<?xml version="1.0" encoding="UTF-8"?><!DOCTYPE article PUBLIC "-//NLM//DTD JATS (Z39.96) Journal Publishing DTD v1.2 20190208//EN" "http://jats.nlm.nih.gov/publishing/1.2/JATS-journalpublishing1.dtd"><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" article-type="research-article" dtd-version="1.2" xml:lang="en">
    <front>
        <journal-meta>
            <journal-id journal-id-type="pmc">F1000Research</journal-id>
            <journal-title-group>
                <journal-title>F1000Research</journal-title>
            </journal-title-group>
            <issn pub-type="epub">2046-1402</issn>
            <publisher>
                <publisher-name>F1000 Research Limited</publisher-name>
                <publisher-loc>London, UK</publisher-loc>
            </publisher>
        </journal-meta>
        <article-meta>
            <article-id pub-id-type="doi">10.12688/f1000research.50786.1</article-id>
            <article-categories>
                <subj-group subj-group-type="heading">
                    <subject>Research Article</subject>
                </subj-group>
                <subj-group>
                    <subject>Articles</subject>
                </subj-group>
            </article-categories>
            <title-group>
                <article-title>Epidemiology of Alzheimer&#x2019;s disease and other dementias: rising global burden and forecasted trends</article-title>
                <fn-group content-type="pub-status">
                    <fn>
                        <p>[version 1; peer review: 1 approved with reservations]</p>
                    </fn>
                </fn-group>
            </title-group>
            <contrib-group>
                <contrib contrib-type="author" corresp="no">
                    <name>
                        <surname>Javaid</surname>
                        <given-names>Syed Fahad</given-names>
                    </name>
                    <role content-type="http://credit.niso.org/">Conceptualization</role>
                    <role content-type="http://credit.niso.org/">Funding Acquisition</role>
                    <role content-type="http://credit.niso.org/">Project Administration</role>
                    <role content-type="http://credit.niso.org/">Supervision</role>
                    <role content-type="http://credit.niso.org/">Writing &#x2013; Original Draft Preparation</role>
                    <role content-type="http://credit.niso.org/">Writing &#x2013; Review &amp; Editing</role>
                    <uri content-type="orcid">https://orcid.org/0000-0001-6467-8150</uri>
                    <xref ref-type="aff" rid="a1">1</xref>
                </contrib>
                <contrib contrib-type="author" corresp="no">
                    <name>
                        <surname>Giebel</surname>
                        <given-names>Clarissa</given-names>
                    </name>
                    <role content-type="http://credit.niso.org/">Writing &#x2013; Review &amp; Editing</role>
                    <xref ref-type="aff" rid="a2">2</xref>
                </contrib>
                <contrib contrib-type="author" corresp="no">
                    <name>
                        <surname>Khan</surname>
                        <given-names>Moien AB</given-names>
                    </name>
                    <role content-type="http://credit.niso.org/">Conceptualization</role>
                    <role content-type="http://credit.niso.org/">Writing &#x2013; Original Draft Preparation</role>
                    <role content-type="http://credit.niso.org/">Writing &#x2013; Review &amp; Editing</role>
                    <uri content-type="orcid">https://orcid.org/0000-0003-4970-4618</uri>
                    <xref ref-type="aff" rid="a3">3</xref>
                </contrib>
                <contrib contrib-type="author" corresp="yes">
                    <name>
                        <surname>Hashim</surname>
                        <given-names>Muhammad Jawad</given-names>
                    </name>
                    <role content-type="http://credit.niso.org/">Conceptualization</role>
                    <role content-type="http://credit.niso.org/">Data Curation</role>
                    <role content-type="http://credit.niso.org/">Formal Analysis</role>
                    <role content-type="http://credit.niso.org/">Investigation</role>
                    <role content-type="http://credit.niso.org/">Methodology</role>
                    <role content-type="http://credit.niso.org/">Project Administration</role>
                    <role content-type="http://credit.niso.org/">Resources</role>
                    <role content-type="http://credit.niso.org/">Supervision</role>
                    <role content-type="http://credit.niso.org/">Validation</role>
                    <role content-type="http://credit.niso.org/">Visualization</role>
                    <role content-type="http://credit.niso.org/">Writing &#x2013; Original Draft Preparation</role>
                    <role content-type="http://credit.niso.org/">Writing &#x2013; Review &amp; Editing</role>
                    <uri content-type="orcid">https://orcid.org/0000-0002-9280-9709</uri>
                    <xref ref-type="corresp" rid="c1">a</xref>
                    <xref ref-type="aff" rid="a3">3</xref>
                </contrib>
                <aff id="a1">
                    <label>1</label>Psychiatry and Behavioural Sciences, United Arab Emirates University, Al Ain, 17666, United Arab Emirates</aff>
                <aff id="a2">
                    <label>2</label>Primary Care and Mental Health, University of Liverpool, Liverpool, UK</aff>
                <aff id="a3">
                    <label>3</label>Family Medicine, United Arab Emirates University, Al Ain, 17666, United Arab Emirates</aff>
            </contrib-group>
            <author-notes>
                <corresp id="c1">
                    <label>a</label>
                    <email xlink:href="mailto:jhashim@uaeu.ac.ae">jhashim@uaeu.ac.ae</email>
                </corresp>
                <fn fn-type="conflict">
                    <p>No competing interests were disclosed.</p>
                </fn>
            </author-notes>
            <pub-date pub-type="epub">
                <day>27</day>
                <month>5</month>
                <year>2021</year>
            </pub-date>
            <pub-date pub-type="collection">
                <year>2021</year>
            </pub-date>
            <volume>10</volume>
            <elocation-id>425</elocation-id>
            <history>
                <date date-type="accepted">
                    <day>31</day>
                    <month>3</month>
                    <year>2021</year>
                </date>
            </history>
            <permissions>
                <copyright-statement>Copyright: &#x00a9; 2021 Javaid SF et al.</copyright-statement>
                <copyright-year>2021</copyright-year>
                <license xlink:href="https://creativecommons.org/licenses/by/4.0/">
                    <license-p>This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
                </license>
            </permissions>
            <self-uri content-type="pdf" xlink:href="https://f1000research.com/articles/10-425/pdf"/>
            <abstract>
                <p>
                    <bold>Background:</bold> The burden associated with Alzheimer&#x2019;s disease is recognized as one of the most pressing issues in healthcare. This study aimed to examine the global and regional burden of Alzheimer&#x2019;s disease and related dementias.</p>
                <p>
                    <bold>Methods</bold>: Epidemiological data from the latest Global Burden of Disease (GBD) dataset were analysed to determine the prevalence, incidence and mortality rates from 1990 to 2019 for 204 countries and world regions. This dataset derives estimates for health metrics by collating primary data from research studies, disease registries and government reports. Temporal forecasting was conducted using the GBD Foresight tool.</p>
                <p>
                    <bold>Results</bold>: An estimated 0.7% of the global population has dementia, translating to 51.6 million people worldwide. The total number of persons affected has more than doubled from 1990 to 2019. Dementia metrics showed a continuous increase in prevalence, incidence, mortality, and disability adjusted life years (DALYs) rates worldwide during the last three decades. Japan has the highest prevalence (3,079 cases per 100,000), followed by Italy, Slovenia, Monaco, Greece and Germany. The prevalence is higher in high-income regions such as Western Europe compared to Asia and Africa. However, total number of affected individuals is substantial in South and East Asian regions, in particular China, Japan and India. Dementia related deaths are projected to increase from the current 2.4 million per year to 5.8 million by 2040. Women are more likely to be affected by dementia than men. Age-standardized rates have not changed indicating possible stability of risk factors.</p>
                <p>
                    <bold>Conclusions</bold>: Alzheimer&#x2019;s disease and other dementias are rising rapidly and will more than double in mortality burden over the next 20 years. The tremendous burden in high- and middle-income countries can potentially overwhelm communities and health systems. Urgent measures are needed to allocate funding and provide residential care for affected persons.</p>
            </abstract>
            <kwd-group kwd-group-type="author">
                <kwd>Alzheimer&#x2019;s disease</kwd>
                <kwd>dementia</kwd>
                <kwd>epidemiology</kwd>
                <kwd>prevalence</kwd>
                <kwd>mortality</kwd>
                <kwd>vascular dementia</kwd>
                <kwd>Lewy body disease</kwd>
                <kwd>frontotemporal lobar degeneration</kwd>
                <kwd>neurocognitive disorders</kwd>
                <kwd>mild cognitive impairment</kwd>
            </kwd-group>
            <funding-group>
                <award-group id="fund-1">
                    <funding-source>National Institute for Health Research Applied Research Collaboration North West Coast (ARC NWC)</funding-source>
                </award-group>
                <funding-statement>This is also independent research funded by the National Institute for Health Research Applied Research Collaboration North West Coast (ARC NWC). The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.</funding-statement>
            </funding-group>
        </article-meta>
    </front>
    <body>
        <sec sec-type="intro">
            <title>Introduction</title>
            <p>Dementia remains one of the leading causes of morbidity and mortality worldwide
                <sup>
                    <xref ref-type="bibr" rid="ref-1">1</xref>
                </sup>. The condition exerts a profound negative impact on families, communities and health care systems alike
                <sup>
                    <xref ref-type="bibr" rid="ref-2">2</xref>
                </sup>. The World Health Organization (WHO) estimates that there are 10 million new cases of dementia each year
                <sup>
                    <xref ref-type="bibr" rid="ref-3">3</xref>
                </sup>. Hence, the financial implication of the condition&#x2014;arising from both the direct medical and social care costs as well as the cost of informal care&#x2014;is equivalent to 1.1% of the global gross domestic product (GDP)
                <sup>
                    <xref ref-type="bibr" rid="ref-4">4</xref>
                </sup>. Those affected by dementia and their informal caregivers also face difficulties and suffer poor health outcomes that are persistent
                <sup>
                    <xref ref-type="bibr" rid="ref-5">5</xref>,
                    <xref ref-type="bibr" rid="ref-6">6</xref>
                </sup>. People living with dementia and their informal caregivers are more likely to be diagnosed with comorbidities and subsequently experience poorer access to health and social care services when compared to their unaffected counterparts
                <sup>
                    <xref ref-type="bibr" rid="ref-7">7</xref>,
                    <xref ref-type="bibr" rid="ref-8">8</xref>
                </sup>. Research also demonstrates that people living with dementia are disproportionately more likely to report a poor quality of life
                <sup>
                    <xref ref-type="bibr" rid="ref-9">9</xref>
                </sup>. This reduced quality of life and other inequalities in outcomes are recognized to be driven by factors such as economic hardship and social isolation that are ultimately caused by the stigma associated with this condition
                <sup>
                    <xref ref-type="bibr" rid="ref-10">10</xref>
                </sup>. Thus, those affected represent a vulnerable population group that could be better served by changes within healthcare and social services systems.</p>
            <p>The burden associated with Alzheimer&#x2019;s disease is now recognized as one of the most pressing issues in the field of public health. There is an urgent need for health care systems to identify novel and innovative solutions to meet the needs. The World Health Assembly (WHA) recently endorsed the &#x201c;Global action plan on the public health response to dementia 2017&#x2013;2025,&#x201d; calling for renewed efforts to increase awareness, research and innovation to tackle this urgent public health issue
                <sup>
                    <xref ref-type="bibr" rid="ref-3">3</xref>
                </sup>. However, an effective response to the challenges arising from dementia first requires an accurate understanding of the patterns of prevalence and burden of dementia
                <sup>
                    <xref ref-type="bibr" rid="ref-11">11</xref>,
                    <xref ref-type="bibr" rid="ref-12">12</xref>
                </sup>.</p>
            <p>The aim of this study was to analyse the global and regional burden as well as trends and forecasts for Alzheimer&#x2019;s disease and related dementias. As a unique contribution, this study assessed yearly trends using age-standardized rates to control for the effect of population aging.</p>
        </sec>
        <sec sec-type="methods">
            <title>Methods</title>
            <sec>
                <title>Data source</title>
                <p>Based on the aim of study, the inclusion criteria for data included prevalence, incidence, mortality rates of dementia for global, regional and national levels. Exclusion criteria included subnational data such as hospital-based records and neurological diseases other than dementia such as Parkinson&#x2019;s disease and stroke. We extracted health metrics on dementia from the 
                    <ext-link ext-link-type="uri" xlink:href="http://ghdx.healthdata.org/">Global Burden of Disease (GBD)</ext-link> dataset. GBD is the largest and most up-to-date repository of epidemiological data for any given condition including dementia
                    <sup>
                        <xref ref-type="bibr" rid="ref-13">13</xref>
                    </sup>. GBD 2019 release has data on 204 countries for 286 causes of death. The robustness of this dataset stems from its reliance on a wide range of primary sources, independent research studies, government reports, vital registration, verbal autopsies, disease registries, healthcare projects and census data. GBD 2019 utilized 990 primary data sources related dementia to develop its estimates. Based on statistical modelling from these data sources, GBD produces reliable estimates of health metrics. Furthermore, GBD incorporates modelling adjustment to address data sampling issues, missing data and variations in case definition.  The methods used are compliant with Guidelines for Accurate and Transparent Health Estimates Reporting (
                    <ext-link ext-link-type="uri" xlink:href="http://gather-statement.org/">GATHER statement</ext-link>).</p>
            </sec>
            <sec>
                <title>Data variables</title>
                <p>Health metrics analysed in the present study included prevalence, incidence, mortality and disability-adjusted life years (DALY). DALY is a better measure of human suffering from a disease than prevalence or mortality, as it combines years lived with disability and the years of life lost due to premature death. Data for dementia were obtained from GBD using the 
                    <ext-link ext-link-type="uri" xlink:href="http://ghdx.healthdata.org/gbd-results-tool">Results tool</ext-link>. Dementia is listed under Neurological Disorders in GBD and coded as B.5.1 Alzheimer&#x2019;s disease and other dementias. Data visualization was conducted in Microsoft Excel 2016 as well as the 
                    <ext-link ext-link-type="uri" xlink:href="https://vizhub.healthdata.org/gbd-compare/">GBD Compare tool</ext-link>. Sub-classification of dementias such as vascular, frontotemporal and dementia with Lewy bodies was not available in this dataset. Epidemiological data on mild cognitive impairments was not included in the GBD.</p>
            </sec>
            <sec>
                <title>Data analysis</title>
                <p>Data were analysed using GBD analytical tools including 
                    <ext-link ext-link-type="uri" xlink:href="http://www.healthdata.org/gbd/data-visualizations">visualizations</ext-link> and forecasting. These tools were utilized in order to achieve the highest fidelity. We analysed both raw and age-adjusted rates of dementia prevalence and incidence. Age-standardized rates remove the effect of population age across countries as well as over time, thus enabling inferences about intrinsic changes in dementia burden. Age of onset of dementia was inferred from age-specific incidence rates. We sought to assess whether the age of onset was decreasing over time by comparing figures from 1990 with those from 2019. Forecasting for projections for the next 20 years was achieved using the 
                    <ext-link ext-link-type="uri" xlink:href="https://vizhub.healthdata.org/gbd-foresight/">GBD Foresight tool</ext-link>, with the following settings: scenario: reference; uncertainty: off; rank: off; and age: all ages (unstandardized). Statistical data analysis was conducted using 
                    <ext-link ext-link-type="uri" xlink:href="https://www.ibm.com/uk-en/analytics/spss-statistics-software">SPSS</ext-link> version 26 (IBM Inc., Armonk, NY, 2019). Paired samples t-tests were used to compare differences in prevalence rates across gender and to evaluate changes in incidence rates over from 1990 to 2019. An alpha level of 0.05 was considered statistically significant.</p>
            </sec>
        </sec>
        <sec sec-type="results">
            <title>Results</title>
            <sec>
                <title>Prevalence</title>
                <p>The global prevalence of dementia was 0.69% [uncertainty interval (UI); 0.59, 0.79] of the world population in 2019 (
                    <xref ref-type="table" rid="T1">Table 1</xref>). The total number of persons affected has more than doubled from 1990 to 2019: increasing from 20.5 million to 51.6 million [UI; 44.2, 59.0 million] globally. The worldwide prevalence rate for all forms of dementia was 667.2 cases per 100,000 persons [UI; 572.2, 762.8]. In comparison to other major neurological diseases, the prevalence of dementia was considerably higher. For example, the prevalence of Parkinson&#x2019;s disease was 110 cases, and multiple sclerosis 22.7 cases per 100,000 persons. Women were more likely to be affected by dementia than men. For instance, among persons over the age of 80, the prevalence rate among women was 20,244 per 100,000 [UI; 16,661, 34,236] compared to 14,378 per 100,000 [UI; 11,667, 17,478] in men.</p>
                <table-wrap id="T1" orientation="portrait" position="anchor">
                    <label>Table 1. </label>
                    <caption>
                        <title>Burden of Alzheimer&#x2019;s disease and other dementias.</title>
                    </caption>
                    <table content-type="article-table" frame="hsides">
                        <thead>
                            <tr>
                                <th align="left" colspan="1" rowspan="1" valign="top">Region</th>
                                <th align="left" colspan="1" rowspan="1" valign="top">Prevalence
                                    <break/>(cases per 100,000
                                    <break/> population)</th>
                                <th align="left" colspan="1" rowspan="1" valign="top">The burden of
                                    <break/> human suffering
                                    <break/>(DALY per 100,000)</th>
                                <th align="left" colspan="1" rowspan="1" valign="top">Total
                                    <break/> number of 
                                    <break/>cases</th>
                            </tr>
                        </thead>
                        <tbody>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">Global average</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">667</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">327</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">51,624,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">Europe</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,443</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">689</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">12,251,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Russia</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,150</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">515</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,686,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Germany</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,864</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">836</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,582,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Italy</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">2,270</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,110</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,369,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;France</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,698</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">881</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,124,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;United Kingdom</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,241</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">651</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">834,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">Asia</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">598</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">297</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">27,230,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;China</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">924</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">420</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">15,299,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Japan</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">3,079</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,613</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">4,579,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;India</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">266</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">153</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">4,249,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;South Korea</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,119</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">537</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">685,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Iran</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">559</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">271</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">542,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">Americas</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">938</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">439</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">9,474,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;United States</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,495</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">618</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">4,902,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Canada</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,459</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">666</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">532,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Mexico</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">430</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">272</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">537,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Brazil</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">786</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">395</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">1,702,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Argentina</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">839</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">393</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">378,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">Africa</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">197</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">108</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">2,591,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;South Africa</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">381</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">192</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">211,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Nigeria</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">124</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">84</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">266,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Egypt</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">299</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">137</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">295,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Algeria</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">461</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">228</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">193,000</td>
                            </tr>
                            <tr>
                                <td align="left" colspan="1" rowspan="1" valign="top">&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;&#x00a0;Morocco</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">485</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">240</td>
                                <td align="right" colspan="1" rowspan="1" valign="top">174,000</td>
                            </tr>
                        </tbody>
                    </table>
                    <table-wrap-foot>
                        <fn>
                            <p>Notes: selected countries shown in this table (all countries were included in the analysis). Data from Global Burden of Disease, 2019. DALY, disability-adjusted life years.</p>
                        </fn>
                    </table-wrap-foot>
                </table-wrap>
                <p>Across regions, high-income Asia Pacific had the highest prevalence followed by Europe, Austrasia and North America (
                    <xref ref-type="fig" rid="f1">Figure 1</xref>). South Asia and Africa ranked the lowest in terms of prevalence of dementia. The highest prevalence rates in descending order were: Japan (3,079 cases per 100,000 population), Italy (2,269 cases per 100,000), Slovenia (1,963 cases), Monaco (1,962 cases), Greece (1,874 cases), and Germany (1,863 cases per 100,000). In terms total number persons living with dementia, China (13.1 million cases), United States (4.9 million), Japan (3.9 million), India (3.6 million) and Brazil (1.7 million) have the highest burden in the world.</p>
                <fig fig-type="figure" id="f1" orientation="portrait" position="float">
                    <label>Figure 1. </label>
                    <caption>
                        <title>Global burden of Alzheimer&#x2019;s disease and other dementias.</title>
                        <p>Notes: prevalence rates per 100,000 population by country. Red, orange and yellow shades indicate higher prevalence. Source: Global Burden of Disease, 2019.</p>
                    </caption>
                    <graphic orientation="portrait" position="float" xlink:href="https://f1000research-files.f1000.com/manuscripts/53871/5db3241e-7309-45ad-9bd2-2ee91fd97b0a_figure1.gif"/>
                </fig>
            </sec>
            <sec>
                <title>Trends</title>
                <p>Dementia metrics showed a continuous increase in prevalence, incidence, mortality, and disability adjusted life years (DALYs) rates worldwide during the 29 years of estimates from 1990 to 2019. Certain regions, such as Western Europe, showed a faster rate of rise than the global average. Japan, in particular, experienced a marked increase in prevalence rates, from 772 cases per 100,000 population in 1990 to 3,079 per 100,000 in 2019. Thus, the total number of cases continued to rise with population growth and aging.</p>
                <p>As prevalence rates are affected by the proportion of elderly in a population, we used age-standardized rates to aid in comparisons between countries. Age standardization adjusts for any differences in underlying population age distributions. After age-standardization (to control for the effect of population aging), incidence and prevalence rates appeared to remain stable during the same period (
                    <xref ref-type="fig" rid="f2">Figure 2</xref>). Hence, there appeared to be no intrinsic increase in rates of dementia after controlling for population aging.</p>
                <fig fig-type="figure" id="f2" orientation="portrait" position="float">
                    <label>Figure 2. </label>
                    <caption>
                        <title>Trends in the burden of dementia.</title>
                        <p>(
                            <bold>a</bold>) Incidence (unadjusted rates). (
                            <bold>b</bold>) Age-standardized incidence.</p>
                    </caption>
                    <graphic orientation="portrait" position="float" xlink:href="https://f1000research-files.f1000.com/manuscripts/53871/5db3241e-7309-45ad-9bd2-2ee91fd97b0a_figure2.gif"/>
                </fig>
            </sec>
            <sec>
                <title>Age of onset</title>
                <p>The age distribution of new cases showed incidence starting from the latter half of the fifth decade of life. The age distribution of new cases of dementia has not changed since 1990 (
                    <xref ref-type="fig" rid="f3">Figure 3A</xref>). As expected, the incidence was highest at older ages (
                    <xref ref-type="fig" rid="f3">Figure 3B</xref>).</p>
                <fig fig-type="figure" id="f3" orientation="portrait" position="float">
                    <label>Figure 3. </label>
                    <caption>
                        <title>Age distribution of dementia.</title>
                        <p>(
                            <bold>a</bold>) Prevalence (per 100 persons) by gender. 
                            <italic toggle="yes">p</italic> = .059, paired samples t-test, comparing prevalence in each age group for males and females. (
                            <bold>b</bold>) Incidence (age of onset of new cases) change over three decades. 
                            <italic toggle="yes">p</italic> = .33, paired samples t-test, comparing incidence in each age group for 1990 and 2019.</p>
                    </caption>
                    <graphic orientation="portrait" position="float" xlink:href="https://f1000research-files.f1000.com/manuscripts/53871/5db3241e-7309-45ad-9bd2-2ee91fd97b0a_figure3.gif"/>
                </fig>
            </sec>
            <sec>
                <title>Mortality</title>
                <p>Mortality rates have been rising rapidly and continuously since 1990. The global death rate due to dementia increased from 10.49 deaths per 100,000 in 1990 to 20.98 deaths per 100,000 in 2019 [UI; 5.27, 54.36]. Statistical forecasting showed a rising rate reaching 66.4 deaths per 100,000 [UI; 51.6, 85.2] by 2040. Most regions are forecasted to continue to follow this rising trend over the next 20 years. The highest death rates due to dementia are expected in Japan at 265 deaths per 100,000 population by 2040. Total deaths due to dementia are projected to increase from the current 2.4 million per year to 5.8 million by 2040 [UI; 4.5, 7.5 million].</p>
            </sec>
        </sec>
        <sec sec-type="discussion">
            <title>Discussion</title>
            <p>This study adds important insights on the global burden of dementia and its predicted trajectory. Based on the latest data from GBD, three key findings have emerged from our analysis. The incidence of dementias is rising especially in Western Europe and Japan. A large burden of dementia (total number of cases) was present in developing countries. When standardized for population aging, the rates are stable. These findings have considerable implications for the health and social care sectors, which need to adapt and prepare in advance to meet the rising demand.</p>
            <p>The burden arising from Alzheimer&#x2019;s disease and other dementias is acknowledged to be markedly high when compared to other non-communicable conditions affecting older age groups
                <sup>
                    <xref ref-type="bibr" rid="ref-14">14</xref>
                </sup>. The associated burden of care correlates with the severity of dementia as the subsequent cognitive and functional decline negatively impacts the affected individual&#x2019;s ability to be independent and engage in activities of daily living
                <sup>
                    <xref ref-type="bibr" rid="ref-15">15</xref>,
                    <xref ref-type="bibr" rid="ref-16">16</xref>
                </sup>. These factors combined with rising prevalence rates due to population growth and aging as well as the absence of curative therapies forecast a bleak picture of the future. It is not surprising that dementia has now become the focus of public health policy and research
                <sup>
                    <xref ref-type="bibr" rid="ref-16">16</xref>&#x2013;
                    <xref ref-type="bibr" rid="ref-18">18</xref>
                </sup>.</p>
            <p>Japan depicts a grim case study of the social burden of dementia. Our analysis revealed a rapid increase in prevalence and mortality rates from 1990 to 2019, and a forecasted meteoric rise over the next two decades. The proportion of Japanese people over the age of 65 is now 26.7%
                <sup>
                    <xref ref-type="bibr" rid="ref-19">19</xref>
                </sup>. Consequently, meeting the healthcare demands of the aging population has become a public health priority. However, the rising demand can easily overwhelm healthcare and social services capacity
                <sup>
                    <xref ref-type="bibr" rid="ref-20">20</xref>
                </sup>. The number of residential care homes in Japan for people living with dementia remains suboptimal and the accessible care available is provided in hospital settings
                <sup>
                    <xref ref-type="bibr" rid="ref-16">16</xref>&#x2013;
                    <xref ref-type="bibr" rid="ref-18">18</xref>
                </sup>. Hospital environments have long been considered inappropriate for long-term care of those affected. These issues raise serious concerns about how countries such as Japan and those in Western Europe will meet this ever-increasing burden of dementia, perhaps representing the greatest challenge for their current and future health care systems. On the other hand, it is important to recognize that the lower prevalence rates of dementia found in certain regions such as South Asia may arise from lack of accessible healthcare services. All forms of dementia are underdiagnosed
                <sup>
                    <xref ref-type="bibr" rid="ref-21">21</xref>
                </sup>. Amongst other factors, the lack of accessible health care may impede timely recognition
                <sup>
                    <xref ref-type="bibr" rid="ref-18">18</xref>,
                    <xref ref-type="bibr" rid="ref-19">19</xref>
                </sup>.</p>
            <p>A novel finding emerging from our analysis is the stability of age-standardized rates. This implies that (apart from age) risk factors for dementia have remained constant over the last three decades. The stability of age-standardized prevalence rates over time may be a reflection of age continuing to represent the strongest predictor of dementia
                <sup>
                    <xref ref-type="bibr" rid="ref-22">22</xref>
                </sup>. Epidemiological studies exploring the relationship between age and dementias have found that the rate of cognitive decline is 10 times greater during the last three years of life, irrespective of the country of residence
                <sup>
                    <xref ref-type="bibr" rid="ref-22">22</xref>
                </sup>. Potential risk factors such as diabetes, hypertension, smoking, sedentary lifestyle and obesity are rising globally, and yet are not reflected in age-standardized rates of dementia. The reasons for this remain unresolved. Insights from certain studies indicate that obesity affects dementia selectively
                <sup>
                    <xref ref-type="bibr" rid="ref-23">23</xref>
                </sup>. A national registry-based study from Denmark indicated a steady decline incidence since 2003
                <sup>
                    <xref ref-type="bibr" rid="ref-24">24</xref>
                </sup>. These results have not been consistently reported in other regions. It is possible that improvements in dietary intake, physical activity level and reductions in tobacco consumption may contribute to these remarkable trends
                <sup>
                    <xref ref-type="bibr" rid="ref-25">25</xref>
                </sup>.</p>
            <p>This study is subject to a few limitations. Country-level comparisons are generalizations that are susceptible to ecological bias. The GBD dataset relies on multiple sources that adopt heterogeneous methodologies including varying case definitions, which can make comparisons less robust. However, statistical modelling techniques employed by GBD adjust for these potential sources of error. At present, GBD provides the most comprehensive and current data available on the burden of dementia.</p>
        </sec>
        <sec sec-type="conclusions">
            <title>Conclusions</title>
            <p>Dementia now represents one of the most pressing issues facing global public health resulting in a burden of care that profoundly impacts families, communities, and healthcare systems alike. Our findings can be used to inform policies and global health agendas that direct the allocation of resources with a need to address and support specific subgroups and regions. Research is needed to identify mild cognitive impairment and early markers of disease progression
                <sup>
                    <xref ref-type="bibr" rid="ref-26">26</xref>
                </sup>. Future research needs to explore differences in prevalence rates of the various forms of dementia and the associated care burden. There remains an urgent need for public health initiatives that aim to promote healthier living among older populations in recognition of the many risk factors now associated with the development of dementia. Otherwise, several countries provide a stark example of the potential for healthcare systems to become overwhelmed.</p>
        </sec>
        <sec>
            <title>Data availability</title>
            <sec>
                <title>Source data</title>
                <p>The data used in this study was obtained from the Institute of Health Metrics and Evaluation, University of Washington. 
                    <ext-link ext-link-type="uri" xlink:href="http://ghdx.healthdata.org/ihme_data">http://ghdx.healthdata.org/ihme_data</ext-link>. The search term used was: B.5.1 Alzheimer&#x2019;s disease and related dementias.</p>
                <p>Data are available under the terms of the Open Data Commons Attribution License.</p>
            </sec>
            <sec>
                <title>Underlying data</title>
                <p>Open Science Foundation: Dementia. 
                    <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.17605/OSF.IO/DYBTM">https://doi.org/10.17605/OSF.IO/DYBTM</ext-link>
                    <sup>
                        <xref ref-type="bibr" rid="ref-27">27</xref>
                    </sup>.</p>
                <p>This project contains the following underlying data:</p>
                <list list-type="bullet">
                    <list-item>
                        <label>-</label>
                        <p>Supplementary Appendix &#x2013; Dementia 2019 data (numeric estimates for prevalence, incidence, mortality and DALYs)</p>
                    </list-item>
                </list>
            </sec>
            <sec>
                <title>Reporting guidelines</title>
                <p>Open Science Foundation: GATHER checklist for &#x2018;Epidemiology of Alzheimer&#x2019;s disease and other dementias: rising global burden and forecasted trends&#x2019;. 
                    <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.17605/OSF.IO/DYBTM">https://doi.org/10.17605/OSF.IO/DYBTM</ext-link>
                    <sup>
                        <xref ref-type="bibr" rid="ref-27">27</xref>
                    </sup>.</p>
                <p>Data are available under the terms of the 
                    <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc/4.0/legalcode">Creative Commons Attribution-NonCommercial 4.0 International</ext-link> (CC BY-NC 4.0).</p>
            </sec>
        </sec>
    </body>
    <back>
        <ack>
            <title>Acknowledgments</title>
            <p>We would like to thank the Institute of Health Metrics, Seattle, for developing the Global Burden of Disease database.</p>
        </ack>
        <ref-list>
            <ref id="ref-1">
                <label>1</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Gandy</surname>
                            <given-names>S</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Bartfai</surname>
                            <given-names>T</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Lees</surname>
                            <given-names>GV</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Midlife interventions are critical in prevention, delay, or improvement of Alzheimer&#x2019;s disease and vascular cognitive impairment and dementia [version 1; peer review: 2 approved].</article-title>
                    <source>

                        <italic toggle="yes">F1000Res.</italic>
</source>
                    <year>2017</year>;<volume>6</volume>:<fpage>413</fpage>.
                    <pub-id pub-id-type="pmid">28491285</pub-id>
                    <pub-id pub-id-type="doi">10.12688/f1000research.11140.1</pub-id>
                    <pub-id pub-id-type="pmcid">5399952</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-2">
                <label>2</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Wong</surname>
                            <given-names>CYT</given-names>
                        </name>
</person-group>:
                    <article-title>Predictors of psychiatric rehospitalization among elderly patients [version 1; peer review: 3 approved].</article-title>
                    <source>

                        <italic toggle="yes">F1000Res.</italic>
</source>
                    <year>2015</year>;<volume>4</volume>:<fpage>926</fpage>.
                    <pub-id pub-id-type="pmid">26870319</pub-id>
                    <pub-id pub-id-type="doi">10.12688/f1000research.7135.1</pub-id>
                    <pub-id pub-id-type="pmcid">4732553</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-3">
                <label>3</label>
                <mixed-citation publication-type="journal">
                    <collab>WHO</collab>:
                    <article-title>Global action plan on the public health response to dementia 2017 - 2025.</article-title>WHO. World Health Organization; [cited 2020 Jun 22].
                    <ext-link ext-link-type="uri" xlink:href="https://www.who.int/mental_health/neurology/dementia/action_plan_2017_2025/en/">Reference Source</ext-link>
                </mixed-citation>
            </ref>
            <ref id="ref-4">
                <label>4</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Wimo</surname>
                            <given-names>A</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Guerchet</surname>
                            <given-names>M</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Ali</surname>
                            <given-names>GC</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>The worldwide costs of dementia 2015 and comparisons with 2010.</article-title>
                    <source>

                        <italic toggle="yes">Alzheimers Dement.</italic>
</source>
                    <year>2017</year>;<volume>13</volume>(<issue>1</issue>):<fpage>1</fpage>&#x2013;<lpage>7</lpage>.
                    <pub-id pub-id-type="pmid">27583652</pub-id>
                    <pub-id pub-id-type="doi">10.1016/j.jalz.2016.07.150</pub-id>
                    <pub-id pub-id-type="pmcid">5232417</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-5">
                <label>5</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Wu</surname>
                            <given-names>YT</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Clare</surname>
                            <given-names>L</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Jones</surname>
                            <given-names>IR</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Inequalities in living well with dementia-The impact of deprivation on well-being, quality of life and life satisfaction: Results from the improving the experience of dementia and enhancing active life study.</article-title>
                    <source>

                        <italic toggle="yes">Int J Geriatr Psychiatry.</italic>
</source>
                    <year>2018</year>;<volume>33</volume>(<issue>12</issue>):<fpage>1736</fpage>&#x2013;<lpage>42</lpage>.
                    <pub-id pub-id-type="pmid">30246354</pub-id>
                    <pub-id pub-id-type="doi">10.1002/gps.4998</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-6">
                <label>6</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Cooper</surname>
                            <given-names>C</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Lodwick</surname>
                            <given-names>R</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Walters</surname>
                            <given-names>K</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Inequalities in receipt of mental and physical healthcare in people with dementia in the UK.</article-title>
                    <source>

                        <italic toggle="yes">Age Ageing.</italic>
</source>
                    <year>2017</year>;<volume>46</volume>(<issue>3</issue>):<fpage>393</fpage>&#x2013;<lpage>400</lpage>.
                    <pub-id pub-id-type="pmid">27916749</pub-id>
                    <pub-id pub-id-type="doi">10.1093/ageing/afw208</pub-id>
                    <pub-id pub-id-type="pmcid">5378291</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-7">
                <label>7</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Stevnsborg</surname>
                            <given-names>L</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Jensen-Dahm</surname>
                            <given-names>C</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Nielsen</surname>
                            <given-names>TR</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Inequalities in Access to Treatment and Care for Patients with Dementia and Immigrant Background: A Danish Nationwide Study.</article-title>
                    <source>

                        <italic toggle="yes">J Alzheimers Dis.</italic>
</source>
                    <year>2016</year>;<volume>54</volume>(<issue>2</issue>):<fpage>505</fpage>&#x2013;<lpage>14</lpage>.
                    <pub-id pub-id-type="pmid">27567820</pub-id>
                    <pub-id pub-id-type="doi">10.3233/JAD-160124</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-8">
                <label>8</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Bunn</surname>
                            <given-names>F</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Burn</surname>
                            <given-names>AM</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Goodman</surname>
                            <given-names>C</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Comorbidity and dementia: a scoping review of the literature.</article-title>
                    <source>

                        <italic toggle="yes">BMC Med.</italic>
</source>
                    <year>2014</year>;<volume>12</volume>(<issue>1</issue>):<fpage>192</fpage>.
                    <pub-id pub-id-type="pmid">25358236</pub-id>
                    <pub-id pub-id-type="doi">10.1186/s12916-014-0192-4</pub-id>
                    <pub-id pub-id-type="pmcid">4229610</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-9">
                <label>9</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Farina</surname>
                            <given-names>N</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Hicks</surname>
                            <given-names>B</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Baxter</surname>
                            <given-names>K</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>DETERMinants of quality of life, care and costs, and consequences of INequalities in people with Dementia and their carers (DETERMIND): A protocol paper.</article-title>
                    <source>

                        <italic toggle="yes">Int J Geriatr Psychiatry.</italic>
</source>
                    <year>2020</year>;<volume>35</volume>(<issue>3</issue>):<fpage>290</fpage>&#x2013;<lpage>301</lpage>.
                    <pub-id pub-id-type="pmid">31876069</pub-id>
                    <pub-id pub-id-type="doi">10.1002/gps.5246</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-10">
                <label>10</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Wright</surname>
                            <given-names>T</given-names>
                        </name>

                        <name name-style="western">
                            <surname>O&#x2019;Connor</surname>
                            <given-names>S</given-names>
                        </name>
</person-group>:
                    <article-title>Reviewing challenges and gaps in European and global dementia policy.</article-title>
                    <source>

                        <italic toggle="yes">J Public Ment Health.</italic>
</source>
                    <year>2018</year>;<volume>17</volume>(<issue>4</issue>):<fpage>157</fpage>&#x2013;<lpage>67</lpage>.
                    <pub-id pub-id-type="pmid">30581491</pub-id>
                    <pub-id pub-id-type="doi">10.1108/JPMH-02-2018-0012</pub-id>
                    <pub-id pub-id-type="pmcid">6290892</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-11">
                <label>11</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Hoffman</surname>
                            <given-names>D</given-names>
                        </name>
</person-group>:
                    <article-title>Alzheimer&#x2019;s Disease Legislation And Policy--Now And In The Future.</article-title>
                    <source>

                        <italic toggle="yes">Health Aff (Millwood).</italic>
</source>
                    <year>2014</year>;<volume>33</volume>(<issue>4</issue>):<fpage>561</fpage>&#x2013;<lpage>5</lpage>.
                    <pub-id pub-id-type="pmid">24711315</pub-id>
                    <pub-id pub-id-type="doi">10.1377/hlthaff.2013.1223</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-12">
                <label>12</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Ienca</surname>
                            <given-names>M</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Vayena</surname>
                            <given-names>E</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Blasimme</surname>
                            <given-names>A</given-names>
                        </name>
</person-group>:
                    <article-title>Big Data and Dementia: Charting the Route Ahead for Research, Ethics, and Policy.</article-title>
                    <source>

                        <italic toggle="yes">Front Med (Lausanne).</italic>
</source>
                    <year>2018</year>;<volume>5</volume>:<fpage>13</fpage>.
                    <pub-id pub-id-type="pmid">29468161</pub-id>
                    <pub-id pub-id-type="doi">10.3389/fmed.2018.00013</pub-id>
                    <pub-id pub-id-type="pmcid">5808247</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-13">
                <label>13</label>
                <mixed-citation publication-type="journal">
                    <collab>University of Washington</collab>:
                    <article-title>Institute for Health Metrics and Evaluation</article-title>. [cited 2016 Nov 27].
                    <ext-link ext-link-type="uri" xlink:href="http://www.healthdata.org/institute-health-metrics-and-evaluation">Reference Source</ext-link>
                </mixed-citation>
            </ref>
            <ref id="ref-14">
                <label>14</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Melis</surname>
                            <given-names>RJF</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Haaksma</surname>
                            <given-names>ML</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Muniz-Terrera</surname>
                            <given-names>G</given-names>
                        </name>
</person-group>:
                    <article-title>Understanding and predicting the longitudinal course of dementia.</article-title>
                    <source>

                        <italic toggle="yes">Curr Opin Psychiatry.</italic>
</source>
                    <year>2019</year>;<volume>32</volume>(<issue>2</issue>):<fpage>123</fpage>&#x2013;<lpage>9</lpage>.
                    <pub-id pub-id-type="pmid">30557268</pub-id>
                    <pub-id pub-id-type="doi">10.1097/YCO.0000000000000482</pub-id>
                    <pub-id pub-id-type="pmcid">6380437</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-15">
                <label>15</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Kawada</surname>
                            <given-names>T</given-names>
                        </name>
</person-group>:
                    <article-title>Risk of caregiver burden in patients with three types of dementia.</article-title>
                    <source>

                        <italic toggle="yes">Int Psychogeriatr.</italic>
</source>
                    <year>2019</year>;<volume>31</volume>(<issue>1</issue>):<fpage>153</fpage>.
                    <pub-id pub-id-type="pmid">30729907</pub-id>
                    <pub-id pub-id-type="doi">10.1017/S1041610218000662</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-16">
                <label>16</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Sudo</surname>
                            <given-names>K</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Kobayashi</surname>
                            <given-names>J</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Noda</surname>
                            <given-names>S</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Japan&#x2019;s healthcare policy for the elderly through the concepts of self-help (Ji-jo), mutual aid (Go-jo), social solidarity care (Kyo-jo), and governmental care (Ko-jo).</article-title>
                    <source>

                        <italic toggle="yes">Biosci Trends.</italic>
</source>
                    <year>2018</year>;<volume>12</volume>(<issue>1</issue>):<fpage>7</fpage>&#x2013;<lpage>11</lpage>.
                    <pub-id pub-id-type="pmid">29479017</pub-id>
                    <pub-id pub-id-type="doi">10.5582/bst.2017.01271</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-17">
                <label>17</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Iwagami</surname>
                            <given-names>M</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Tamiya</surname>
                            <given-names>N</given-names>
                        </name>
</person-group>:
                    <article-title>The Long-Term Care Insurance System in Japan: Past, Present, and Future.</article-title>
                    <source>

                        <italic toggle="yes">JMA J.</italic>
</source>
                    <year>2019</year>;<volume>2</volume>(<issue>1</issue>):<fpage>67</fpage>&#x2013;<lpage>9</lpage>.
                    <pub-id pub-id-type="doi">10.31662/jmaj.2018-0015</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-18">
                <label>18</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Hirakawa</surname>
                            <given-names>Y</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Chiang</surname>
                            <given-names>C</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Aoyama</surname>
                            <given-names>A</given-names>
                        </name>
</person-group>:
                    <article-title>A qualitative study on barriers to achieving high-quality, community-based integrated dementia care.</article-title>
                    <source>

                        <italic toggle="yes">J Rural Med JRM.</italic>
</source>
                    <year>2017</year>;<volume>12</volume>(<issue>1</issue>):<fpage>28</fpage>&#x2013;<lpage>32</lpage>.
                    <pub-id pub-id-type="pmid">28593014</pub-id>
                    <pub-id pub-id-type="doi">10.2185/jrm.2927</pub-id>
                    <pub-id pub-id-type="pmcid">5458349</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-19">
                <label>19</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Tham</surname>
                            <given-names>TY</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Tran</surname>
                            <given-names>TL</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Prueksaritanond</surname>
                            <given-names>S</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Integrated health care systems in Asia: an urgent necessity.</article-title>
                    <source>

                        <italic toggle="yes">Clin Interv Aging.</italic>
</source>
                    <year>2018</year>;<volume>13</volume>:<fpage>2527</fpage>&#x2013;<lpage>38</lpage>.
                    <pub-id pub-id-type="pmid">30587945</pub-id>
                    <pub-id pub-id-type="doi">10.2147/CIA.S185048</pub-id>
                    <pub-id pub-id-type="pmcid">6298881</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-20">
                <label>20</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>George</surname>
                            <given-names>J</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Long</surname>
                            <given-names>S</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Vincent</surname>
                            <given-names>C</given-names>
                        </name>
</person-group>:
                    <article-title>How can we keep patients with dementia safe in our acute hospitals? A review of challenges and solutions.</article-title>
                    <source>

                        <italic toggle="yes">J R Soc Med.</italic>
</source>
                    <year>2013</year>;<volume>106</volume>(<issue>9</issue>):<fpage>355</fpage>&#x2013;<lpage>61</lpage>.
                    <pub-id pub-id-type="pmid">23759885</pub-id>
                    <pub-id pub-id-type="doi">10.1177/0141076813476497</pub-id>
                    <pub-id pub-id-type="pmcid">3758672</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-21">
                <label>21</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Lang</surname>
                            <given-names>L</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Clifford</surname>
                            <given-names>A</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Wei</surname>
                            <given-names>L</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Prevalence and determinants of undetected dementia in the community: a systematic literature review and a meta-analysis.</article-title>
                    <source>

                        <italic toggle="yes">BMJ Open.</italic>
</source>
                    <year>2017</year>;<volume>7</volume>(<issue>2</issue>):<fpage>e011146</fpage>.
                    <pub-id pub-id-type="pmid">28159845</pub-id>
                    <pub-id pub-id-type="doi">10.1136/bmjopen-2016-011146</pub-id>
                    <pub-id pub-id-type="pmcid">5293981</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-22">
                <label>22</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Jansen</surname>
                            <given-names>WJ</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Wilson</surname>
                            <given-names>RS</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Visser</surname>
                            <given-names>PJ</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Age and the association of dementia-related pathology with trajectories of cognitive decline.</article-title>
                    <source>

                        <italic toggle="yes">Neurobiol Aging.</italic>
</source>
                    <year>2018</year>;<volume>61</volume>:<fpage>138</fpage>&#x2013;<lpage>45</lpage>.
                    <pub-id pub-id-type="pmid">29078129</pub-id>
                    <pub-id pub-id-type="doi">10.1016/j.neurobiolaging.2017.08.029</pub-id>
                    <pub-id pub-id-type="pmcid">5721665</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-23">
                <label>23</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Singh&#x2010;Manoux</surname>
                            <given-names>A</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Dugravot</surname>
                            <given-names>A</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Shipley</surname>
                            <given-names>M</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Obesity trajectories and risk of dementia: 28 years of follow-up in the Whitehall II Study.</article-title>
                    <source>

                        <italic toggle="yes">Alzheimers Dement.</italic>
</source>
                    <year>2018</year>;<volume>14</volume>(<issue>2</issue>):<fpage>178</fpage>&#x2013;<lpage>86</lpage>.
                    <pub-id pub-id-type="pmid">28943197</pub-id>
                    <pub-id pub-id-type="doi">10.1016/j.jalz.2017.06.2637</pub-id>
                    <pub-id pub-id-type="pmcid">5805839</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-24">
                <label>24</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Taudorf</surname>
                            <given-names>L</given-names>
                        </name>

                        <name name-style="western">
                            <surname>N&#x00f8;rgaard</surname>
                            <given-names>A</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Islamoska</surname>
                            <given-names>S</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Declining incidence of dementia: A national registry-based study over 20 years.</article-title>
                    <source>

                        <italic toggle="yes">Alzheimers Dement.</italic>
</source>
                    <year>2019</year>;<volume>15</volume>(<issue>11</issue>):<fpage>1383</fpage>&#x2013;<lpage>91</lpage>.
                    <pub-id pub-id-type="pmid">31587994</pub-id>
                    <pub-id pub-id-type="doi">10.1016/j.jalz.2019.07.006</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-25">
                <label>25</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Casaletto</surname>
                            <given-names>KB</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Staffaroni</surname>
                            <given-names>AM</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Wolf</surname>
                            <given-names>A</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title>Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.</article-title>
                    <source>

                        <italic toggle="yes">Alzheimers Dement.</italic>
</source>
                    <year>2020</year>;<volume>16</volume>(<issue>1</issue>):<fpage>91</fpage>&#x2013;<lpage>105</lpage>.
                    <pub-id pub-id-type="pmid">31914227</pub-id>
                    <pub-id pub-id-type="doi">10.1002/alz.12001</pub-id>
                    <pub-id pub-id-type="pmcid">6953618</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-26">
                <label>26</label>
                <mixed-citation publication-type="journal">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Begcevic</surname>
                            <given-names>I</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Tsolaki</surname>
                            <given-names>M</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Brinc</surname>
                            <given-names>D</given-names>
                        </name>

                        <etal/>
</person-group>:
                    <article-title> Neuronal pentraxin receptor-1 is a new cerebrospinal fluid biomarker of Alzheimer&#x2019;s disease progression [version 1; peer review: 4 approved].</article-title>
                    <source>

                        <italic toggle="yes">F1000Res.</italic>
</source>
                    <year>2018</year>;<volume>7</volume>:<fpage>1012</fpage>.
                    <pub-id pub-id-type="pmid">30191060</pub-id>
                    <pub-id pub-id-type="doi">10.12688/f1000research.15095.1</pub-id>
                    <pub-id pub-id-type="pmcid">6081984</pub-id>
                </mixed-citation>
            </ref>
            <ref id="ref-27">
                <label>27</label>
                <mixed-citation publication-type="data">
                    <person-group person-group-type="author">

                        <name name-style="western">
                            <surname>Hashim</surname>
                            <given-names>MJ</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Khan</surname>
                            <given-names>M</given-names>
                        </name>

                        <name name-style="western">
                            <surname>Javaid</surname>
                            <given-names>SF</given-names>
                        </name>
</person-group>:
                    <article-title>Global epidemiology of Alzheimer&#x2019;s disease and related dementias</article-title>.<year>2021</year>.
                    <ext-link ext-link-type="uri" xlink:href="http://www.doi.org/10.17605/OSF.IO/DYBTM">http://www.doi.org/10.17605/OSF.IO/DYBTM</ext-link>
                </mixed-citation>
            </ref>
        </ref-list>
    </back>
    <sub-article article-type="reviewer-report" id="report100620">
        <front-stub>
            <article-id pub-id-type="doi">10.5256/f1000research.53871.r100620</article-id>
            <title-group>
                <article-title>Reviewer response for version 1</article-title>
            </title-group>
            <contrib-group>
                <contrib contrib-type="author">
                    <name>
                        <surname>Suehiro</surname>
                        <given-names>Takashi</given-names>
                    </name>
                    <xref ref-type="aff" rid="r100620a1">1</xref>
                    <role>Referee</role>
                </contrib>
                <aff id="r100620a1">
                    <label>1</label>Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan</aff>
            </contrib-group>
            <author-notes>
                <fn fn-type="conflict">
                    <p>
                        <bold>Competing interests: </bold>No competing interests were disclosed.</p>
                </fn>
            </author-notes>
            <pub-date pub-type="epub">
                <day>7</day>
                <month>1</month>
                <year>2022</year>
            </pub-date>
            <permissions>
                <copyright-statement>Copyright: &#x00a9; 2022 Suehiro T</copyright-statement>
                <copyright-year>2022</copyright-year>
                <license xlink:href="https://creativecommons.org/licenses/by/4.0/">
                    <license-p>This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
                </license>
            </permissions>
            <related-article ext-link-type="doi" id="relatedArticleReport100620" related-article-type="peer-reviewed-article" xlink:href="10.12688/f1000research.50786.1"/>
            <custom-meta-group>
                <custom-meta>
                    <meta-name>recommendation</meta-name>
                    <meta-value>approve-with-reservations</meta-value>
                </custom-meta>
            </custom-meta-group>
        </front-stub>
        <body>
            <p>In this paper, the authors reported the global and regional burden of Alzheimer&#x2019;s disease (AD) and related dementias using the data extracted from the Global Burden of Disease (GBD) 2019 dataset. The increasing number of people with dementia, regional differences in the prevalence, and the stability of age-standardized rates were described as the key findings.</p>
            <p> </p>
            <p> While the results of this paper were considered very important from the viewpoint of the future healthcare system, there are several issues and concerns. 
                <list list-type="order">
                    <list-item>
                        <p>Several previous articles have already reported the epidemiology of AD and related dementias. In particular, one of the reports used the GBD 2016 dataset
                            <sup>
                                <xref ref-type="bibr" rid="rep-ref-100620-1">1</xref>
                            </sup>.&#x00a0;The authors may want to consider revising the title to specify that this study used the GBD 2019 data.</p>
                    </list-item>
                    <list-item>
                        <p>In the introduction section, the authors need to refer to the previous articles about the epidemiology of dementia and put more emphasis on the added values of this study. The authors considered that the assessment of yearly trends with the age-standardized rates was the unique approach, and the reviewer agrees with the idea. To clarify the strength of the study, the authors should describe the reasons why the control of the population-aging effect is important.</p>
                    </list-item>
                    <list-item>
                        <p>While the authors referred to the death rates relating to dementia, the age-standardized death rates were not assessed. Because the death rates can be influenced by the population aging as well as the prevalence rate, the age-standardized death rates would also be assessed.</p>
                    </list-item>
                    <list-item>
                        <p>Because the age-standardized prevalence ratio is one of the important findings, the method of age standardization should be explained in the methods section.</p>
                    </list-item>
                    <list-item>
                        <p>Although the estimated mortality rates in the point of 2040 were described in the results section, those estimations are not the main outcome of this article and could be addressed in the discussion.</p>
                    </list-item>
                    <list-item>
                        <p>In Figure 3B, the legend needs an explanation of the &#x201c;age group&#x201d;.</p>
                    </list-item>
                    <list-item>
                        <p>There was no discussion about the statistical comparison of the prevalence rates across the gender. The authors should address this point in the discussion section.</p>
                    </list-item>
                    <list-item>
                        <p>While the suggestion that age-standardized prevalence might be stable over the last thirty years was interesting, the statistical assessment was not conducted about this part and it was purely speculative. The reviewer thinks the statistical comparison of age-standardized prevalence between 1990 and 2019 should be included.</p>
                    </list-item>
                    <list-item>
                        <p>The sentence in the discussion section, &#x201c;
                            <italic>Potential risk factors such as diabetes, hypertension, smoking, sedentary lifestyle and obesity are rising globally, and yet are not reflected in age-standardized rates of dementia</italic>&#x201d; was interesting. It would be more convincing if the concrete data or references about the increase in the incidence rate of the risk factors are added.</p>
                    </list-item>
                </list>
            </p>
            <p>Is the work clearly and accurately presented and does it cite the current literature?</p>
            <p>Partly</p>
            <p>If applicable, is the statistical analysis and its interpretation appropriate?</p>
            <p>Yes</p>
            <p>Are all the source data underlying the results available to ensure full reproducibility?</p>
            <p>Yes</p>
            <p>Is the study design appropriate and is the work technically sound?</p>
            <p>Yes</p>
            <p>Are the conclusions drawn adequately supported by the results?</p>
            <p>Yes</p>
            <p>Are sufficient details of methods and analysis provided to allow replication by others?</p>
            <p>Partly</p>
            <p>Reviewer Expertise:</p>
            <p>Psychogeriatrics, neurology</p>
            <p>I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.</p>
        </body>
        <back>
            <ref-list>
                <title>References</title>
                <ref id="rep-ref-100620-1">
                    <label>1</label>
                    <mixed-citation publication-type="journal">
                        <person-group person-group-type="author"/>:
                        <article-title>Global, regional, and national burden of Alzheimer's disease and other dementias, 1990&#x2013;2016: a systematic analysis for the Global Burden of Disease Study 2016</article-title>.
                        <source>
                            <italic>The Lancet Neurology</italic>
                        </source>.<year>2019</year>;<volume>18</volume>(<issue>1</issue>) :
                        <elocation-id>10.1016/S1474-4422(18)30403-4</elocation-id>
                        <fpage>88</fpage>-<lpage>106</lpage>
                        <pub-id pub-id-type="doi">10.1016/S1474-4422(18)30403-4</pub-id>
                    </mixed-citation>
                </ref>
            </ref-list>
        </back>
    </sub-article>
</article>
