Abstract
Background
Alzheimer's disease and other dementias disproportionally impacts women. Novel treatment makes understanding of early-onset cases unprecedentedly important.
Objective
We aimed to examine Alzheimer's disease and other dementias incidence, DALYs, trends, and risk factors among women aged under 65 years from 1990 to 2021.
Methods
Using Global Burden of Diseases Study, we estimated the trend of Alzheimer's diseases and other dementias age-standardized incidence and disability-adjusted life-years (DALYs) among women aged under 65 years by social development index (SDI) worldwide during 1990 to 2021.
Results
Globally, in 2021 there were 4.3 million prevalent cases among middle-aged women, with the incident cases doubled from 0.4 million to 0.8 million during 1990–2021. The largest increases in incidence and DALYs were found in high-middle SDI countries (0.27%/year) and low-middle SDI countries (0.19%/year), respectively. The incidence rate doubled once with every five years of age increase. The two contributors, which were high body mass index and high fasting plasma glucose, rapidly grew from 1990 to 2021.
Conclusions
The substantial increase of early-onset Alzheimer's disease and other dementias among middle-aged women requires attention, especially targeted at the increasing reversible lifestyle risk factors.
Keywords
Introduction
Currently, more than 55 million people are living with dementia globally, Alzheimer's disease is the most common form of dementia and may contribute to 60–80% of cases.1,2 Risk factors for dementia include genetic variations, lifestyle such as smoking and excessive alcohol consumption, and vascular conditions like diabetes, obesity, and high blood pressure. 3 Dementia is classified by age at onset into young-onset dementia (<65 years) and late-onset dementia (>65 years).4,5 Due to global population aging, the high prevalence of dementia in older adults often overshadows the significance of early-onset cases.4,6 However, young-onset dementia is characterized by atypical symptoms, more aggressive disease progression, higher mortality, and lower life expectancy compared to late-onset dementia.7,8
Women are disproportionately affected by young-onset dementia,2,9,10 which may partly attributable to biological factors, such as hormonal changes and genetic variations.11,12 Female with young-onset dementia exhibit faster disease progression and greater pathology burden than males. 12 There are billions of middle-aged women worldwide, playing the most crucial and irreplaceable roles in their careers and families. This disparity results in higher disability-adjusted life years (DALYs) and more socioeconomic burden during their prime time.1,13 In 2024, the Alzheimer's disease drug landscape saw significant advancements with the approval of new medications and ongoing clinical trials, including the treatment of mild cognitive impairment in the early stages.14,15 These advancements addressed the ethical requirements and clinical importance of early diagnosis and intervention for dementia.
In this study, we aimed to examine Alzheimer's disease and other dementias incidence, DALYs, trends, and risk factors among women aged under 65 years from 1990 to 2021; to stratify the global trends by age subgroups, social demographic index (SDI); and to identify the regions and nations with the largest burden and most substantial changes.
Methods
Study population and data collection
Via repeated cross-sectional data from the Global Burden of Disease Study (GBD) 2021, our study focused on Alzheimer's disease and other dementias among females under 65 years. The data on incidence, mortality, DALYs, prevalence, and attributable risk factors (with corresponding 95% uncertainty intervals (UIs)) were directly obtained from the Institute for Health Metrics and Evaluation (IHME) website. The 95% UIs were defined as the 25th and 975th values of the ordered 1000 draws. The GBD 2021 mainly uses the diagnosis from DSM III, IV, or V, ICD case criteria to define Alzheimer's disease and other dementias. 16 The input data and methodological summary can be found in the Supplemental Material, the disease modelling method has been described in previous studies. 17
In this study, data on Alzheimer's disease and other dementias were collected across 21 regions and 204 countries and territories from 1990 to 2021. It was assumed that there was no case in which a diagnosis occurred before the age of 40 years, data among females in five age groups (40–44 years, 45–49 years, 50–54 years, 55–59 years, 60–64 years) were collected. The sociodemographic index (SDI) is calculated as the geometric mean of values ranging from 0 to 1, which is a composite indicator of development status strongly correlated with health outcomes, developed by GBD researchers. 17 Therefore, the SDI applies equally to both males and females in certain country or region. The fertility rate was actually fertility rate under the age of 25 years old (TFU25), which was chosen as one of the three dimensions of development of the country or region, reflecting the fertility patterns of local young population. The other two dimensions are education level using mean education for those ages 15 and older (EDU15+), and the economic level using lag distributed income (LDI) per capita. Here, 0 represents the highest fertility rate, lowest education level, and lowest per capita income. The 204 countries in GBD 2021 are grouped into five quintiles based on their SDI levels (low, low-middle, middle, high-middle, and high).
Statistical analysis
The age-standardized incidence (per 100,000 population), age-standardized prevalence (per 100,000 population), and age-standardized DALYs (per 100,000 population) were compared across different age groups, global regions, and countries. We calculated age-standardized rates and corresponding 95% confidence intervals (95% CIs) by standardization based on the world standard population reported in the GBD 2021.
18
Rates in our estimates are shown per 100,000 population. The equation for calculating was:
We calculated the estimated annual percent changes (EAPCs) between 1990 and 2021 through a linear regression approach. The natural logarithm of age-standardized rate is assumed to fit the linear regression model y=α + βx + ε, where y is equal to ln (age-standardized rate), and x refers to the calendar year. Then, the estimated annual percentage change is equal to 100 × (eβ – 1). This aided in revealing the changing trends over time in the burden of Alzheimer's disease and other dementias across different age groups and geographical regions. Changes in rate are reflected in the EAPC values and their corresponding 95% CIs. When the 95% CI included 0, the change in age-standardized rate was considered stable. It is deemed to be increasing when both the EAPC and the upper and lower limits of the 95% CI are positive and decreasing when they are all negative. All statistical analyses were conducted using RStudio software (version 4.4.2).
Results
Global trends
Globally, the number of incident cases due to Alzheimer's disease and other dementias among women under 65 years increased by 116% between 1990 and 2021, from 354.4 thousand (95% UI 229.6 thousand to 504.9 thousand) in 1990 to 764.5 thousand (95% UI 495.5 thousand to 1.1 million) in 2021, whereas the incidence rate increased at an EAPC of 0.1 (95% CI 0.08 to 0.13), from 66.4 (95% UI 43.1 to 94.7) per 100,000 population in 1990 to 69.3 (95% UI 44.8 to 98.4) per 100,000 population in 2021 (Table 1). The number of DALYs among women under 65 years doubled between 1990 and 2021, from 1.0 million in 1990 to 2.1 million in 2021. During the same period, the DALYs rate substantially increased (EAPC of 0.06 [95% CI 0.05 to 0.07]) (Table 1). The number of prevalent cases was more than doubled among women younger than 65 years, from 2.0 million in 1990 to 4.3 million in 2021, yielding a prevalence rate of 386.8 per 100,000 population (95% UI 292.3 to 502.1) (Supplemental Table 1). Globally, the incident cases among middle-aged men doubled from 0.3 million to 0.6 million during 1990–2021. The number of DALYs among men under 65 years doubled between 1990 and 2021, from 0.8 million in 1990 to 1.6 million in 2021. In 2021, there were 3.5 million prevalent cases among middle-aged men, with a prevalence rate of 323.9 per 100,000 population (95% UI 240.6 to 421.9) among men younger than 65 years (Supplemental Table 1).
The age-standardized incidence and DALYs of Alzheimer's diseases and other dementias in middle-adulthood women and their EAPCs from 1990 to 2021 at the global and regional levels.
Estimates are for women aged 40–64. EAPCs: estimated annual percent changes; CI: confidence interval; DALYs: disability-adjusted life years; p: p value for the significant test of EAPCs.
Global trends by age group
In 2021, with every five years of age increase among women aged 45 to 64 years, the incidence rate was doubled once, which led to an exponential growth from 32.3 per 100,000 population (95% UI 20.2 to 47.5) among 45–49 years to 189.6 per 100,000 population (95% UI 126.6 to 262.3) among 60–64 years (Table 1). Notably, for women aged from 40–44 years to 45–49 years, the incidence rate tripled from 11.0 per 100,000 population (95% UI 4.8 to 18.4) to 32.3 per 100,000 population (95% UI 20.2 to 47.5) (Table 1). In 2021, the DALYs rate also increased with age and at least double every five years of age from 45 to 64 years. (Table 1) Notably, when women aged from 40–44 years to 45–49 years, their DALYs rate increased 7 times from 5.3 per 100,000 population (95% UI 2.3 to 10.7) to 38.7 per 100,000 population (95% UI 19.8 to 77.0) (Table 1).
Global trends by SDI
The incidence cases of Alzheimer's disease and other dementias among women under 65 years almost doubled between 1990 and 2021 in all SDI countries (Table 1). The incidence rate of Alzheimer's disease and other dementias was higher in the high-middle and middle SDI countries than those in other SDI countries in 2021 (Table 1). The largest increase in incidence rate among women under 65 years was found in high-middle SDI countries with EAPC of 0.27 (95% CI 0.24 to 0.3) and high SDI countries with EAPC of 0.2 (95% CI 0.18 to 0.23), while in countries with a low SDI (EAPC −0.17 [95% CI −0.18 to −0.16]) and low-middle SDI countries (EAPC −0.12 [95% CI −0.14 to −0.11]), decreasing trends were observed (Table 1). However, the low-SDI countries (184.2 [95% UI 77.8 to 449.4]) had the same level of DALYs rate as high-SDI countries (184.8 [95% UI 88.5 to 404.6]) (Table 1). The increase in DALYs rate among women under 65 years was observed in countries with all SDI levels, except middle SDI countries (EAPC −0.05 [95% CI −0.06 to −0.03]). The largest increase in DALYs rates among women under 65 years was found in low-middle SDI countries (EAPC 0.19 [95% CI 0.18 to 0.21]) and low SDI countries (EAPC 0.16 [95% CI 0.12 to 0.2]), countries at the two tops of SDI levels had less substantial increase (Table 1).
Regional trends
Almost all the regions had at least double the incidence case of Alzheimer's disease and other dementia among women under 65 years between 1990 and 2021, except for Central Europe, Eastern Europe, High-income Asia Pacific, and Western Europe (Table 1). In 2021, the top three regions with the highest incidence rate per 100,000 population of Alzheimer's diseases and other dementias among women aged under 65 years were East Asia (89.6 [95% UI 57.9 to 127.4]), High-income North America (85.1 [95% UI 56.0 to 120.4]) and Tropical Latin America (83.6 [95% UI 54.3 to 118.9]) (Table 1).The only three regions with the increasing trend in incidence rates among women under 65 years were East Asia (EAPC 0.35 [95% CI 0.3 to 0.41]), High-income Asia Pacific (EAPC 0.24 [95% CI 0.21 to 0.27]), and High-income North America (EAPC 0.16 [95% CI 0.1 to 0.23]) (Table 1). In 2021, the highest DALYs rate per 100,000 population was found in Central Sub-Saharan Africa (255.3 [95% UI 102.1 to 617.0]) (Table 1). The top three regions with the largest increase in DALYs rate among women under 65 years were Central Sub-Saharan Africa (EAPC 0.36 [95% CI 0.29 to 0.43]), South Asia (EAPC 0.23 [95% CI 0.2 to 0.27]), and Eastern Sub-Saharan Africa (EAPC 0.22 [95% CI 0.2 to 0.24]) (Table 1).
National trends
The top five countries with the highest incidence rate per 100,000 population among women under 65 years were China (90.7 [95% UI 58.7 to 129.1]), Canada (86.87 [60.29 to 117.44]), United States of America (84.9 [54.8 to 121.2]), Central African Republic (84.3 [52.8 to 121.5]), and Brazil (83.9 [54.4 to 119.2]) (Figure 1 and Supplemental Table 3).
Global map of 2021 incidence (A) and DALYs (B) and estimated annual percentage change in incidence(C) and DALYs (D) from 1990 to 2021 of Alzheimer's disease and other dementias among middle-aged females. EAPC: estimated annual percentage change; DALYs: disability-adjusted life-years.
Risk factors
Globally, GBD estimate three risk factors contributors to DALYs among women under 65 years were high body-mass index (BMI), high fasting plasma glucose, and smoking, which accounted for 18.9 (95% UI −5.0 to 62.9), 21.5 (1.3 to 58.6), and 6.0 (2.4 to 13.8) DALYs per 100,000 population, respectively in 2021 (Table 2). From 1990 to 2021, the EAPCs for these factors were 1.89 (95% UI 1.89 to 1.93), 1.23 (1.19 to 1.27), and −1.22 (−1.25 to −1.19), respectively (Table 2). Notably, high-SDI countries contributed the most to the burden attributed to these three risk factors among women under 65 years in 2021(Table 2). The risk factors of BMI and high fasting plasma glucose had an increasing trend among women under 65 years in all SDI countries, while the risk factor of smoking had a reduction trend in all SDI countries (Table 2). By contrast, men of the same age had lower DALYs from high BMI 11.4 (95% CI −2.1 to 40.7) and high fasting glucose 18.1 (95% CI 1.07 to 50.3), whereas smoking-related DALYs were much higher in men 22.3 (95% CI 8.8 to 53.1) per 100,000 population, respectively in 2021(Supplemental Table 4).
Leading risk factors at the most detailed level for age-standardized DALYs of Alzheimer's disease and other dementias in middle-adulthood women and their EAPCs in 1990 and 2021.
Estimates are for women aged 40–64. EAPCs: estimated annual percent changes; CI: confidence interval; DALYs: disability-adjusted life years; p: p value for the significant test of EAPCs.
In 2021, all risk factors contributing to DALYs increased as age rises among middle-aged women (Supplemental Table 5). For example, high fasting plasma glucose contributes to the DALYs rate per 100,000 population from 0.31 (95% UI 0.02 to 0.78) among women aged 40–44 years to 84.5 (5.1 to 237.6) among women aged 60–64 years (Supplemental Table 5).
Discussion
To our knowledge, this is the first study to describe the 4.3 million cases and trends of Alzheimer's disease and other dementias among middle-aged women globally over the past three decades. Even though medical care has advanced greatly in the past decades, both the incidence and DALYs increased substantially among middle-aged women. Substantial nation-level inequality exists, with women in low-SDI countries having 10 times the increasing speed of DALY rates of high-SDI countries. Key turning points of disease burden lie in the age of 40–44 to 45–49 years among women. The contribution from high BMI and high fasting plasma glucose substantially increased among this population worldwide. The above evidence addresses intervention of early-onset Alzheimer's diseases among middle-aged women, especially when new treatments become available and the most contributed risk factors are reversible, to support women in their early stages of life.
In 2021, despite the 4.3 million prevalent cases among women globally, there were also 0.8 million incident cases in the same year, which was only half in 1990. We found a substantially increasing incidence rate which is eight to three times higher than the range of 8.3/100,000 to 22.8/100,000 reported in 2013. 19 Compared with results from a meta-analysis of young-onset dementia among both genders, 20 our results revealed higher incidence in women and every age subgroup. For example, in the age group of 60 to 64 years old, we revealed more than triple the rates. Explanations could also be influenced by the geographical scope, with the previous meta-analysis focusing primarily on European countries, whereas our study included 204 countries worldwide.
We identified key turning points of this disease burden among early-aged women. Between ages 40–44 to 45–49, the incidence rate exponentially tripled and the DALYs rate increased sevenfold. This age coincides with menopause (typically 45–55 years), 21 a phase marked by a decrease in hormone levels, especially estrogen, 22 which is strongly correlated with an increased dementia risk. 23 During this transition, nearly 60–70% women report subjective cognitive difficulties, often described as memory problems.24,25 Research indicates that these symptoms during menopause period can trigger treatment-seeking behavior: in the UK, approximately 15.5% of women consulted a doctor for forgetfulness or memory problems (brain fog), 26 and 8.7% of participants initially visited the neurology department for menopausal symptoms. 27 Seeking medical care may help clinicians distinguish menopausal cognitive changes from dementia for patients.
However, diagnosing dementia in individuals under 65 is challenging. It is often delayed, missed, or wrong due to symptom heterogeneity, low prevalence, constraints on clinician time, and patients and healthcare providers dismiss symptoms as part of the normal aging process.28,29 Patients with early-onset dementias usually delay from two to over six years between the first symptom onset and a diagnosis of early-onset dementias.30,31 Our finding further specified the previous concept of incidence rates of dementia doubling every 5 years of age.20,32 Age is the greatest risk factor for dementia, and its progressive nature that worsens over time may increases healthcare-seeking opportunities.2,9 The true incidence rates of early-onset dementia for each age group may be underestimated due to diagnostic delays.
Our results show substantial inequality in early-onset burden between countries with different SDI. High SDI countries had higher incidence rate of dementia than low SDI countries, but similar DALYs rate. Since the diagnosis of Alzheimer's disease is complex and typically involves expensive and sometimes invasive tests not commonly available outside of highly specialized clinical settings. 33 Dementia is under-recognized, under-disclosed, under-treated, and under-managed, particularly in low-income and middle-income countries (LMICs), with middle-income countries showing particularly above 90% of under-detection in comparison to around 60% in high-income countries.34,35 Even within the same country, the diagnostic capabilities for early-onset dementia in rural areas are far lower than urban areas. 36 While research showed that individuals of low socioeconomic status (educational level, income level, and occupation) are at a higher risk of early-onset dementia. 37 The true incidence rates of early-onset dementia may be much higher in low SDI countries.
Identifying modifiable and non-modifiable risk factors helps develop targeted interventions to prevent young-onset dementia. Approximately 5% to 10% of young-onset dementia patients displays an autosomal-dominant pattern of inheritance. 38 APOE4, APP, PSEN1, and PSEN2 were the major genetic risk factors in young-onset dementia.39–41 The effect of APOE4 carrier status on pathology burden was more significant in females with early-onset Alzheimer's dementia than in males. 12 Recent research has increasingly focused on modifiable risk factors, with evidence suggesting that modifying 14 risk factors might prevent or delay nearly half of dementia cases. 3 These modifiable risk factors may also involve complex interactions, research showed diabetes management, obesity control, and smoking cessation collectively decrease vascular damage, attenuate dementia-related neuropathology, and reduce stress and inflammation, thereby lowering the risk of dementia. 3 Notably, multicomponent interventions addressing several risk factors potentially benefit individuals with either high or low genetic dementia risk. 3 The biological factors like genetic variations may play an important role in early-onset dementia. However, research shows that a healthy lifestyle can lower dementia risk even in people with high genetic risk (ε2ε4, ε3ε4, or ε4ε4 genotypes). 42 For instance, one study found that among those with high genetic risk, only 1.13% with a healthy lifestyle developed dementia, compared to 1.78% with an unhealthy lifestyle. 43 Findings require further research to early-onset dementia as above research involved participants aged 60–73. All risk factors for DALYs increase as age rises among middle-aged women, which might have emerged decades before clinical symptoms of dementia are detected. The preventable lifestyle risk factors for dementia during middle adulthood are important for women, it is never too early in the life course for dementia prevention.
Limitations
This study suffers from the general limitations of GBD studies. The first is that the GBD dataset aggregates estimates Alzheimer's disease and other dementias without differentiation, this study report combined estimates without a detailed categorization of the above two categories. The second is that GBD 2021 used the standard GBD reference, which includes a series of criteria for defining Alzheimer's disease and other dementias, rather than the definitions used in the new International Classification of Diseases-11. Although GBD 2021 made efforts to correct non-reference case definitions in GBD source data, variations in health information systems and reporting mechanisms across different countries and regions may affect the quality and accuracy of the data. The third is that diagnosing early-onset dementia is complex and involves highly specialized clinical settings, often resulting in delayed diagnoses, where the true incidence of early-onset dementia may be significantly higher, particularly in LMICs. Finally, this study only estimated three modifiable risk factors, further high-quality research on additional modifiable determinants of early-onset dementia is required.
Conclusions
The incidence and DALYs rate from young-onset Alzheimer's disease and other dementias constantly increased among middle-aged women globally, especially after the menopause period. Inequality of care is substantial between different SDI levels. The contribution of reversible lifestyle risk factors including high BMI and high glucose rapidly increased. Attention from public health resources is urgently required.
Supplemental Material
sj-docx-1-alr-10.1177_25424823251395223 - Supplemental material for Global, regional, and national burdens of early-onset Alzheimer's disease and other dementias in women, 1990 to 2021
Supplemental material, sj-docx-1-alr-10.1177_25424823251395223 for Global, regional, and national burdens of early-onset Alzheimer's disease and other dementias in women, 1990 to 2021 by Fanshun Zhao, Yongze Li, Chenju Yi, Xiaohong Li, Guomei Huang, Xi Chen, Yao Li and Jing Zhang in Journal of Alzheimer's Disease Reports
Footnotes
Acknowledgements
We are grateful for the work of the Global Burden of Disease study 2021 collaborators.
Ethical considerations
This study does not contain personal or medical information about identifiable living individuals, and animal subjects were not involved. The study did not need approval because it used publicly available data. This study followed the Guidelines for Accurate and Transparent Health Estimates Reporting Guidelines for cross-sectional studies.
Consent to participate
Not required as this study used secondary data aggregated at country level.
Consent for publication
Not applicable
Author contribution(s)
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported by the National Natural Science Foundation of China (Grant No. 82304201 and 82000753) and the China Postdoctoral Science Foundation (Grant No. 2021MD703910 and 2023T160724). The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data availability statement
All data will be made available on request to the corresponding author. Proposals will be reviewed and approved by the sponsor, investigator, and collaborators based on scientific merit. After approval of a proposal, data will be shared through a secure online platform after the signing of a data access agreement.
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References
Supplementary Material
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