 to 527.9), respectively. From 2010 to 2021, the countries with the fastest ASDR increases included Gambia and Ghana in Western Sub-Saharan Africa, followed by the Solomon Islands and India, with AAPCs of 1.24% (95% CI 0.62 to 1.86), 0.81% (95% CI 0.73 to 0.88), 0.69% (95% CI 0.39 to 0.99), and 0.65% (95% CI 0.57 to 0.73), respectively (Fig. 4; Supplementary file 1: Table S4).

Attributable risk factors for DALY in EOD

Figure 5A shows the PAFs of various risk factors for EOD-related DALYs in different regions in 2021. Globally, high fasting plasma glucose was the most significant risk factor for increased EOD-related DALYs, with a PAF of 11.4%. High BMI and smoking had similar PAFs, at 8.8% and 8.1%, respectively. As the SDI increased, the PAF for high BMI also increased: from 4.4% in low SDI regions to 12.4% in high SDI regions. The PAF for smoking similarly trended upward with increasing SDI. Among the 21 regions, the highest PAF for DALYs attributable to high BMI in 2021 was in High-income North America at 16.5%. Oceania had the highest PAF for high fasting plasma glucose at 15.9%, while East Asia had the highest PAF for smoking at 10.5%.

Figure 5B shows the difference in PAFs between males and females for various risk factors in 2021, calculated as male PAF minus female PAF. Globally, across different SDIs and in all 21 regions, the PAF for smoking was higher in males than females, with the largest difference in East Asia at 18.7%. Except for High-income North America, the PAF for high BMI was higher in females across all SDI levels and regions, with the largest difference in Southern Sub-Saharan Africa at 7.4%. The difference in PAFs for high fasting plasma glucose between the sexes was less than 3% in all regions and showed no consistent pattern.

Figure 5C illustrates the changes in PAFs for various risk factors between 1990 and 2021, calculated as the PAF in 2021 minus the PAF in 1990. Globally, across different SDIs and in all 21 regions, the PAFs for high BMI and high fasting plasma glucose increased significantly in 2021 compared to 1990. The largest increases were observed in North Africa and the Middle East, with both risk factors' PAFs rising by approximately 7%. Conversely, the PAF for smoking decreased in 2021 compared to 1990 in all regions except Eastern Europe.

This study systematically analyzed trends in the prevalence and DALYs of EOD globally, regionally, and nationally from 1990 to 2021 and assessed modifiable attributable risk factors. Over the past 30 years, global EOD cases and related DALYs nearly doubled, although the ASPR and ASDR increased only slightly. In 2021, high-middle SDI countries had the highest ASPR, while middle SDI countries had the highest ASDR. Correlation analysis showed no significant relationship between SDI and ASPR but revealed a significant negative correlation between SDI and ASDR. High blood glucose was the most important attributable risk factor globally in 2021. Compared to 1990, the PAFs for high BMI and high blood glucose increased in most regions by 2021, while the PAF for smoking decreased. Additionally, high BMI was a more significant risk factor for females, whereas smoking was more prominent in males.

This study shows that in 2021, the global ASPR for EOD was 355.9 per 100,000. In contrast, Xue Li et al. reported a global ASPR for all-age dementia of 682.48 per 100,000 in 2019, about twice that of EOD. Neither ASPR showed significant changes compared to 1990¹⁸. Stevie et al. found the global EOD ASPR for ages 30 to 64 to be 119.0 per 100,000, significantly lower than our findings. Stevie's study, based on the average estimates from 95 population-based studies conducted between 1990 and 2020, did not provide year-over-year trends and primarily relied on data from Europe, Asia, North America, and Oceania, lacking global representation⁹. In contrast, our study used the most recent GBD 2021 data, covering epidemiological data from the past two years and incorporating a broader range of data sources, offering extensive global representation and a comprehensive reflection of EOD burden across regions. The GBD data employs standardized analytical methods, reducing data heterogeneity and ensuring comparability and consistency. Additionally, our study analyzed temporal trends in EOD burden, aiding in understanding its dynamic changes. Furthermore, both our study and Stevie's research found slightly higher ASPRs in females than males, with the highest EOD ASPR in upper-middle-income countries⁹.

This study conducted a stratified analysis by SDI, revealing that as SDI decreases, the proportion of dementia cases and related DALYs in the 40–64 age group increases. In low-SDI countries, this proportion is about 25%. Li et al. also reported that individuals under 65 account for approximately 25% of dementia cases in China¹⁹. Additionally, our correlation analysis showed no significant relationship between SDI and ASPR, but a significant negative correlation with ASDR. As the economies and populations of low- and middle-income countries grow rapidly, these countries will bear an increasing economic burden of dementia-related DALYs, while the relative share in high-income countries will decrease. Arindam et al. recently projected that by 2050, the economic burden of Alzheimer's disease and related dementias will increase by 12.8-fold in low-income countries, 16.5-fold in lower-middle-income countries, and 21.7-fold in upper-middle-income countries, compared to a 2.6-fold increase in high-income countries². Our study also shows that the EOD burden is highest in high-middle and middle SDI countries, and EOD-related DALYs decrease as SDI increases, consistent with Arindam et al.'s findings².

Our Joinpoint regression analysis revealed significant shifts in ASPR and ASDR during the COVID-19 pandemic across global and various SDI countries, suggesting that COVID-19 may have directly or indirectly impacted the EOD burden. A cross-sectional study of 18 young patients recovering from mild to moderate COVID-19 found that 78% experienced persistent mild cognitive impairment, particularly in short-term memory and attention²⁰. Another study involving 87 dementia centers in Italy reported that during COVID-19 isolation, over half of dementia patients (55.1%) experienced cognitive decline, 51.9% had worsened behavioral symptoms, and 36.7% had deteriorated motor functions, significantly increasing caregiver burden²¹. The SARS-CoV-2 virus may enter the brain via ACE2 receptors, causing neuroinflammation, impairing energy production and protein folding, and accelerating neurodegeneration, leading to long-term cognitive and neuropsychiatric symptoms^22,23.

Additionally, COVID-19 isolation measures increased loneliness, reduced physical activity, and decreased social interaction, potentially accelerating cognitive decline and worsening neuropsychiatric symptoms^22,24. A longitudinal study showed that after six months of strict isolation, 42% of mild cognitive impairment (MCI) patients, 54.3% of Alzheimer's disease (AD) patients, and 72.7% of dementia with Lewy bodies (DLB) patients had decreased Mini-Mental State Examination (MMSE) scores, and 54.4% of DLB patients had worsened Neuropsychiatric Inventory (NPI) scores²⁴. Previously, there was a lack of systematic analysis of EOD prevalence and DALY burden changes before and after the COVID-19 pandemic. Our study fills this gap, showing that from 2019 to 2021, the global EOD ASPR and ASDR reversed the declining trend seen from 2015 to 2019, with annual growth rates of 0.66% and 0.3%, respectively. Notably, contrary to trends in other SDI countries, ASPR and ASDR in high SDI countries declined during COVID-19. The reasons for this discrepancy are unclear but may be related to how COVID-19 isolation measures affected dementia diagnosis and management.

The GBD data included only three dementia-related risk factors, not fully exploring the impact of additional factors on EOD burden. Systematic reviews by Monica and colleagues, and data from the UK Biobank by Stevie and colleagues, identified low education, cardiovascular disease, social isolation, depression, traumatic brain injury, and mental illness as risk factors for increased EOD risk^25,26. Despite this, our study's strength lies in dynamically comparing the impact of different risk factors on EOD burden over time and across regions. Our results indicate that metabolic risk factors like high fasting plasma glucose and obesity have an increasingly significant impact on the EOD burden, particularly among females. Obesity and high blood glucose increase dementia risk through systemic inflammation, elevating inflammatory cytokines such as interleukin-6, disrupting the blood-brain barrier, and affecting hippocampal synaptic plasticity and neurogenesis, leading to memory and cognitive decline. Leptin and insulin resistance impair their cognitive-enhancing effects in the brain and may lead to the formation of central and peripheral amyloid-beta plaques, triggering neuroinflammation and neuronal death, ultimately exacerbating neurodegeneration^27,28.

Based on GBD 2021 data, this study analyzed the trends in prevalence and DALY burden of EOD in individuals aged 40–65 from 1990 to 2021 and assessed related risk factors. However, there are several limitations. First, the study did not differentiate specific dementia subtypes, which may impact understanding the overall burden and developing targeted interventions. Although high fasting plasma glucose, high BMI, and smoking were evaluated, not all known dementia-related risk factors were included, potentially underestimating the burden. Confidence intervals rather than uncertainty intervals were reported for ASPR and ASDR, which might not account for statistical uncertainty in areas with sparse or non-existent data. Data gaps or low-quality data in certain regions might result in an underestimation of the dementia burden. Variability in diagnostic criteria, technologies, and medical records over time could affect the accuracy of trend analysis. Additionally, the study did not adequately assess the impact of the COVID-19 pandemic on EOD burden; interruptions in healthcare services and social isolation measures during the pandemic may have significantly influenced the diagnosis, management, and reporting of dementia. Despite these limitations, the study provides valuable insights into the burden and risk factors of EOD at global and regional levels.

Global EOD cases and related DALYs nearly doubled in number, although ASPR and ASDR increased only slightly from 1990 to 2021. The EOD burden was highest in high-middle and middle SDI countries, particularly with a significant upward trend during the COVID-19 pandemic, while it decreased in high-SDI countries. Additionally, the impact of high blood glucose and obesity on EOD burden has become more significant, especially among females. These findings highlight the need for targeted public health policies and resource allocation to reduce the EOD burden.

Acknowledgements

We highly appreciate the work of the Global Burden of Disease Study 2021 collaborators and the Institute for Health Metrics and Evaluation (IHME) for sharing valuable GBD data.

Author contributions statement

CL, YZ, and HA contributed equally to this work. They wrote the statistical analysis plan, analyzed the data, interpreted the results, and drafted the manuscript. FW and HQ contributed to the interpretation of the data and accessed and verified the data. JBL and JNL conceived the study idea and revised the manuscript. JNL obtained funding, checked the data and results, and supervised the study. All authors have read and approved the final manuscript.

Funding

This research was funded by the Tianjin Science and Technology Committee [grant number 18ZXDBSY00120] and the Science and Technology Project of the Tianjin Municipal Health Commission [grant number ZD20006].

Data availability statement

The data used for these analyses are publicly accessible through the Global Health Data Exchange (GHDx) at the GBD online repository (https://vizhub.healthdata.org/gbd-results/).

Additional information

Ethics approval

Ethical approval and informed consent were not required as the GBD data is publicly available and contains no identifiable information.

Competing interests statement

The authors declare no competing interests.

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Global, regional, and national trends in prevalence and disability-adjusted life years (DALYs) for early-onset dementias, 1990-2021: Insights from the Global Burden of Disease Study 2021

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Sex and SDI stratification

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