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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Nutr.</journal-id>
<journal-title>Frontiers in Nutrition</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Nutr.</abbrev-journal-title>
<issn pub-type="epub">2296-861X</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.3389/fnut.2023.1104255</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Nutrition</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Meta-analysis of the association between dietary inflammatory index and cognitive health</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author"><name><surname>Ding</surname> <given-names>Tianze</given-names></name>
<xref rid="aff1" ref-type="aff"><sup>1</sup></xref>
<xref rid="aff2" ref-type="aff"><sup>2</sup></xref>
<xref rid="fn0001" ref-type="author-notes"><sup>&#x2020;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/2108113/overview"/>
</contrib>
<contrib contrib-type="author"><name><surname>Aimaiti</surname> <given-names>Maimaitiyusupu</given-names></name>
<xref rid="aff1" ref-type="aff"><sup>1</sup></xref>
<xref rid="aff2" ref-type="aff"><sup>2</sup></xref>
<xref rid="fn0001" ref-type="author-notes"><sup>&#x2020;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/2184225/overview"/>
</contrib>
<contrib contrib-type="author"><name><surname>Cui</surname> <given-names>Shishuang</given-names></name>
<xref rid="aff3" ref-type="aff"><sup>3</sup></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Shen</surname> <given-names>Junhao</given-names></name>
<xref rid="aff2" ref-type="aff"><sup>2</sup></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lu</surname> <given-names>Mengjie</given-names></name>
<xref rid="aff4" ref-type="aff"><sup>4</sup></xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Wang</surname> <given-names>Lei</given-names></name>
<xref rid="aff1" ref-type="aff"><sup>1</sup></xref>
<xref rid="c001" ref-type="corresp"><sup>&#x002A;</sup></xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Bian</surname> <given-names>Dongsheng</given-names></name>
<xref rid="aff4" ref-type="aff"><sup>4</sup></xref>
<xref rid="aff5" ref-type="aff"><sup>5</sup></xref>
<xref rid="c001" ref-type="corresp"><sup>&#x002A;</sup></xref>
<uri xlink:href="https://loop.frontiersin.org/people/2109419/overview"/>
</contrib>
</contrib-group>
<aff id="aff1"><sup>1</sup><institution>Department of Geriatrics, Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine</institution>, <addr-line>Shanghai</addr-line>, <country>China</country></aff>
<aff id="aff2"><sup>2</sup><institution>Department of Nutrition, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine</institution>, <addr-line>Shanghai</addr-line>, <country>China</country></aff>
<aff id="aff3"><sup>3</sup><institution>Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine</institution>, <addr-line>Shanghai</addr-line>, <country>China</country></aff>
<aff id="aff4"><sup>4</sup><institution>School of Public Health, Shanghai Jiao Tong University School of Medicine</institution>, <addr-line>Shanghai</addr-line>, <country>China</country></aff>
<aff id="aff5"><sup>5</sup><institution>Department of Clinical Nutrition, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine</institution>, <addr-line>Shanghai</addr-line>, <country>China</country></aff>
<author-notes>
<fn id="fn0002" fn-type="edited-by">
<p>Edited by: Usune Etxeberria, Basque Culinary Center, Spain</p>
</fn>
<fn id="fn0003" fn-type="edited-by">
<p>Reviewed by: Kioko Rubi Guzman-Ramos, Autonomous Metropolitan University, Lerma, Mexico; Sokratis Charisis, National and Kapodistrian University of Athens, Greece</p>
</fn>
<corresp id="c001">&#x002A;Correspondence: Dongsheng Bian, <email>bds04159@rjh.com.cn</email>; Lei Wang, <email>wl10779@rjh.com.cn</email></corresp>
<fn id="fn0001" fn-type="equal">
<p><sup>&#x2020;</sup>These authors have contributed equally to this work</p>
</fn>
<fn id="fn0004" fn-type="other">
<p>This article was submitted to Nutrition, Psychology and Brain Health, a section of the journal Frontiers in Nutrition</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>04</day>
<month>04</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="collection">
<year>2023</year>
</pub-date>
<volume>10</volume>
<elocation-id>1104255</elocation-id>
<history>
<date date-type="received">
<day>21</day>
<month>11</month>
<year>2022</year>
</date>
<date date-type="accepted">
<day>20</day>
<month>03</month>
<year>2023</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#x00A9; 2023 Ding, Aimaiti, Cui, Shen, Lu, Wang and Bian.</copyright-statement>
<copyright-year>2023</copyright-year>
<copyright-holder>Ding, Aimaiti, Cui, Shen, Lu, Wang and Bian</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>Some studies have shown that a pro-inflammatory diet may be associated with cognitive function, but their conclusions have varied considerably. We here present a meta-analysis of the current published literature on DII score and its association with cognitive health.</p>
</sec>
<sec>
<title>Methods</title>
<p>In this meta-analysis, the PubMed, Embase, Web of Science, and Cochrane databases were searched in September 2022. The reported indexes, specifically OR, RR, and &#x03B2;, were extracted and analyzed using R version 3.1.0.</p>
</sec>
<sec>
<title>Results</title>
<p>A total of 636 studies in databases were identified, and 12 were included in the meta-analysis. Higher DII was associated with an increased risk of AD and MCI (OR&#x2009;=&#x2009;1.34; 95% CI&#x2009;=&#x2009;1.21&#x2013;1.49). Meanwhile, it may also cause global function impairment (categorical: OR&#x2009;=&#x2009;1.63; 95% CI&#x2009;=&#x2009;1.36&#x2013;1.96) and verbal fluency impairment (continuous: OR&#x2009;=&#x2009;0.18; 95% IC&#x2009;=&#x2009;0.08&#x2013;0.42). But there was no significant association between DII and executive function (categorical: OR&#x2009;=&#x2009;1.12; 95% IC&#x2009;=&#x2009;0.84&#x2013;1.49; continuous: OR&#x2009;=&#x2009;0.48; 95% IC&#x2009;=&#x2009;0.19&#x2013;1.21) or episodic memory (continuous: OR&#x2009;=&#x2009;0.56; 95% IC&#x2009;=&#x2009;0.30&#x2013;1.03).</p>
</sec>
<sec>
<title>Conclusion</title>
<p>A pro-inflammatory diet is related to AD, MCI, and the functions of some cognitive domains (specifically global function and verbal fluency). However, the current evidence on the role of diet-induced inflammation in different cognitive domains should be supported by further studies in the future.</p>
</sec>
</abstract>
<kwd-group>
<kwd>cognitive health</kwd>
<kwd>mild cognitive impairment</kwd>
<kwd>dietary inflammatory index</kwd>
<kwd>cognitive impairment</kwd>
<kwd>pro-inflammatory diet</kwd>
</kwd-group>
<contract-num rid="cn1">YG2022QN011</contract-num>
<contract-num rid="cn1">2020YJZX0139</contract-num>
<contract-sponsor id="cn1">Shanghai Jiao Tong University<named-content content-type="fundref-id">10.13039/501100004921</named-content></contract-sponsor>
<counts>
<fig-count count="3"/>
<table-count count="2"/>
<equation-count count="2"/>
<ref-count count="41"/>
<page-count count="10"/>
<word-count count="5850"/>
</counts>
</article-meta>
</front>
<body>
<sec id="sec5" sec-type="intro">
<title>Introduction</title>
<p>The aging of today&#x2019;s population has become a critical challenge worldwide. The proportion of the elderly population has been gradually increasing. By 2030, the proportion of people aged 60 and over may increase from 1 billion to 1.4 billion. By 2050, the world&#x2019;s population aged 60 and older may double (2.1 billion) (<xref ref-type="bibr" rid="ref1">1</xref>). Many issues come with this demographic shift, including increased rates of cognitive decline and dementia. According to WHO, there are 55 million people with dementia at present around the world, and nearly 10 million new cases annually (<xref ref-type="bibr" rid="ref2">2</xref>). The most common form of dementia is Alzheimer&#x2019;s disease, which may cause 60&#x2013;80% of cases (<xref ref-type="bibr" rid="ref3">3</xref>). Alzheimer&#x2019;s disease and other types of dementia are reported to be the seventh leading cause of death among the elderly and some of the most common causes of disability worldwide (<xref ref-type="bibr" rid="ref2">2</xref>). Mild cognitive impairment (MCI) is considered a precursor stage of dementia. One study found that 32% of patients with mild cognitive impairment progressed to dementia within 5&#x2009;years (<xref ref-type="bibr" rid="ref4">4</xref>), so that effective measures to prevent such cognitive impairment are essential.</p>
<p>Inflammation has been confirmed to be one possible mechanism underlying cognitive impairment (AD, dementia, and MCI) in recent studies (<xref ref-type="bibr" rid="ref5">5</xref>, <xref ref-type="bibr" rid="ref6">6</xref>). Whether it is dietary patterns, dietary composition, or compounds in the diet, diet seems to be related to the level of inflammation in the body (<xref ref-type="bibr" rid="ref7">7</xref>, <xref ref-type="bibr" rid="ref8">8</xref>). From this perspective, diet might affect cognition by modulating inflammation in the body. Some studies have investigated the association between diet and cognitive health, and their findings suggest that different diets increase (<xref ref-type="bibr" rid="ref8">8</xref>) or decrease (<xref ref-type="bibr" rid="ref9">9</xref>) the risk of cognitive impairment. Establishing a means of quantitatively measuring the inflammatory potential of diet would allow observation of a direct and dynamic link between the ability of diet to modulate levels of inflammation <italic>in vivo</italic> and cognitive health. This would make it possible to prevent or delay cognitive impairment with specific modifications to dietary factors within a flexible range.</p>
<p>In order to determine the inflammatory potential of a given diet, Shivappa et al. proposed a dietary inflammatory index (DII), which includes 36 anti-inflammatory parameters for fiber, alcohol, monounsaturated fatty acids, polyunsaturated fatty acids, omega 3, omega 6, niacin, thiamin, riboflavin, vitamin B6, B12, zinc, magnesium, selenium, vitamin A, vitamin C, vitamin D, vitamin E, folic acid, &#x03B2; carotene, anthocyanidins, flavan-3-ols, flavonols, flavanones, flavones, isoflavones, garlic, ginger, onions, thyme, oregano, saffron, turmeric, rosemary, eugenol, caffeine and tea, and 9 pro-inflammatory parameters for energy, carbohydrates, proteins, total fat, trans fat, cholesterol, vitamin B12, saturated fatty acids, and iron, for a total of 45 parameters. Individuals&#x2019; diets were classified along the DII according to inflammatory potential on a continuum from maximum pro-inflammatory to maximum anti-inflammatory. The higher the DII score, the greater the inflammatory potential of the given diet (<xref ref-type="bibr" rid="ref10">10</xref>).</p>
<p>Existing epidemiological studies have explored the association between DII and cognitive impairment (MCI, dementia, and AD) and cognitive function (global cognition, episodic memory, executive function, verbal fluency, tested using mini-mental state examination (MMSE), or other common cognitive function tests such as the digit span-backward test or MoCA-score). All studies on the relationship between DII and the incidence of MCI or AD showed a positive relationship (<xref ref-type="bibr" rid="ref11 ref12 ref13 ref14 ref15">11&#x2013;15</xref>). Some studies showed a negative relationship between DII and global cognition and verbal fluency (<xref ref-type="bibr" rid="ref12">12</xref>, <xref ref-type="bibr" rid="ref14">14</xref>, <xref ref-type="bibr" rid="ref16 ref17 ref18 ref19 ref20">16&#x2013;20</xref>). Other studies searched for a relationship between DII and episodic memory and executive function and found none (<xref ref-type="bibr" rid="ref19 ref20 ref21">19&#x2013;21</xref>). Some systematic reviews have focused on the effects of DII on mental health (<xref ref-type="bibr" rid="ref22">22</xref>, <xref ref-type="bibr" rid="ref23">23</xref>) and the influences of dietary factors on cognitive health (<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref24">24</xref>), but, as far as we know, no systematic review has investigated the effects of DII on cognitive disorders or cognitive function. Given this, we performed a meta-analysis to comprehensively examine the association between DII and cognitive health including cognitive disorders (impairment) and cognitive function.</p>
</sec>
<sec id="sec6" sec-type="methods">
<title>Methods</title>
<p>This meta-analysis was performed in accordance with the PRISMA statement to ensure comprehensive and transparent reporting of methods and results.</p>
<sec id="sec7">
<title>Search strategy</title>
<p>The literature databases PubMed, EMBASE, Web of Science, and Cochrane were searched in September 2022 and the search terms used were &#x201C;mild cognitive impairment&#x201D; OR dementia OR &#x201C;Alzheimer disease&#x201D; OR &#x201C;cognitive function&#x201D; OR &#x201C;cognitive decline&#x201D; AND &#x201C;dietary inflammatory index&#x201D; OR &#x201C;anti-inflammatory diet&#x201D; OR &#x201C;inflammatory diet.&#x201D; Two authors independently screened each title and abstract and then read the full text to assess the article for compliance with the inclusion and exclusion criteria which will be mentioned later. Disagreements were resolved through consensus.</p>
</sec>
<sec id="sec8">
<title>Selection criteria</title>
<p>Studies included in this meta-analysis met all the following inclusion criteria: (1) studies that focused on humans and were published in English; (2) investigated the association between the DII/E-DII and cognitive function (global cognition, episodic memory, executive function, verbal fluency) or the risk of cognitive disorders (MCI, dementia, AD); (3) the study design was case&#x2013;control, cohort or cross-sectional study. (4) If multiple studies were published using the same cohort, only the most recent study was selected. If more than one article based on the same cohort was from a different population or reported different results, both were included. Studies were excluded if they were systematic reviews or narrative reviews, reports, letters, <italic>in vitro</italic> studies, animal studies or duplicate studies.</p>
</sec>
<sec id="sec9">
<title>Data extraction</title>
<p>Two authors (TD and MA) screened the papers and abstracted the data independently, and conflicts were resolved by a third reviewer (DB) who was blinded to the authors and institutions of the studies undergoing review. The following information was extracted from each study: name of the first author, year of publication, country, study design, sample size, study period, dietary assessment method, number of food parameters, cognitive assessment methods, cognitive domains, results, and covariates used for adjustment.</p>
</sec>
<sec id="sec10">
<title>Statistical analysis</title>
<p>In this meta-analysis, all the reported effects, odds ratios (ORs), hazard ratios (HRs), risk ratios (RRs) and &#x03B2; with 95% confidence intervals and effect size were extracted. The heterogeneity test was assessed using Cochrane&#x2019;s <italic>Q</italic> test and the <italic>I</italic><sup>2</sup>statistic. Significance was defined as <italic>p</italic> &#x003C;&#x2009;0.05. The <italic>I</italic><sup>2</sup> statistic represents the amount of total variation that could be attributed to heterogeneity. <italic>I</italic><sup>2</sup> values &#x2264;25%, &#x2264;50%, &#x2264;75%, and &#x003E;75% indicated no, little, moderate, and high heterogeneity, respectively. For lower heterogeneity (<italic>I</italic><sup>2</sup> &#x2264;&#x2009;50%), the fixed effect models were used, and random effect models were used for higher heterogeneity (<italic>I</italic><sup>2</sup> &#x003E;&#x2009;50%). A sensitivity analysis had been conducted by excluding one study at a time to identify potential sources of heterogeneity when the result had a high heterogeneity (<italic>I</italic><sup>2</sup> &#x003E;&#x2009;50%). The meta-analysis was performed using the &#x201C;<italic>meta</italic>&#x201D; package in R. Statistical analyses were performed using R version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria).</p>
</sec>
</sec>
<sec id="sec11" sec-type="results">
<title>Results</title>
<sec id="sec12">
<title>Literature selection</title>
<p>A total of 636 studies were identified in the PubMed, Embase, Web of Science, and Cochrane databases. Of these, 605 studies were excluded after reviewing their titles and abstracts to assess relevance and eligibility. Then 16 articles were excluded because they were duplicates. After careful perusal of the full texts of these articles, 3 were excluded because of unavailable or unclear outcomes and inappropriate design. Finally, 12 studies were included in the meta-analysis (<xref rid="fig1" ref-type="fig">Figure 1</xref>).</p>
<fig position="float" id="fig1"><label>Figure 1</label>
<caption>
<p>Study identification and selection.</p>
</caption>
<graphic xlink:href="fnut-10-1104255-g001.tif"/>
</fig>
</sec>
<sec id="sec13">
<title>Study characteristics</title>
<p>The characteristics of the included studies are summarized in <xref rid="tab1" ref-type="table">Table 1</xref>. Of these studies (<xref ref-type="bibr" rid="ref11 ref12 ref13 ref14 ref15 ref16 ref17 ref18 ref19 ref20 ref21">11&#x2013;21</xref>, <xref ref-type="bibr" rid="ref25">25</xref>) were published between 2017 and 2022, and their sample sizes varied from 222 to 7,085 participants with a total number of 24,823 individuals from seven countries on four continents. Four studies were carried out in the United States, three studies (<xref ref-type="bibr" rid="ref12 ref13 ref14">12&#x2013;14</xref>) in China, and one each in France (<xref ref-type="bibr" rid="ref20">20</xref>), Greece (<xref ref-type="bibr" rid="ref15">15</xref>), Poland (<xref ref-type="bibr" rid="ref17">17</xref>), Australia (<xref ref-type="bibr" rid="ref25">25</xref>), and South Korea (<xref ref-type="bibr" rid="ref16">16</xref>). The average age of participants varied from 61.00 to 74.04. In terms of dietary assessment, six studies (<xref ref-type="bibr" rid="ref11 ref12 ref13 ref14 ref15">11&#x2013;15</xref>, <xref ref-type="bibr" rid="ref25">25</xref>) used Food Frequency Questionnaire (FFQ), five studies (<xref ref-type="bibr" rid="ref16">16</xref>, <xref ref-type="bibr" rid="ref18 ref19 ref20 ref21">18&#x2013;21</xref>) used 24-h recall, and only one study (<xref ref-type="bibr" rid="ref17">17</xref>) used three-day food diaries. Regarding the number of food parameters used to calculate DII score, two studies (<xref ref-type="bibr" rid="ref15">15</xref>, <xref ref-type="bibr" rid="ref17">17</xref>) used all 45 parameters; three studies (<xref ref-type="bibr" rid="ref18">18</xref>, <xref ref-type="bibr" rid="ref21">21</xref>, <xref ref-type="bibr" rid="ref25">25</xref>) used the E-DII score, which contains 27 parameters; and other studies varied between 22 and 35 parameters. More detailed summaries of each article are included in <xref rid="tab2" ref-type="table">Table 2</xref>, which provides information regarding assessment instruments for cognitive function and results for each study. Cognitive function was assessed using a large number of tests to quantify the cognitive domains of global cognition, episodic memory, executive function, and verbal fluency. There were differences among individual studies. For example, studies used different assessment instruments, including MoCA, MMSE, Petersen&#x2019;s Criteria, CERAD, DSM-IV-TR criteria, DSST, Animal Fluency Test, and RI-48.</p>
<table-wrap position="float" id="tab1"><label>Table 1</label>
<caption>
<p>Main characteristics of the included studies.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th/>
<th align="left" valign="top">Author (Ref.)</th>
<th align="left" valign="top">Study location</th>
<th align="left" valign="top">Study design</th>
<th align="center" valign="top">Study period</th>
<th align="center" valign="top">Study instrument</th>
<th align="center" valign="top">Number of food parameters</th>
<th align="center" valign="top">Sample size</th>
<th align="center" valign="top">Average age</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="middle">1</td>
<td align="left" valign="middle">Wang et al. (<xref ref-type="bibr" rid="ref13">13</xref>)</td>
<td align="left" valign="middle">China</td>
<td align="left" valign="middle">Cross-sectional</td>
<td align="center" valign="middle">2020&#x2009;~&#x2009;2021</td>
<td align="center" valign="middle">33-item FFQ</td>
<td align="center" valign="middle">23</td>
<td align="center" valign="middle">1,050</td>
<td align="char" valign="middle" char=".">70.00</td>
</tr>
<tr>
<td align="left" valign="middle">2</td>
<td align="left" valign="middle">Zhang et al. (<xref ref-type="bibr" rid="ref14">14</xref>)</td>
<td align="left" valign="middle">China</td>
<td align="left" valign="middle">Prospective cohort</td>
<td align="center" valign="middle">2014&#x2009;~&#x2009;2018</td>
<td align="center" valign="middle">FFQ</td>
<td align="center" valign="middle">24</td>
<td align="center" valign="middle">2,239</td>
<td align="char" valign="middle" char=".">58.80</td>
</tr>
<tr>
<td align="left" valign="middle">3</td>
<td align="left" valign="middle">Hayden et al. (<xref ref-type="bibr" rid="ref11">11</xref>)</td>
<td align="left" valign="middle">America</td>
<td align="left" valign="middle">Prospective cohort</td>
<td align="center" valign="middle">1996&#x2009;~&#x2009;2008</td>
<td align="center" valign="middle">122-item FFQ</td>
<td align="center" valign="middle">32</td>
<td align="center" valign="middle">7,085</td>
<td align="char" valign="middle" char=".">71.00</td>
</tr>
<tr>
<td align="left" valign="middle">4</td>
<td align="left" valign="middle">Frith et al. (<xref ref-type="bibr" rid="ref19">19</xref>)</td>
<td align="left" valign="middle">America</td>
<td align="left" valign="middle">Cross-sectional</td>
<td align="center" valign="middle">2011&#x2009;~&#x2009;2014</td>
<td align="center" valign="middle">24-h recall</td>
<td align="center" valign="middle">26</td>
<td align="center" valign="middle">1723</td>
<td align="char" valign="middle" char=".">68.40</td>
</tr>
<tr>
<td align="left" valign="middle">5</td>
<td align="left" valign="middle">Kesse-Guyot et al. (<xref ref-type="bibr" rid="ref20">20</xref>)</td>
<td align="left" valign="middle">France</td>
<td align="left" valign="middle">Prospective cohort</td>
<td align="center" valign="middle">1994&#x2009;~&#x2009;2009</td>
<td align="center" valign="middle">24-h recall</td>
<td align="center" valign="middle">35</td>
<td align="center" valign="middle">3,080</td>
<td align="char" valign="middle" char=".">65.40</td>
</tr>
<tr>
<td align="left" valign="middle">6</td>
<td align="left" valign="middle">Sun et al. (<xref ref-type="bibr" rid="ref18">18</xref>)</td>
<td align="left" valign="middle">America</td>
<td align="left" valign="middle">Cross-sectional</td>
<td align="center" valign="middle">2011&#x2009;~&#x2009;2014</td>
<td align="center" valign="middle">24-h recall</td>
<td align="center" valign="middle">27</td>
<td align="center" valign="middle">1,198</td>
<td align="char" valign="middle" char=".">69.30</td>
</tr>
<tr>
<td align="left" valign="middle">7</td>
<td align="left" valign="middle">Charisis et al. (<xref ref-type="bibr" rid="ref15">15</xref>)</td>
<td align="left" valign="middle">Greece</td>
<td align="left" valign="middle">Prospective cohort</td>
<td align="center" valign="middle">2011&#x2009;~&#x2009;2022</td>
<td align="center" valign="middle">FFQ</td>
<td align="center" valign="middle">45</td>
<td align="center" valign="middle">1,059</td>
<td align="char" valign="middle" char=".">73.10</td>
</tr>
<tr>
<td align="left" valign="middle">8</td>
<td align="left" valign="middle">Shin et al. (<xref ref-type="bibr" rid="ref18">18</xref>)</td>
<td align="left" valign="middle">Korean</td>
<td align="left" valign="middle">Cross-sectional</td>
<td align="center" valign="middle">2012</td>
<td align="center" valign="middle">24-h recall</td>
<td align="center" valign="middle">20</td>
<td align="center" valign="middle">239</td>
<td align="char" valign="middle" char=".">74.04</td>
</tr>
<tr>
<td align="left" valign="middle">9</td>
<td align="left" valign="middle">Song et al. (<xref ref-type="bibr" rid="ref21">21</xref>)</td>
<td align="left" valign="middle">America</td>
<td align="left" valign="middle">Cross-sectional</td>
<td align="center" valign="middle">2011&#x2009;~&#x2009;2014</td>
<td align="center" valign="middle">24-h recall</td>
<td align="center" valign="middle">27</td>
<td align="center" valign="middle">2,901</td>
<td align="char" valign="middle" char=".">69.61</td>
</tr>
<tr>
<td align="left" valign="middle">10</td>
<td align="left" valign="middle">Liu et al. (<xref ref-type="bibr" rid="ref12">12</xref>)</td>
<td align="left" valign="middle">China</td>
<td align="left" valign="middle">Cross-sectional</td>
<td align="center" valign="middle">2018&#x2009;~&#x2009;2019</td>
<td align="center" valign="middle">30-item FFQ</td>
<td align="center" valign="middle">22</td>
<td align="center" valign="middle">3,386</td>
<td align="char" valign="middle" char=".">67.61</td>
</tr>
<tr>
<td align="left" valign="middle">11</td>
<td align="left" valign="middle">Skoczek-Rubi&#x0144;ska et al. (<xref ref-type="bibr" rid="ref17">17</xref>)</td>
<td align="left" valign="middle">Poland</td>
<td align="left" valign="middle">Cross-sectional</td>
<td align="center" valign="middle">2014&#x2009;~&#x2009;2020</td>
<td align="center" valign="middle">Three-day food diary</td>
<td align="center" valign="middle">45</td>
<td align="center" valign="middle">222</td>
<td align="char" valign="middle" char=".">61.00</td>
</tr>
<tr>
<td align="left" valign="middle">12</td>
<td align="left" valign="middle">Zabetian-Targhi et al. (<xref ref-type="bibr" rid="ref25">25</xref>)</td>
<td align="left" valign="middle">Australia</td>
<td align="left" valign="middle">Cross-sectional</td>
<td align="center" valign="middle">2005&#x2009;~&#x2009;2011</td>
<td align="center" valign="middle">80-item FFQ</td>
<td align="center" valign="middle">27</td>
<td align="center" valign="middle">641</td>
<td align="char" valign="middle" char=".">67.70</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap position="float" id="tab2"><label>Table 2</label>
<caption>
<p>Methods and results of the included studies (by cognitive domain).</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" valign="top">Author (Ref.)</th>
<th align="left" valign="top">Country</th>
<th align="left" valign="top">Method</th>
<th align="center" valign="top"><italic>N</italic></th>
<th align="center" valign="top">Index</th>
<th align="center" valign="top">95%CI</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" colspan="6">
<bold>MCI</bold>
</td>
</tr>
<tr>
<td align="left" valign="top">Wang et al. (<xref ref-type="bibr" rid="ref13">13</xref>)</td>
<td align="left" valign="top">China</td>
<td align="left" valign="top">MoCA</td>
<td align="center" valign="top">1,050</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;1.23</td>
<td align="char" valign="top" char=".">1.03, 1.47</td>
</tr>
<tr>
<td align="left" valign="top">Hayden et al. (<xref ref-type="bibr" rid="ref11">11</xref>)</td>
<td align="left" valign="top">America</td>
<td align="left" valign="top">MMSE</td>
<td align="center" valign="top">7,085</td>
<td align="char" valign="top" char=".">HR&#x2009;=&#x2009;1.27</td>
<td align="char" valign="top" char=".">1.06, 1.25</td>
</tr>
<tr>
<td align="left" valign="top">Liu et al. (<xref ref-type="bibr" rid="ref12">12</xref>)</td>
<td align="left" valign="top">China</td>
<td align="left" valign="top">Petersen&#x2019;s criteria (modified)</td>
<td align="center" valign="top">3,386</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;1.595</td>
<td align="char" valign="top" char=".">1.189, 2.140</td>
</tr>
<tr>
<td align="left" valign="top">Zhang et al. (<xref ref-type="bibr" rid="ref14">14</xref>)</td>
<td align="left" valign="top">China</td>
<td align="left" valign="top">MMSE and MoCA</td>
<td align="center" valign="top">2,239</td>
<td align="char" valign="top" char=".">RR&#x2009;=&#x2009;1.46</td>
<td align="char" valign="top" char=".">1.14, 1.87</td>
</tr>
<tr>
<td align="left" valign="top" colspan="6">
<bold>AD</bold>
</td>
</tr>
<tr>
<td align="left" valign="top">Charisis et al. (<xref ref-type="bibr" rid="ref15">15</xref>)</td>
<td align="left" valign="top">Greece</td>
<td align="left" valign="top">DSM-IV-TR criteria</td>
<td align="center" valign="top">1,059</td>
<td align="char" valign="top" char=".">HR&#x2009;=&#x2009;3.01</td>
<td align="char" valign="top" char=".">1.24, 7.26</td>
</tr>
<tr>
<td align="left" valign="top" colspan="6">
<bold>Global cognitive</bold>
</td>
</tr>
<tr>
<td align="left" valign="top">Skoczek-Rubi&#x0144;ska et al. (<xref ref-type="bibr" rid="ref17">17</xref>)</td>
<td align="left" valign="top">Poland</td>
<td align="left" valign="top">MMSE</td>
<td align="center" valign="top">222</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;11.1</td>
<td align="char" valign="top" char=".">2.22, 55.56</td>
</tr>
<tr>
<td align="left" valign="top">Shin et al. (<xref ref-type="bibr" rid="ref18">18</xref>)</td>
<td align="left" valign="top">Korean</td>
<td align="left" valign="top">MMSE</td>
<td align="center" valign="top">239</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;6.32</td>
<td align="char" valign="top" char=".">1.18, 33.78</td>
</tr>
<tr>
<td align="left" valign="top">Liu et al. (<xref ref-type="bibr" rid="ref12">12</xref>)</td>
<td align="left" valign="top">China</td>
<td align="left" valign="top">Petersen&#x2019;s criteria (modified)</td>
<td align="center" valign="top">3,386</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;1.595</td>
<td align="char" valign="top" char=".">1.189, 2.140</td>
</tr>
<tr>
<td align="left" valign="top">Zhang et al. (<xref ref-type="bibr" rid="ref14">14</xref>)</td>
<td align="left" valign="top">China</td>
<td align="left" valign="top">MMSE &#x0026; MoCA</td>
<td align="center" valign="top">2,239</td>
<td align="char" valign="top" char=".">RR&#x2009;=&#x2009;1.46</td>
<td align="char" valign="top" char=".">1.14, 1.87</td>
</tr>
<tr>
<td align="left" valign="top">Sun et al. (<xref ref-type="bibr" rid="ref18">18</xref>)</td>
<td align="left" valign="top">America</td>
<td align="left" valign="top">CERAD-WL and AF and DSST</td>
<td align="center" valign="top">1,198</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;1.479</td>
<td align="char" valign="top" char=".">1.009, 2.168</td>
</tr>
<tr>
<td align="left" valign="top">Wang et al. (<xref ref-type="bibr" rid="ref13">13</xref>)</td>
<td align="left" valign="top">China</td>
<td align="left" valign="top">MoCA</td>
<td align="center" valign="top">1,050</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;0.363</td>
<td align="char" valign="top" char=".">&#x2212;0.625, &#x2212;0.101</td>
</tr>
<tr>
<td align="left" valign="top">Kesse-Guyot et al. (<xref ref-type="bibr" rid="ref20">20</xref>)</td>
<td align="left" valign="top">France</td>
<td align="left" valign="top">Composite cognitive score</td>
<td align="center" valign="top">3,080</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;1.76</td>
<td align="char" valign="top" char=".">&#x2212;2.81, &#x2212;0.72</td>
</tr>
<tr>
<td align="left" valign="top">Zabetian-Targhi et al. (<xref ref-type="bibr" rid="ref25">25</xref>)</td>
<td align="left" valign="top">Australia</td>
<td align="left" valign="top">A battery of neuropsychological tests</td>
<td align="center" valign="top">641</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;0.01</td>
<td align="char" valign="top" char=".">&#x2212;0.04, 0.06</td>
</tr>
<tr>
<td align="left" valign="top" colspan="6">
<bold>Episodic memory</bold>
</td>
</tr>
<tr>
<td align="left" valign="top">Song et al. (<xref ref-type="bibr" rid="ref21">21</xref>)</td>
<td align="left" valign="top">America</td>
<td align="left" valign="top">CERAD-WL</td>
<td align="center" valign="top">2,901</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;1.24</td>
<td align="char" valign="top" char=".">0.87, 1.76</td>
</tr>
<tr>
<td align="left" valign="top">Song et al. (<xref ref-type="bibr" rid="ref21">21</xref>)</td>
<td align="left" valign="top">America</td>
<td align="left" valign="top">CERAD-DR</td>
<td align="center" valign="top">2,901</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;0.93</td>
<td align="char" valign="top" char=".">0.57, 1.51</td>
</tr>
<tr>
<td align="left" valign="top">Frith et al. (<xref ref-type="bibr" rid="ref19">19</xref>)</td>
<td align="left" valign="top">America</td>
<td align="left" valign="top">CERAD</td>
<td align="center" valign="top">1723</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;0.39</td>
<td align="char" valign="top" char=".">&#x2212;0.79, 0.00</td>
</tr>
<tr>
<td align="left" valign="top">Kesse-Guyot et al. (<xref ref-type="bibr" rid="ref20">20</xref>)</td>
<td align="left" valign="top">France</td>
<td align="left" valign="top">RI-48</td>
<td align="center" valign="top">3,080</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;1.38</td>
<td align="char" valign="top" char=".">&#x2212;2.50, &#x2212;0.27</td>
</tr>
<tr>
<td align="left" valign="top" colspan="6">
<bold>Executive function</bold>
</td>
</tr>
<tr>
<td align="left" valign="top">Song et al. (<xref ref-type="bibr" rid="ref21">21</xref>)</td>
<td align="left" valign="top">America</td>
<td align="left" valign="top">DSST</td>
<td align="center" valign="top">2,901</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;1.97</td>
<td align="char" valign="top" char=".">1.08, 3.58</td>
</tr>
<tr>
<td align="left" valign="top">Frith et al. (<xref ref-type="bibr" rid="ref19">19</xref>)</td>
<td align="left" valign="top">America</td>
<td align="left" valign="top">DSST</td>
<td align="center" valign="top">1,723</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;2.80</td>
<td align="char" valign="top" char=".">&#x2212;5.58, &#x2212;0.02</td>
</tr>
<tr>
<td align="left" valign="top">Kesse-Guyot et al. (<xref ref-type="bibr" rid="ref20">20</xref>)</td>
<td align="left" valign="top">France</td>
<td align="left" valign="top">TMT</td>
<td align="center" valign="top">3,080</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;0.61</td>
<td align="char" valign="top" char=".">&#x2212;1.67, 0.45</td>
</tr>
<tr>
<td align="left" valign="top">Kesse-Guyot et al. (<xref ref-type="bibr" rid="ref20">20</xref>)</td>
<td align="left" valign="top">France</td>
<td align="left" valign="top">Forward digit span tasks</td>
<td align="center" valign="top">3,080</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;0.07</td>
<td align="char" valign="top" char=".">&#x2212;1.05, 1.18</td>
</tr>
<tr>
<td align="left" valign="top">Kesse-Guyot et al. (<xref ref-type="bibr" rid="ref20">20</xref>)</td>
<td align="left" valign="top">France</td>
<td align="left" valign="top">Backward digit span tasks</td>
<td align="center" valign="top">3,080</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;0.86</td>
<td align="char" valign="top" char=".">&#x2212;1.96, 0.25</td>
</tr>
<tr>
<td align="left" valign="top" colspan="6">
<bold>Verbal fluency</bold>
</td>
</tr>
<tr>
<td align="left" valign="top">Song et al. (<xref ref-type="bibr" rid="ref21">21</xref>)</td>
<td align="left" valign="top">America</td>
<td align="left" valign="top">AF</td>
<td align="center" valign="top">2,901</td>
<td align="char" valign="top" char=".">OR&#x2009;=&#x2009;1.76</td>
<td align="char" valign="top" char=".">1.30, 2.37</td>
</tr>
<tr>
<td align="left" valign="top">Frith et al. (<xref ref-type="bibr" rid="ref19">19</xref>)</td>
<td align="left" valign="top">America</td>
<td align="left" valign="top">AF</td>
<td align="center" valign="top">1723</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;1.18</td>
<td align="char" valign="top" char=".">&#x2212;2.17, &#x2212;0.20</td>
</tr>
<tr>
<td align="left" valign="top">Kesse-Guyot et al. (<xref ref-type="bibr" rid="ref20">20</xref>)</td>
<td align="left" valign="top">France</td>
<td align="left" valign="top">Phonemic fluency task</td>
<td align="center" valign="top">3,080</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;1.42</td>
<td align="char" valign="top" char=".">&#x2212;2.52, &#x2212;0.33</td>
</tr>
<tr>
<td align="left" valign="top">Kesse-Guyot et al. (<xref ref-type="bibr" rid="ref20">20</xref>)</td>
<td align="left" valign="top">France</td>
<td align="left" valign="top">Semantic fluency task</td>
<td align="center" valign="top">3,080</td>
<td align="char" valign="top" char=".">&#x03B2;&#x2009;=&#x2009;&#x2212;2.57</td>
<td align="char" valign="top" char=".">&#x2212;3.67, &#x2212;1.48</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<p>MoCA, Montreal Cognitive Assessment; MMSE, Mini-Mental State Examination; CERAD, the Consortium to Establish a Registry for Alzheimer&#x2019;s Disease: Word Learning/Delayed Recall; AF, Animal Fluency Test; DSST, Digit Symbol Substitution Test; RI-48, Rappel Indic&#x00E9;-48; TMT, Delis&#x2013;Kaplan trail-making test.</p>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="sec14">
<title>Meta-analysis</title>
<p>The forest plots of the meta-analysis were shown in <xref rid="fig2" ref-type="fig">Figure 2</xref> (categorical variables) and <xref rid="fig3" ref-type="fig">Figure 3</xref> (continuous variables). The weight in each plot was calculated by the inverse-variance method (shown below), which meant that if a study had more participants, more events and a narrower confidence interval, it would have a higher weight.<disp-formula id="E1">
<mml:math id="M1">
<mml:mi mathvariant="italic">Weight</mml:mi>
<mml:mo>=</mml:mo>
<mml:mfrac>
<mml:mn>1</mml:mn>
<mml:mrow>
<mml:mi mathvariant="italic">variance</mml:mi>
<mml:mspace width="0.25em"/>
<mml:mi mathvariant="italic">of</mml:mi>
<mml:mspace width="0.25em"/>
<mml:mi mathvariant="italic">estimate</mml:mi>
</mml:mrow>
</mml:mfrac>
<mml:mo>=</mml:mo>
<mml:mfrac>
<mml:mn>1</mml:mn>
<mml:mrow>
<mml:mi>S</mml:mi>
<mml:msup>
<mml:mi>E</mml:mi>
<mml:mn>2</mml:mn>
</mml:msup>
</mml:mrow>
</mml:mfrac>
</mml:math>
</disp-formula><disp-formula id="E2">
<mml:math id="M2">
<mml:mi mathvariant="italic">Pooled</mml:mi>
<mml:mspace width="0.25em"/>
<mml:mi mathvariant="italic">estimate</mml:mi>
<mml:mo>=</mml:mo>
<mml:mfrac>
<mml:mrow>
<mml:mi mathvariant="italic">sum</mml:mi>
<mml:mspace width="thickmathspace"/>
<mml:mi mathvariant="italic">of</mml:mi>
<mml:mspace width="thickmathspace"/>
<mml:mfenced open="(" close=")">
<mml:mrow>
<mml:mi mathvariant="italic">estimate</mml:mi>
<mml:mo>&#x00D7;</mml:mo>
<mml:mi mathvariant="italic">weight</mml:mi>
</mml:mrow>
</mml:mfenced>
</mml:mrow>
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</mml:math>
</disp-formula>Four studies (<xref ref-type="bibr" rid="ref11 ref12 ref13 ref14">11&#x2013;14</xref>) investigated the association between DII and morbidity rate of MCI (<xref rid="fig2" ref-type="fig">Figure 2</xref>). All showed a significant positive association (OR&#x2009;=&#x2009;1.33; 95% CI&#x2009;=&#x2009;1.19&#x2013;1.47) with low heterogeneity (<italic>I</italic><sup>2</sup> =&#x2009;0%, <italic>p</italic> =&#x2009;0.39). After taking the article (<xref ref-type="bibr" rid="ref15">15</xref>) which studied the association between DII and the morbidity rate of AD into account, the results did not change much (OR&#x2009;=&#x2009;1.34; 95% CI&#x2009;=&#x2009;1.21&#x2013;1.49).</p>
<fig position="float" id="fig2"><label>Figure 2</label>
<caption>
<p>Odds ratios (ORs) of the highest versus lowest category of DII and cognitive health (MCI, MCI&#x2009;+&#x2009;Dementia, Global Cognition and Episodic Memory). Categorical variables.</p>
</caption>
<graphic xlink:href="fnut-10-1104255-g002.tif"/>
</fig>
<fig position="float" id="fig3"><label>Figure 3</label>
<caption>
<p>Odds ratios (ORs) of the highest versus lowest category of DII and cognitive health (Global Cognition, Episodic Memory, Executive Function, and Verbal Fluency). Continuous variables.</p>
</caption>
<graphic xlink:href="fnut-10-1104255-g003.tif"/>
</fig>
<p>The association between DII and global cognition was shown in <xref rid="fig2" ref-type="fig">Figures 2</xref>, <xref rid="fig3" ref-type="fig">3</xref>. There were eight (<xref ref-type="bibr" rid="ref12 ref13 ref14">12&#x2013;14</xref>, <xref ref-type="bibr" rid="ref16 ref17 ref18">16&#x2013;18</xref>, <xref ref-type="bibr" rid="ref20">20</xref>, <xref ref-type="bibr" rid="ref25">25</xref>) studies. And the outcome variables of five of them (<xref ref-type="bibr" rid="ref12">12</xref>, <xref ref-type="bibr" rid="ref14">14</xref>, <xref ref-type="bibr" rid="ref16 ref17 ref18">16&#x2013;18</xref>) were categorical variables while the other three&#x2019;s (<xref ref-type="bibr" rid="ref13">13</xref>, <xref ref-type="bibr" rid="ref20">20</xref>, <xref ref-type="bibr" rid="ref25">25</xref>) were continuous variables. As to the five studies that used categorical variables, there is a negative association (OR&#x2009;=&#x2009;1.56; 95% CI&#x2009;=&#x2009;1.32&#x2013;1.85) between DII and global cognition with no evidence of statistically significant heterogeneity between the studies (<italic>I</italic><sup>2</sup> =&#x2009;54%, <italic>p</italic> =&#x2009;0.07). The sensitivity analysis (<xref ref-type="supplementary-material" rid="SM1">Supplementary Figure S1</xref>) revealed that the result from Skoczek-Rubi&#x0144;ska was the largest contributor to the heterogeneity and its exclusion reduced heterogeneity to 0% (<italic>p</italic> =&#x2009;0.39) with substantially unchanged effect size (OR&#x2009;=&#x2009;1.53; 95% CI&#x2009;=&#x2009;1.29&#x2013;1.81). However, when it comes to the other three studies which used continuous variables, the relationship between DII and global cognition is not significant (OR&#x2009;=&#x2009;0.56; 95% CI&#x2009;=&#x2009;0.22&#x2013;1.46) and heterogeneity is high (<italic>I</italic><sup>2</sup> =&#x2009;87%, <italic>p</italic> &#x003C;&#x2009;0.01). The sensitivity analysis (<xref ref-type="supplementary-material" rid="SM1">Supplementary Table S1</xref>) conducted by excluding one study at a time showed that the heterogeneities between every two articles were high.</p>
<p>Only three studies (<xref ref-type="bibr" rid="ref19 ref20 ref21">19&#x2013;21</xref>) evaluated the relationship between DII and episodic memory (<xref rid="fig2" ref-type="fig">Figures 2</xref>, <xref rid="fig3" ref-type="fig">3</xref>). The study (<xref ref-type="bibr" rid="ref21">21</xref>) that used categorical variables evaluated episodic memory <italic>via</italic> two parts from the same instrument. The results showed that there is no relationship between DII and episodic memory (categorical: OR&#x2009;=&#x2009;1.12; 95% IC&#x2009;=&#x2009;0.84&#x2013;1.49; continuous: OR&#x2009;=&#x2009;0.48; 95% CI&#x2009;=&#x2009;0.19&#x2013;1.21). Both heterogeneities were not high (categorical: <italic>I</italic><sup>2</sup> =&#x2009;0%, <italic>p</italic> =&#x2009;0.35; continuous: <italic>I</italic><sup>2</sup> =&#x2009;63%, <italic>p</italic> =&#x2009;0.10).</p>
<p>In terms of the association between DII and executive function, two articles (<xref ref-type="bibr" rid="ref19">19</xref>, <xref ref-type="bibr" rid="ref20">20</xref>) used four methods to evaluate it (<xref rid="fig3" ref-type="fig">Figure 3</xref>). Both articles took continuous variables as their outcome variables. Results showed DII has no association with executive function (OR&#x2009;=&#x2009;0.56; 95% CI&#x2009;=&#x2009;0.30&#x2013;1.03) and there was no evidence of statistically significant heterogeneity between the studies (<italic>I</italic><sup>2</sup> =&#x2009;25%, <italic>p</italic> =&#x2009;0.26).</p>
<p>The association between DII and verbal fluency is shown in <xref rid="fig3" ref-type="fig">Figure 3</xref>. The two articles are the articles mentioned above which studied the association between DII and executive function. The results showed that DII score is associated with verbal fluency (OR&#x2009;=&#x2009;0.18; 95% CI&#x2009;=&#x2009;0.08&#x2013;0.42) and the heterogeneity is medium (<italic>I</italic><sup>2</sup> =&#x2009;47%, <italic>p</italic> =&#x2009;0.15).</p>
</sec>
</sec>
<sec id="sec15" sec-type="discussions">
<title>Discussion</title>
<p>This meta-analysis summarizes the evidence underlying associations between DII and cognitive function. High DII was associated with an increased risk of overall cognitive decline, including the morbidity rate of AD and MCI, decline of both global cognition and verbal fluency. However, there was hardly any association detected between DII and either executive function or episodic memory.</p>
<p>The dietary inflammation index (DII) (<xref ref-type="bibr" rid="ref10">10</xref>) is a quantitative measure of pro-inflammatory diets and is associated with systemic inflammatory markers including tumor necrosis factor (TNF), interleukins (IL), and Interferon gamma (IFN-&#x03B3;) (<xref ref-type="bibr" rid="ref10">10</xref>, <xref ref-type="bibr" rid="ref26">26</xref>). It was created based on nearly 6,500 studies and has 45 dietary components, including common food items, micronutrients, and important bioactive polyphenols. All these components can affect an individual&#x2019;s level of inflammation. It is generally acknowledged that neuroinflammation plays an important role in the pathogenesis of Alzheimer&#x2019;s disease (<xref ref-type="bibr" rid="ref27">27</xref>, <xref ref-type="bibr" rid="ref28">28</xref>) and there are more inflammatory markers (TNF&#x03B1;, IL-1&#x03B2;, IL-6, IL-10) in patients with AD and mild cognitive impairment (MCI) than in healthy controls (<xref ref-type="bibr" rid="ref29 ref30 ref31 ref32">29&#x2013;32</xref>). Consistently, previous findings in humans and animals have suggested that neuroinflammation is associated with cognitive decline, especially learning and memory (<xref ref-type="bibr" rid="ref5">5</xref>, <xref ref-type="bibr" rid="ref33">33</xref>). Although we have yet to establish how these inflammatory markers damage our brains, there are some studies that have tried to explain this pathogenesis. One study conducted in Japan (<xref ref-type="bibr" rid="ref34">34</xref>) suggested that TNF&#x03B1; competes with the cAMP signaling pathway, thereby inhibiting memory retrieval by blocking cAMP-PKA-GluA1 S845 signaling. In this way, TNF&#x03B1; could cause cognitive decline. Moreover, other studies focused on IL-1 found that IL-1&#x03B2; could act directly on hippocampal neurons to interfere with memory reconsolidation and the mice&#x2019;s working memory impairment was prevented by global IL-1R1 knockout (<xref ref-type="bibr" rid="ref35 ref36 ref37">35&#x2013;37</xref>). Given these links, it is not surprising that we observed such a positive association between pro-inflammatory diets (higher DII) and AD, MCI, and poor global function in the present work.</p>
<p>Among all the forest plots in this article, only the global cognition plot (continuous variables) in <xref rid="fig3" ref-type="fig">Figure 3</xref>. Shows high heterogeneity (<italic>I</italic><sup>2</sup> =&#x2009;87%, <italic>p</italic> &#x003C;&#x2009;0.01). And the source of heterogeneity could not be found by sensitivity analysis (<xref ref-type="supplementary-material" rid="SM1">Supplementary Table S1</xref>). This could have been due to differences in the global cognition scoring methods and dietary questionnaires used in the studies. Specifically, Kesse-Guyot (<xref ref-type="bibr" rid="ref20">20</xref>) used such methods as RI-48, TMT, and forward and backward digit span tasks to create a composite cognitive score and then used this score to evaluate global cognition. Wang (<xref ref-type="bibr" rid="ref13">13</xref>) only used MoCA. Zabetian-Targhi et al. (<xref ref-type="bibr" rid="ref25">25</xref>) used the Rey-Osterrieth Complex Figure, a delayed reproduction after 20&#x2009;min and other 7 tests. Global cognitive function was calculated as the standardized mean of all tests. In theory, comprehensive neuropsychological test batteries used by Kesse-Guyot and Zabetian-Targhi are more sensitive than cognitive decline screening tests such as the MoCA used in Wang&#x2019;s research to capture subtle changes in cognition in individuals with no severe deterioration of cognitive functions and with no clinical dementia. In addition, the dietary assessment method is another reason for the differences between studies since the DII scores are calculated on them. At present, the most used method is the food frequency questionnaire, and the more items, the more accurate the results are. The 24-h recall used by Kesse-Guyot is relatively less accurate.</p>
<p>The global cognition plot (categorical variables) in <xref rid="fig2" ref-type="fig">Figure 2</xref>. Also has a relatively high heterogeneity (<italic>I</italic><sup>2</sup> =&#x2009;54%, <italic>p</italic> =&#x2009;0.07). After excluding the paper written by Skoczek-Rubi&#x0144;ska, the heterogeneity was reduced to 0% (<italic>p</italic> =&#x2009;0.39) with a substantially unchanged effect size (OR&#x2009;=&#x2009;1.53; 95% CI&#x2009;=&#x2009;1.29&#x2013;1.81). Although the small sample size and the single assessment method may be one of the reasons for the larger contribution to heterogeneity, we believe that the greatest feature of this article is the study of postmenopausal women as a specific population. Depletion of estrogen due to menopausal transition is also associated with a decline in cognitive health in women. This happens since estrogen benefits hippocampal and prefrontal cortical function, potentially enhancing verbal memory and executive function (<xref ref-type="bibr" rid="ref38">38</xref>, <xref ref-type="bibr" rid="ref39">39</xref>). Therefore, we believed that the difference in the study population is the main reason for the high heterogeneity. But all in all, either include or exclude this article, the conclusion that higher DII, poorer global cognition does not change.</p>
<p>Our study also showed that high DII scores are negatively associated with verbal fluency, but there was no significant association between DII and executive function or episodic memory. Only three articles (<xref ref-type="bibr" rid="ref19 ref20 ref21">19&#x2013;21</xref>) studied the association between DII and these three cognitive domains. Song used categorical variables, while Frith and Kesse-Guyot used continuous variables. As to the meta-analysis of episodic memory (categorical variables) in <xref rid="fig2" ref-type="fig">Figure 2</xref>, we can find that the two data are from the same article, the participants are the same, and the evaluation method is two different parts of CERAD, so there is probably a bias. And when it comes to the meta-analysis of episodic memory (continuous variables) in <xref rid="fig3" ref-type="fig">Figure 3</xref>, the heterogeneity was relatively high (<italic>I</italic><sup>2</sup> =&#x2009;63%, <italic>p</italic> =&#x2009;0.10). However, because only two articles were included in the meta-analysis, we were unable to perform a sensitivity analysis to identify the source of heterogeneity. We can only speculate that the possible reasons for the high heterogeneity are different study populations (one was American while another was French) and different episodic memory assessment methods (one used CERAD while another used RI-48). Although few papers took these three cognitive domains into account, we did find one paper published in 2020 that did so (<xref ref-type="bibr" rid="ref40">40</xref>). Its authors found that there was no association between CRP and verbal fluency. To some extent, this is inconsistent with our own conclusion. However, the paper&#x2019;s participants were not elderly, and it only took CRP into account. There are many inflammatory cytokines other than CRP, such as TNF&#x03B1;, IL-6, and IL-10, that may be related to cognitive function. This could be why its conclusion differed from ours. Regarding executive function and episodic memory, one study conducted in the United States (<xref ref-type="bibr" rid="ref41">41</xref>) suggested that TNF&#x03B1; had no association with executive function or episodic memory. Its findings were consistent with our conclusion. Even so, the evidence of the connection between DII and verbal fluency, executive function, and episodic memory is limited.</p>
<p>Several limitations of this work should be addressed. Firstly, most of the included studies were cross-sectional studies. Although we found that DII was associated with MCI and AD, further prospective cohort studies with different ethnic or age groups are still needed to confirm the results. For example, prospective cohort studies that include more young and healthy groups for long-term follow-up. Furthermore, a recently developed plasma biomarker for imaging, cerebrospinal fluid, or plasma biomarkers of amyloid and tau pathology can be used to assist in the early screening and diagnosis of MCI and AD, as well as the use of cognitive-related scales. Secondly, although there is convincing evidence from observational studies, including the evidence presented in the present meta-analysis, that a dietary intervention with an anti-inflammatory diet might be beneficial to counteract the risk of developing dementia or cognitive decline, there are no clinical trials to definitively support this result. Therefore, it is important for future research to address this issue. A pro-inflammatory diet might be a good candidate for an easy-to-implement, relatively cheap, and safe intervention that can be studied in association with dementia and cognitive decline using an experimental design. Thirdly, when conducting subgroup analysis, such as episodic memory (continuous variables, heterogeneities were high level), because fewer than three studies were included, we were unable to conduct sensitivity analysis to further identify the source of heterogeneity. Meanwhile, although current evidence suggests that inflammation has influences on cognitive function to some extent, the mechanism is still not clear. We look forward to further studies to address this issue in the future.</p>
<p>In conclusion, data from this study support an association between DII and increased risk of AD and MCI. A negative association was observed between DII and global cognition and verbal fluency. However, there was no significant association observed between DII and executive function or episodic memory. This study indicates that an anti-inflammatory diet can help prevent cognitive decline. However, current evidence on the role of diet-induced inflammation in different cognitive domains should be supplemented with further work in the future.</p>
</sec>
<sec id="sec16">
<title>Author contributions</title>
<p>DB: conceptualization, formal analysis, resources, writing &#x2013; review and editing, and funding acquisition. DB, LW, SC, TD, and MA: methodology and investigation. TD and MA: writing &#x2013; original draft preparation. JS: visualization. All authors contributed to the article and approved the submitted version.</p>
</sec>
<sec id="sec17" sec-type="funding-information">
<title>Funding</title>
<p>This research was funded by Medicine and Engineering Interdisciplinary Research Fund of Shanghai Jiao Tong University, grant number (YG2022QN011), Shanghai Municipal Health Commission, grant number (2020YJZX0139), Shanghai Municipal Science and Technology (22692191800) and National Key Research and Development Program of China (2021YFE0111800).</p>
</sec>
<sec id="conf1" sec-type="COI-statement">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec id="sec100" sec-type="disclaimer">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
</body>
<back>
<sec id="sec19" sec-type="supplementary-material">
<title>Supplementary material</title>
<p>The Supplementary material for this article can be found online at: <ext-link xlink:href="https://www.frontiersin.org/articles/10.3389/fnut.2023.1104255/full#supplementary-material" ext-link-type="uri">https://www.frontiersin.org/articles/10.3389/fnut.2023.1104255/full#supplementary-material</ext-link></p>
<supplementary-material xlink:href="Data_Sheet_1.docx" id="SM1" mimetype="application/vnd.openxmlformats-officedocument.wordprocessingml.document" xmlns:xlink="http://www.w3.org/1999/xlink"/>
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