Type II diabetes interacts with Alzheimer’s disease risk factors to predict functional decline

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content="INDEX,NOFOLLOW,NOARCHIVE"> <meta name="citation_journal_title" content="Alzheimer disease and associated disorders"> <meta name="citation_title" content="Type II diabetes interacts with Alzheimer’s disease risk factors to predict functional decline"> <meta name="citation_author" content="Kelsey R Thomas"> <meta name="citation_author_institution" content="Veterans Affairs San Diego Healthcare System, San Diego, CA"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author" content="Katherine J Bangen"> <meta name="citation_author_institution" content="Veterans Affairs San Diego Healthcare System, San Diego, CA"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author" content="Alexandra J Weigand"> <meta name="citation_author_institution" content="Veterans Affairs San Diego Healthcare System, San Diego, CA"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author_institution" content="San Diego State University/University of California, San Diego (SDSU/UCSD) Joint Doctoral Program in Clinical Psychology, San Diego, CA"> <meta name="citation_author" content="Emily C Edmonds"> <meta name="citation_author_institution" content="Veterans Affairs San Diego Healthcare System, San Diego, CA"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author" content="Erin Sundermann"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author" content="Christina G Wong"> <meta name="citation_author_institution" content="Veterans Affairs San Diego Healthcare System, San Diego, CA"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author" content="Joel S Eppig"> <meta name="citation_author_institution" content="Veterans Affairs San Diego Healthcare System, San Diego, CA"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author_institution" content="San Diego State University/University of California, San Diego (SDSU/UCSD) Joint Doctoral Program in Clinical Psychology, San Diego, CA"> <meta name="citation_author" content="Madeleine L Werhane"> <meta name="citation_author_institution" content="Veterans Affairs San Diego Healthcare System, San Diego, CA"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author_institution" content="San Diego State University/University of California, San Diego (SDSU/UCSD) Joint Doctoral Program in Clinical Psychology, San Diego, CA"> <meta name="citation_author" content="Lisa Delano-Wood"> <meta name="citation_author_institution" content="Veterans Affairs San Diego Healthcare System, San Diego, CA"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author" content="Mark W Bondi"> <meta name="citation_author_institution" content="Veterans Affairs San Diego Healthcare System, San Diego, CA"> <meta name="citation_author_institution" content="Dept. of Psychiatry, University of California, San Diego, La Jolla, CA"> <meta name="citation_author" content="Alzheimer’s Disease Neuroimaging Initiative"> <meta name="citation_publication_date" content="2020 Jan-Mar"> <meta name="citation_volume" content="34"> <meta name="citation_issue" content="1"> <meta name="citation_firstpage" content="10"> <meta name="citation_doi" content="10.1097/WAD.0000000000000332"> <meta name="citation_pmid" content="31305320"> <meta name="citation_abstract_html_url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC6952586/"> <meta name="citation_fulltext_html_url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC6952586/"> <meta name="citation_pdf_url" content="https://pmc.ncbi.nlm.nih.gov/articles/PMC6952586/pdf/nihms-1530734.pdf"> <meta name="description" content="The current study examined the interactive effect of type II diabetes and Alzheimer’s disease (AD) risk factors on rate of functional decline in cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative. Participants ..."> <meta name="og:title" content="Type II diabetes interacts with Alzheimer’s disease risk factors to predict functional decline"> <meta name="og:type" content="article"> <meta name="og:site_name" content="PubMed Central (PMC)"> <meta name="og:description" content="The current study examined the interactive effect of type II diabetes and Alzheimer’s disease (AD) risk factors on rate of functional decline in cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative. 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Author manuscript; available in PMC: 2021 Jan 1.</div> <div> <em>Published in final edited form as: </em>Alzheimer Dis Assoc Disord. 2020 Jan-Mar;34(1):10–17. doi: <a href="https://doi.org/10.1097/WAD.0000000000000332" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">10.1097/WAD.0000000000000332</a> </div> <nav id="journal_context_menu" hidden="hidden"><ul class="menu-list font-family-ui" role="menu"> <li role="presentation"><a href="https://www.ncbi.nlm.nih.gov/pmc/?term=%22Alzheimer%20Dis%20Assoc%20Disord%22%5Bjour%5D" class="usa-link" role="menuitem">Search in PMC</a></li> <li role="presentation"><a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Alzheimer%20Dis%20Assoc%20Disord%22%5Bjour%5D" lang="en" class="usa-link" role="menuitem">Search in PubMed</a></li> <li role="presentation"><a href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Alzheimer%20Dis%20Assoc%20Disord%22%5BTitle%20Abbreviation%5D" class="usa-link" role="menuitem">View in NLM Catalog</a></li> <li role="presentation"><a href="?term=%22Alzheimer%20Dis%20Assoc%20Disord%22%5Bjour%5D" class="usa-link" role="menuitem" data-add-to-search="true">Add to search</a></li> </ul></nav></section><section class="front-matter"><div class="ameta p font-secondary font-xs"> <hgroup><h1>Type II diabetes interacts with Alzheimer’s disease risk factors to predict functional decline</h1></hgroup><div class="cg p"> <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Thomas%20KR%22%5BAuthor%5D" class="usa-link" aria-describedby="id1"><span class="name western">Kelsey R Thomas</span></a><div hidden="hidden" id="id1"> <h3> <span class="name western">Kelsey R Thomas</span>, <span class="degrees">Ph.D.</span> </h3> <div class="p"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Thomas%20KR%22%5BAuthor%5D" class="usa-link"><span class="name western">Kelsey R Thomas</span></a> </div> </div> <sup>1,</sup><sup>2</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bangen%20KJ%22%5BAuthor%5D" class="usa-link" aria-describedby="id2"><span class="name western">Katherine J Bangen</span></a><div hidden="hidden" id="id2"> <h3> <span class="name western">Katherine J Bangen</span>, <span class="degrees">Ph.D.</span> </h3> <div class="p"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bangen%20KJ%22%5BAuthor%5D" class="usa-link"><span class="name western">Katherine J Bangen</span></a> </div> </div> <sup>1,</sup><sup>2</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Weigand%20AJ%22%5BAuthor%5D" class="usa-link" aria-describedby="id3"><span class="name western">Alexandra J Weigand</span></a><div hidden="hidden" id="id3"> <h3> <span class="name western">Alexandra J Weigand</span>, <span class="degrees">B.A</span> </h3> <div class="p"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p"> <sup>3</sup>San Diego State University/University of California, San Diego (SDSU/UCSD) Joint Doctoral Program in Clinical Psychology, San Diego, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Weigand%20AJ%22%5BAuthor%5D" class="usa-link"><span class="name western">Alexandra J Weigand</span></a> </div> </div> <sup>1,</sup><sup>2,</sup><sup>3</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Edmonds%20EC%22%5BAuthor%5D" class="usa-link" aria-describedby="id4"><span class="name western">Emily C Edmonds</span></a><div hidden="hidden" id="id4"> <h3> <span class="name western">Emily C Edmonds</span>, <span class="degrees">Ph.D.</span> </h3> <div class="p"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Edmonds%20EC%22%5BAuthor%5D" class="usa-link"><span class="name western">Emily C Edmonds</span></a> </div> </div> <sup>1,</sup><sup>2</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sundermann%20E%22%5BAuthor%5D" class="usa-link" aria-describedby="id5"><span class="name western">Erin Sundermann</span></a><div hidden="hidden" id="id5"> <h3> <span class="name western">Erin Sundermann</span>, <span class="degrees">Ph.D.</span> </h3> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Sundermann%20E%22%5BAuthor%5D" class="usa-link"><span class="name western">Erin Sundermann</span></a> </div> </div> <sup>2</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wong%20CG%22%5BAuthor%5D" class="usa-link" aria-describedby="id6"><span class="name western">Christina G Wong</span></a><div hidden="hidden" id="id6"> <h3> <span class="name western">Christina G Wong</span>, <span class="degrees">Ph.D.</span> </h3> <div class="p"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Wong%20CG%22%5BAuthor%5D" class="usa-link"><span class="name western">Christina G Wong</span></a> </div> </div> <sup>1,</sup><sup>2</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Eppig%20JS%22%5BAuthor%5D" class="usa-link" aria-describedby="id7"><span class="name western">Joel S Eppig</span></a><div hidden="hidden" id="id7"> <h3> <span class="name western">Joel S Eppig</span>, <span class="degrees">M.S.</span> </h3> <div class="p"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p"> <sup>3</sup>San Diego State University/University of California, San Diego (SDSU/UCSD) Joint Doctoral Program in Clinical Psychology, San Diego, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Eppig%20JS%22%5BAuthor%5D" class="usa-link"><span class="name western">Joel S Eppig</span></a> </div> </div> <sup>1,</sup><sup>2,</sup><sup>3</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Werhane%20ML%22%5BAuthor%5D" class="usa-link" aria-describedby="id8"><span class="name western">Madeleine L Werhane</span></a><div hidden="hidden" id="id8"> <h3> <span class="name western">Madeleine L Werhane</span>, <span class="degrees">M.S.</span> </h3> <div class="p"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p"> <sup>3</sup>San Diego State University/University of California, San Diego (SDSU/UCSD) Joint Doctoral Program in Clinical Psychology, San Diego, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Werhane%20ML%22%5BAuthor%5D" class="usa-link"><span class="name western">Madeleine L Werhane</span></a> </div> </div> <sup>1,</sup><sup>2,</sup><sup>3</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Delano-Wood%20L%22%5BAuthor%5D" class="usa-link" aria-describedby="id9"><span class="name western">Lisa Delano-Wood</span></a><div hidden="hidden" id="id9"> <h3> <span class="name western">Lisa Delano-Wood</span>, <span class="degrees">Ph.D.</span> </h3> <div class="p"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Delano-Wood%20L%22%5BAuthor%5D" class="usa-link"><span class="name western">Lisa Delano-Wood</span></a> </div> </div> <sup>1,</sup><sup>2</sup>, <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bondi%20MW%22%5BAuthor%5D" class="usa-link" aria-describedby="id10"><span class="name western">Mark W Bondi</span></a><div hidden="hidden" id="id10"> <h3> <span class="name western">Mark W Bondi</span>, <span class="degrees">Ph.D.</span> </h3> <div class="p"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div class="p"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div class="p">Find articles by <a href="https://pubmed.ncbi.nlm.nih.gov/?term=%22Bondi%20MW%22%5BAuthor%5D" class="usa-link"><span class="name western">Mark W Bondi</span></a> </div> </div> <sup>1,</sup><sup>2</sup>; <span class="collab">Alzheimer’s Disease Neuroimaging Initiative</span><sup>*</sup> </div> <ul class="d-buttons inline-list"> <li><button class="d-button" aria-controls="aip_a" aria-expanded="false">Author information</button></li> <li><button class="d-button" aria-controls="clp_a" aria-expanded="false">Copyright and License information</button></li> </ul> <div class="d-panels font-secondary-light"> <div id="aip_a" class="d-panel p" style="display: none"> <div class="p" id="A1"> <sup>1</sup>Veterans Affairs San Diego Healthcare System, San Diego, CA</div> <div id="A2"> <sup>2</sup>Dept. of Psychiatry, University of California, San Diego, La Jolla, CA</div> <div id="A3"> <sup>3</sup>San Diego State University/University of California, San Diego (SDSU/UCSD) Joint Doctoral Program in Clinical Psychology, San Diego, CA</div> <div class="author-notes p"> <div class="fn" id="FN1"><p id="P1">* Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (<a href="http://adni.loni.usc.edu" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://adni.loni.usc.edu</a>). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: <a href="http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf</a></p></div> <div class="fn" id="CR1"> <sup>✉</sup><p class="display-inline"><strong>Corresponding Author:</strong> Mark W. Bondi, PhD, VA San Diego Healthcare System, 3350 La Jolla Village Drive (116B), San Diego, CA 92161, USA, Phone: 858-552-8585 ext. 2809, Fax: 858-642-1218, <span>mbondi@ucsd.edu</span></p> </div> </div> </div> <div id="clp_a" class="d-panel p" style="display: none"><div class="p"><a href="/about/copyright/" class="usa-link">PMC Copyright notice</a></div></div> </div> <div>PMCID: PMC6952586 NIHMSID: NIHMS1530734 PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/31305320/" class="usa-link">31305320</a> </div> <div class="ra xbox p" role="complementary" aria-label="Related or updated information about this article"><div>The publisher's version of this article is available at <a href="https://doi.org/10.1097/WAD.0000000000000332" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">Alzheimer Dis Assoc Disord</a> </div></div> </div></section></section><section aria-label="Article content"><section class="body main-article-body"><section class="abstract" id="ABS1"><h2>Abstract</h2> <section id="S1"><h3 class="pmc_sec_title">Objective:</h3> <p id="P2">The current study examined the interactive effect of type II diabetes and Alzheimer’s disease (AD) risk factors on rate of functional decline in cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative.</p></section><section id="S2"><h3 class="pmc_sec_title">Methods:</h3> <p id="P3">Participants underwent annual assessments that included the Functional Activities Questionnaire, an informant-rated measure of everyday functioning. Multilevel modeling, controlling for demographic variables and ischemic risk, examined the interactive effects of diabetes status (diabetes n=69; no diabetes n=744) and AD risk factors in the prediction of five-year longitudinal change in everyday functioning. One model was run for each AD risk factor, including: objectively-defined subtle cognitive decline (Obj-SCD) and genetic susceptibility (APOE ε4) as well as cerebrospinal fluid β-amyloid (Aβ), total tau (tau), and hyperphosphorylated-tau (p-tau).</p></section><section id="S3"><h3 class="pmc_sec_title">Results:</h3> <p id="P4">The three-way diabetes × AD risk factor × time interaction predicted increased rates of functional decline in models that examined Obj-SCD, APOE ε4, tau and p-tau positivity, but not Aβ positivity.</p></section><section id="S4"><h3 class="pmc_sec_title">Conclusions:</h3> <p id="P5">Participants with both diabetes and at least one AD risk factor (i.e., Obj-SCD, APOE ε4, tau, p-tau positivity) demonstrated faster functional decline compared to those without both risk factors (diabetes or AD). These findings have implications for early identification of, and perhaps earlier intervention for, diabetic individuals at risk for future functional difficulty.</p></section><section id="kwd-group1" class="kwd-group"><p><strong>Keywords:</strong> Diabetes, Alzheimer’s disease, Everyday Functioning, Subtle Cognitive Decline</p></section></section><section id="S5"><h2 class="pmc_sec_title">INTRODUCTION</h2> <p id="P7">Type II diabetes mellitus (DM) is a growing public health concern, as over 30 million adults in the United States have diabetes (12.2% of all U.S. adults).<sup><a href="#R1" class="usa-link" aria-describedby="R1">1</a></sup> There is consistent evidence that DM is a risk factor for cognitive decline and dementia<sup><a href="#R2" class="usa-link" aria-describedby="R2">2</a>–<a href="#R4" class="usa-link" aria-describedby="R4">4</a></sup> and a significant portion of older Medicare beneficiaries with dementia have co-existing diabetes (37%).<sup><a href="#R5" class="usa-link" aria-describedby="R5">5</a></sup> However, the specific relationship between DM and Alzheimer’s disease (AD) is not well understood. Research has shown that people with DM are at greater risk for developing amnestic mild cognitive impairment (MCI)<sup><a href="#R2" class="usa-link" aria-describedby="R2">2</a></sup> and AD, as well as vascular dementia.<sup><a href="#R6" class="usa-link" aria-describedby="R6">6</a></sup> While DM increases the risk of a clinical diagnosis of AD, there does not appear to be a clear relationship between DM and β-amyloid (Aβ) pathology, which is a defining feature of AD.<sup><a href="#R4" class="usa-link" aria-describedby="R4">4</a>,<a href="#R7" class="usa-link" aria-describedby="R7">7</a>–<a href="#R9" class="usa-link" aria-describedby="R9">9</a></sup> Indeed, prior work from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study showed that DM was associated with cerebrospinal fluid (CSF) total tau (tau) and hyperphosphorylated tau (p-tau), but not CSF or PET measures of Aβ.<sup><a href="#R10" class="usa-link" aria-describedby="R10">10</a></sup></p> <p id="P8">Research on the interactive effects of DM and risk factors for AD-related dementia [e.g., apolipoprotein E (APOE) ε4 allele, MCI] shows that those with both DM and an AD risk factor such as MCI have poorer cognitive outcomes,<sup><a href="#R11" class="usa-link" aria-describedby="R11">11</a>,<a href="#R12" class="usa-link" aria-describedby="R12">12</a></sup> reduced brain volume and glucose metabolism,<sup><a href="#R13" class="usa-link" aria-describedby="R13">13</a></sup> and more severe AD pathology<sup><a href="#R14" class="usa-link" aria-describedby="R14">14</a></sup> relative to having either DM or an AD risk factor alone. However, there is minimal research on cognitively normal individuals with DM, or how DM in combination with AD risk factors predicts longitudinal changes in everyday functioning. Further, our recent work has shown that objectively-defined subtle cognitive decline (Obj-SCD), operationally-defined using sensitive neuropsychological scores, may be a promising indicator of those at risk for future progression to MCI and dementia.<sup><a href="#R15" class="usa-link" aria-describedby="R15">15</a></sup> It is currently unknown whether subtle cognitive changes in those with DM are predictive of faster functional decline.</p> <p id="P9">Everyday functioning is a key feature that differentiates MCI from dementia; while MCI may have very mild functional changes,<sup><a href="#R16" class="usa-link" aria-describedby="R16">16</a></sup> more significant functional impairment is needed for a diagnosis of dementia.<sup><a href="#R17" class="usa-link" aria-describedby="R17">17</a>,<a href="#R18" class="usa-link" aria-describedby="R18">18</a></sup> Cognitive performance, particularly in the domains of memory and executive functioning, have been shown to predict changes in everyday functioning.<sup><a href="#R19" class="usa-link" aria-describedby="R19">19</a>–<a href="#R21" class="usa-link" aria-describedby="R21">21</a></sup> Additionally, CSF Aβ and p-tau significantly predict decline on the Functional Activities Questionnaire (FAQ)<sup><a href="#R22" class="usa-link" aria-describedby="R22">22</a></sup> in cognitively unimpaired older adults, with p-tau being the most sensitive predictor of functional decline.<sup><a href="#R23" class="usa-link" aria-describedby="R23">23</a></sup> Everyday functioning may be a particularly relevant outcome with regard to tracking disease severity in the context of DM, as DM has been shown to be an independent risk factor for functional disability.<sup><a href="#R24" class="usa-link" aria-describedby="R24">24</a>–<a href="#R26" class="usa-link" aria-describedby="R26">26</a></sup> Further, since individuals with DM often need to be able to manage complex medication regimens and medical appointments, mild declines in everyday function may result in a feedback loop such that cognitive and functional declines impact medication management, which in turn lead to greater cognitive and functional difficulties.<sup><a href="#R27" class="usa-link" aria-describedby="R27">27</a></sup></p> <p id="P10">To our knowledge, there are no studies that examine the interaction of DM with different AD risk factors to predict everyday functioning in those without MCI or dementia, despite the common co-occurrence of both DM and AD.<sup><a href="#R5" class="usa-link" aria-describedby="R5">5</a></sup> Taken together, the current study aimed to examine the moderating effect of DM on AD risk factors in predicting functional decline in older adults without a neurocognitive disorder to determine whether DM and AD risk factors act synergistically to promote functional impairment beyond their independent contributions.</p></section><section id="S6"><h2 class="pmc_sec_title">METHODS</h2> <p id="P11">Data used in the preparation of this article were obtained from the ADNI database (<a href="http://adni.loni.usc.edu" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">http://adni.loni.usc.edu</a>). ADNI was launched in 2003 as a public-private partnership. The primary goal of ADNI has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of MCI and early AD. For up-to-date information on ADNI, see <a href="http://www.adni-info.org/" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">www.adni-info.org</a>. This study was approved by the Institutional Review Boards at each of the participating institutions, and written informed consent was obtained from all participants or authorized representatives at each site.</p> <section id="S7"><h3 class="pmc_sec_title">Participants</h3> <p id="P12">The specific enrollment inclusion/exclusion criteria for ADNI as well as detailed MCI and dementia criteria have been described elsewhere.<sup><a href="#R17" class="usa-link" aria-describedby="R17">17</a>,<a href="#R28" class="usa-link" aria-describedby="R28">28</a>–<a href="#R30" class="usa-link" aria-describedby="R30">30</a></sup> Participants were included in the current study if they were considered to be cognitively normal (CN) and had a FAQ score at their baseline visit (N=813). Participants were excluded if they met Jak/Bondi’s comprehensive neuropsychological criteria for MCI<sup><a href="#R28" class="usa-link" aria-describedby="R28">28</a>,<a href="#R29" class="usa-link" aria-describedby="R29">29</a></sup> or ADNI’s criteria for dementia.<sup><a href="#R17" class="usa-link" aria-describedby="R17">17</a>,<a href="#R30" class="usa-link" aria-describedby="R30">30</a></sup> In addition to a baseline visit, participants had follow-up visits that occurred at 6- (n=756), 12- (n=693), 24- (n=682), 36- (n=459), 48- (n=388), and 60-months (n=211).</p> <p id="P13">Jak/Bondi neuropsychological MCI criteria were defined by: (1) performance >1 SD below the demographically-adjusted (age, education, sex) mean on two neuropsychological measures within the same cognitive domain <em>or</em> (2) performance >1 SD below the demographically-adjusted mean on at least one measure across all three sampled cognitive domains.<sup><a href="#R15" class="usa-link" aria-describedby="R15">15</a>,<a href="#R28" class="usa-link" aria-describedby="R28">28</a>,<a href="#R29" class="usa-link" aria-describedby="R29">29</a></sup> Six neuropsychological test scores were used in the Jak/Bondi diagnostic criteria for MCI.<sup><a href="#R29" class="usa-link" aria-describedby="R29">29</a></sup> There were two measures in three cognitive domains: <em>memory</em> [Rey Auditory Verbal Learning Test (AVLT) delayed free recall correct responses and AVLT recognition (hits minus false positives)], <em>language</em> [30-item Boston Naming Test (BNT) total correct, Animal Fluency total score], and <em>attention/executive function</em> [Trail Making Test (TMT) Part A and Part B times to completion]. The neuropsychological demographically-adjusted z-scores were based on regression coefficients derived from a sample of ADNI’s CN participants who did not progress to MCI for the duration of their study participation (i.e., “robust” controls; N=385).<sup><a href="#R31" class="usa-link" aria-describedby="R31">31</a>,<a href="#R32" class="usa-link" aria-describedby="R32">32</a></sup> Non-demented participants that did not meet Jak/Bondi criteria for MCI were considered CN.</p> <p id="P14">The dementia criteria used in ADNI<sup><a href="#R30" class="usa-link" aria-describedby="R30">30</a></sup> were: (1) subjective memory complaint reported by the subject, study partner, or clinician; (2) abnormal memory function defined by scoring below the education-adjusted cutoffs on the Logical Memory delayed recall subscale from the Wechsler Memory Scale–Revised; (3) Mini Mental State Exam (MMSE) score <27; (4) Clinical Dementia Rating (CDR)=0.5 or 1.0; and (5) met NINCDS/ADRDA criteria for probable AD.<sup><a href="#R17" class="usa-link" aria-describedby="R17">17</a></sup></p></section><section id="S8"><h3 class="pmc_sec_title">Materials and Procedure</h3> <section id="S9"><h4 class="pmc_sec_title">Functional Assessment.</h4> <p id="P15">The FAQ<sup><a href="#R22" class="usa-link" aria-describedby="R22">22</a></sup> is an informant-rated questionnaire measuring functional difficulty over the preceding four weeks. It is part of the Uniform Data Set compiled by the National Alzheimer’s Coordinating Center as a measure of functioning on instrumental activities of daily living.<sup><a href="#R33" class="usa-link" aria-describedby="R33">33</a></sup> The FAQ has good reliability with item-total correlations ≥0.80 and effectively distinguishes between cognitively normal individuals and those with dementia (0.85–0.98 sensitivity, 0.71–0.91 specificity),<sup><a href="#R22" class="usa-link" aria-describedby="R22">22</a>,<a href="#R34" class="usa-link" aria-describedby="R34">34</a></sup> as well as between MCI and early dementia (0.80 sensitivity, 0.87 specificity).<sup><a href="#R34" class="usa-link" aria-describedby="R34">34</a></sup> An FAQ total score of > 5 has been shown to best distinguish between MCI and early dementia.<sup><a href="#R34" class="usa-link" aria-describedby="R34">34</a></sup></p> <p id="P16">The measure includes 10 IADL items: (1) writing checks, paying bills, balancing a checkbook; (2) assembling tax records, business affairs; (3) shopping; (4) playing a game of skill; (5) heating water, making coffee; (6) preparing a balanced meal; (7) keeping track of current events; (8) paying attention and understanding a television program or book; (9) remembering appointments, dates, medications; (10) traveling out of the neighborhood. Difficulty on each item was rated as 0 (normal or never did, but could do now); 1 (has difficulty, but does by self or never did, but would have difficulty now); 2 (requires assistance); or 3 (dependent). The total FAQ score was included in analyses; if an FAQ item was missing (e.g., skipped by participant), the FAQ score for that occasion was considered missing. The FAQ was completed at the baseline assessment as well as at each follow-up visit.</p></section><section id="S10"><h4 class="pmc_sec_title">Diabetes classification.</h4> <p id="P17">DM classification was determined via the ADNI medical history database<sup><a href="#R13" class="usa-link" aria-describedby="R13">13</a></sup> or presence of glucose-lowering agents.<sup><a href="#R10" class="usa-link" aria-describedby="R10">10</a></sup> Consistent with previous work in ADNI,<sup><a href="#R13" class="usa-link" aria-describedby="R13">13</a></sup> the following search terms were used to identify participants with DM at baseline from medical history: diabetes, diabetic, insulin, insulin-dependent diabetes mellitus, and non-insulin dependent diabetes mellitus. Those with type I diabetes were excluded. The majority of the participants classified as DM were classified based on their medical history (n=51); a smaller proportion (n=18) were classified based the presence of a diabetes medication; 7 participants were prescribed insulin. A subset of individuals who also underwent FDG-PET have blood glucose values (n=642); however, the length of the fast prior to the blood draw varied (some participants had a 4-hour fast, others had an 8-hour fast, some may have been longer), so these values were not used for diabetes classification.</p></section><section id="S11"><h4 class="pmc_sec_title">AD risk factors.</h4> <p id="P18">Objectively-defined subtle cognitive decline (Obj-SCD) is thought to be part of the preclinical AD trajectory<sup><a href="#R35" class="usa-link" aria-describedby="R35">35</a>,<a href="#R36" class="usa-link" aria-describedby="R36">36</a></sup> and has been previously shown to predict progression to MCI and dementia.<sup><a href="#R15" class="usa-link" aria-describedby="R15">15</a></sup> Consistent with our recent work, Obj-SCD status was determined by the following criteria: (1) one impaired total test score (>1 SD below demographically-adjusted mean) in two different cognitive domains (memory, language, attention/executive), <em>or</em> (2) two impaired neuropsychological process scores from the AVLT (learning slope, retroactive interference, intrusion errors), <em>or</em> (3) one impaired total test score and one impaired process score.<sup><a href="#R15" class="usa-link" aria-describedby="R15">15</a></sup> Neuropsychological process scores quantify error-types or other aspects of an individual’s performance that allow one to determine the approach by which an individual achieved the total score on a neuropsychological measure. The process scores used in the Obj-SCD definition have previously been shown to predict progression from CN to MCI or dementia in ADNI.<sup><a href="#R37" class="usa-link" aria-describedby="R37">37</a></sup> A determination of Obj-SCD status was available for 754 participants (DM− n=693, DM+ n=61) with non-missing neuropsychological data.</p> <p id="P19">APOE ε4 positivity (APOE ε4+) was based on presence of at least 1 ε4 allele. A subset of participants underwent a lumbar puncture (N=586; DM− n=536, DM+ n=50) and CSF biomarkers of AD were measured using Elecsys® immunoassays. Biomarker positivity was determined by cut-off scores proposed by Schindler and colleages:<sup><a href="#R38" class="usa-link" aria-describedby="R38">38</a></sup> β-amyloid positivity (Aβ+) <1,098 pg/ml, total tau positivity (tau+) >242 pg/ml, and hyperphosphorylated tau positivity (p-tau+) >19.2 pg/ml.</p></section></section><section id="S12"><h3 class="pmc_sec_title">Statistical analyses</h3> <p id="P20">Baseline demographic and clinical characteristics by DM status were examined using independent t-tests (for continuous variables), Mann-Whitney tests (for nonparametric variables), or chi-squared test (for categorical variables).</p> <p id="P21">Multilevel modeling (MLM) was used to examine whether there were differential rates of functional difficulty (FAQ) over time by DM and AD risk status. The Time variable included seven assessment visit time points over five years and was modeled as a continuous parameter. Both linear and quadratic effects of Time were examined, but including the quadratic term for Time did not improve model-fit based on −2 log likelihood (−2LL), Akaike information criterion (AIC), and Bayesian information criterion (BIC). Covariates included demographic variables (age, education, sex), variables that are related to everyday functioning, including: the geriatric depression scale (GDS) to adjust for depressive symptoms and the Mini Mental State Exam (MMSE) to adjust for global cognition, as well as the Hachinski Ischemia Scale (HIS) to adjust for ischemic risk since this differed between DM+ and DM− groups. Pulse pressure (PP; systolic blood pressure - diastolic blood pressure) was considered for inclusion to adjust for arterial stiffness, but was removed for parsimony in the final analyses since it was not a significant predictor in any of the models and did not differ between DM+ and DM− groups. The random effect of intercept and slope were included in the model. All available data (full information maximum likelihood) were included, which reduces bias relative to other methods (e.g., listwise deletion).<sup><a href="#R39" class="usa-link" aria-describedby="R39">39</a></sup> Variables were centered around their respective mean prior to being entered in the model. One MLM was run for each AD risk factor (Obj-SCD, APOE, Aβ, tau, p-tau), and all main effects, two-, and three-way interactions were examined for DM, AD risk factor, and Time. Each AD risk factor was included as a dichotomous variable based on presence of the risk factor (for Obj-SCD and APOE ε4) or the positivity threshold described in the methods (Aβ, tau, p-tau). The three-way DM × AD risk factor × Time interaction is discussed in the Results section since this is the primary outcome of interest. Sensitivity analyses, excluding participants with incident dementia, were then completed to examine the extent to which incident dementia cases are driving the results. Given the small sample of those with both DM and an AD risk factor, and alpha of .05 was used to determine statistical significance.</p></section></section><section id="S13"><h2 class="pmc_sec_title">RESULTS</h2> <p id="P22"><a href="#T1" class="usa-link">Table 1</a> shows the baseline characteristics of the total sample and split by DM status. At baseline, there were significant differences (<em>p</em><.05) between DM− and DM+ groups on sex, HIS, and blood glucose values but not other demographic, clinical, cognitive, or AD risk factor variables. Notably, there were not differences between DM− and DM+ groups on baseline FAQ score. The baseline characteristics by AD risk factor status are included in <a href="#SD1" class="usa-link">Supplementary Digital Content 1</a>. Across all participants (n=813), there were 355 (43.7%) who progressed to MCI or dementia at any point during the five-year follow-up interval; 70 of these 355 participants progressed to dementia during this interval.</p> <section class="tw xbox font-sm" id="T1"><h3 class="obj_head">Table 1.</h3> <div class="caption p"><p id="P51">Baseline demographic, clinical, and AD risk variables by DM status</p></div> <div class="tbl-box p" tabindex="0"><table class="content" frame="hsides" rules="groups"> <colgroup span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> </colgroup> <thead> <tr> <th align="left" valign="top" style="border-bottom: solid 1px" rowspan="1" colspan="1"></th> <th align="center" valign="middle" style="border-bottom: solid 1px" rowspan="1" colspan="1">Total Sample N=813</th> <th align="center" valign="middle" style="border-bottom: solid 1px" rowspan="1" colspan="1">DM− N=744</th> <th align="center" valign="middle" style="border-bottom: solid 1px" rowspan="1" colspan="1">DM+ N=69</th> <th align="center" valign="top" style="border-bottom: solid 1px" rowspan="1" colspan="1"> <em>t, U</em>, or <em>χ</em><sup><em>2</em></sup> </th> <th align="center" valign="top" style="border-bottom: solid 1px" rowspan="1" colspan="1"><em>p</em></th> </tr> <tr> <th align="left" valign="top" style="border-bottom-style: hidden;" rowspan="1" colspan="1"></th> <th align="center" valign="middle" rowspan="1" colspan="1">Mean (SD)</th> <th align="center" valign="middle" rowspan="1" colspan="1">Mean (SD)</th> <th align="center" valign="middle" rowspan="1" colspan="1">Mean (SD)</th> <th align="center" valign="top" rowspan="1" colspan="1"></th> <th align="center" valign="top" rowspan="1" colspan="1"></th> </tr> </thead> <tbody> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Age</td> <td align="left" valign="middle" rowspan="1" colspan="1">73.62 (6.91)</td> <td align="left" valign="middle" rowspan="1" colspan="1">73.72 (6.99)</td> <td align="left" valign="middle" rowspan="1" colspan="1">72.60 (6.02)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>t=</em>1.28</td> <td align="left" valign="top" rowspan="1" colspan="1">.200</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Education</td> <td align="left" valign="middle" rowspan="1" colspan="1">16.26 (2.71)</td> <td align="left" valign="middle" rowspan="1" colspan="1">16.30 (2.72)</td> <td align="left" valign="middle" rowspan="1" colspan="1">15.77 (2.59)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>t=</em>1.56</td> <td align="left" valign="top" rowspan="1" colspan="1">.120</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Female, N (%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">377 (46.4%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">353 (47.4%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">24 (34.8%)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>χ</em><sup><em>2</em></sup><em>=</em>4.07</td> <td align="left" valign="top" rowspan="1" colspan="1">.<strong>044</strong> </td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">FAQ</td> <td align="left" valign="middle" rowspan="1" colspan="1">1.20 (2.62)</td> <td align="left" valign="middle" rowspan="1" colspan="1">1.17 (2.58)</td> <td align="left" valign="middle" rowspan="1" colspan="1">1.48 (3.04)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>U</em>=25,924.00</td> <td align="left" valign="top" rowspan="1" colspan="1">.869</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">GDS</td> <td align="left" valign="middle" rowspan="1" colspan="1">1.20 (1.32)</td> <td align="left" valign="middle" rowspan="1" colspan="1">1.21 (1.34)</td> <td align="left" valign="middle" rowspan="1" colspan="1">1.17 (1.16)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>U</em>=26,252.00</td> <td align="left" valign="top" rowspan="1" colspan="1">.743</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">HIS</td> <td align="left" valign="middle" rowspan="1" colspan="1">0.58 (0.67)</td> <td align="left" valign="middle" rowspan="1" colspan="1">0.57 (0.68)</td> <td align="left" valign="middle" rowspan="1" colspan="1">0.71 (0.57)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>U</em>=29.656.50</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.016</strong></td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">PP</td> <td align="left" valign="middle" rowspan="1" colspan="1">60.16 (14.75)</td> <td align="left" valign="middle" rowspan="1" colspan="1">60.15 (14.92)</td> <td align="left" valign="middle" rowspan="1" colspan="1">60.29 (12.86)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>t=</em>1.28</td> <td align="left" valign="top" rowspan="1" colspan="1">.939</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">MMSE</td> <td align="left" valign="middle" rowspan="1" colspan="1">28.63 (1.52)</td> <td align="left" valign="middle" rowspan="1" colspan="1">28.65 (1.48)</td> <td align="left" valign="middle" rowspan="1" colspan="1">28.35 (1.89)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>U</em>=23,556.50</td> <td align="left" valign="top" rowspan="1" colspan="1">.239</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Obj-SCD+, N (%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">260 (34.5%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">233 (33.6%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">27 (44.3%)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>χ</em><sup><em>2</em></sup><em>=</em>2.81</td> <td align="left" valign="top" rowspan="1" colspan="1">.094</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">APOE ε4+, N (%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">269 (33.2%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">242 (32.7%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">27 (39.1%)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>χ</em><sup><em>2</em></sup><em>=</em>1.19</td> <td align="left" valign="top" rowspan="1" colspan="1">.275</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Aβ+, N (%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">271 (46.2%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">250 (46.6%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">21 (42.0%)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>χ</em><sup><em>2</em></sup><em>=</em>0.40</td> <td align="left" valign="top" rowspan="1" colspan="1">.529</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">tau+, N (%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">243 (41.5%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">226 (42.2%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">17 (34.0%)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>χ</em><sup><em>2</em></sup><em>=</em>1.26</td> <td align="left" valign="top" rowspan="1" colspan="1">.262</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">p-tau+, N (%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">323 (55.1%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">300 (56.0%)</td> <td align="left" valign="middle" rowspan="1" colspan="1">23 (46.0%)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>χ</em><sup><em>2</em></sup><em>=</em>1.84</td> <td align="left" valign="top" rowspan="1" colspan="1">.175</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Blood glucose</td> <td align="left" valign="middle" rowspan="1" colspan="1">100.42 (17.21)</td> <td align="left" valign="middle" rowspan="1" colspan="1">99.40 (15.56)</td> <td align="left" valign="middle" rowspan="1" colspan="1">110.91 (27.24)</td> <td align="left" valign="top" rowspan="1" colspan="1"> <em>t=</em>−3.14</td> <td align="left" valign="top" rowspan="1" colspan="1">.<strong>003</strong> </td> </tr> </tbody> </table></div> <div class="p text-right font-secondary"><a href="table/T1/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <div class="tw-foot p"><div class="fn" id="TFN1"><p id="P52">AD=Alzheimer’s disease; DM=Type II diabetes mellitus; FAQ=Functional Activities Questionnaire; GDS=Geriatric Depression Scale; HIS=Hachinski Ischemia Scale; PP=pulse pressure; MMSE=Mini Mental State Exam; Obj-SCD+= Objectively-defined Subtle Cognitive Decline positive; APOE ε4+=apolipoprotein E ε4 positive; Aβ+=β-amyloid positive; tau+=total tau positive; p-tau+=hyperphosphorylated tau positive. Blood glucose (mg/dL) was available for 642 participants (DM− n=585, DM+ n=57), but the fasting period varied (as little as 4 hours). The subset of participants with Obj-SCD values is n=754 (DM− n=693, DM+ n=61) and the subset with Aβ, tau, and p-tau values is n=586 (DM− n=536, DM+ n=50).</p></div></div></section><p id="P23">Prior to the running the MLMs, t-tests and chi-square tests were performed to examine whether there were demographic (e.g., age, sex, education) or clinical characteristics (e.g., GDS, MMSE, HIS, FAQ, DM status) that differed between participants who were present or missing at the five-year follow-up visit. Across these variables, there were no significant differences between these groups (all <em>p</em>s>.05).</p> <p id="P24">An initial MLM including the main effect of DM and the two-way DM × Time interaction on functional difficulty (without the AD risk factor main effect and interactions) found that after adjusting for relevant covariates, there was not a significant main effect of DM on level of functional difficulty [<em>F</em>(1, 842.60)=3.57, <em>p</em>=.059, <em>r</em>=.065], but there was a significant interaction such that those with DM had an increased rate of functional difficulty over time [<em>F</em>(1, 790.78)=6.00, <em>p</em>=.015, <em>r</em>=.087]. However, in the models where the AD risk factor and associated interactions were included, this two-way DM × Time interaction becomes nonsignificant and seems to be moderated by the AD risk factors (via the three-way interaction).</p> <p id="P25"><a href="#F1" class="usa-link">Figure 1</a> shows the FAQ trajectories by DM and AD risk factor status, and <a href="#T2" class="usa-link">Table 2</a> shows the parameter estimates for each of the AD risk factor MLMs. The three-way DM × AD risk factor × Time interactions were significant for the Obj-SCD, APOE ε4, tau, and p-tau models. Specifically, the DM × Obj-SCD × Time [<em>F</em>(1, 663.00)=3.96, <em>p</em>=.047, <em>r</em>=.077], DM × APOE ε4 × Time [<em>F</em>(1, 775.44)=12.52, <em>p</em><.001, <em>r</em>=.126], DM × tau × Time [<em>F</em>(1, 539.51)=6.29, <em>p</em>=.012, <em>r</em>=.108], and DM × p-tau × Time [<em>F</em>(1, 555.97)=4.15, <em>p</em>=.042, <em>r</em>=.086] interactions showed that participants who had both DM and one of these four AD risk factors had a fastest rate of functional decline over five years compared to those without both risk factors. The three-way DM × Aβ × Time interaction was non-significant [<em>F</em>(1, 554.81)=0.35, <em>p</em>=.555, <em>r</em>=.025]. By the five-year follow-up, only those with both DM and an AD risk factor had predicted FAQ scores above the threshold that best distinguishes MCI and dementia (FAQ >5).</p> <figure class="fig xbox font-sm" id="F1"><h3 class="obj_head">Figure 1: FAQ trajectories by DM and AD risk factor.</h3> <p class="img-box line-height-none margin-x-neg-2 tablet:margin-x-0 text-center"><a class="tileshop" target="_blank" href="https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=6952586_nihms-1530734-f0001.jpg"><img class="graphic zoom-in" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76cf/6952586/b1c15f67f726/nihms-1530734-f0001.jpg" loading="lazy" height="688" width="800" alt="Figure 1:"></a></p> <div class="p text-right font-secondary"><a href="figure/F1/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <figcaption><p id="P50">Each panel shows a different AD risk factor: a) Objectively-defined Subtle Cognitive Decline (Obj-SCD); b) Apolipoprotein E (APOE) ε4 status; c) Total Tau (tau); d) Hyperphosphorylated Tau (p-tau); e) β-Amyloid (Aβ). Error bars represent 95% confidence interval. The light grey line shows the optimal threshold for distinguishing MCI and dementia.</p></figcaption></figure><section class="tw xbox font-sm" id="T2"><h3 class="obj_head">Table 2.</h3> <div class="caption p"><p id="P53">Estimates for models predicting change in FAQ by DM and AD risk factor status.</p></div> <div class="tbl-box p" tabindex="0"><table class="content" frame="hsides" rules="groups"> <colgroup span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> <col align="left" valign="middle" span="1"> </colgroup> <thead> <tr> <th align="left" valign="top" style="border-bottom: solid 1px" rowspan="1" colspan="1"></th> <th colspan="4" align="center" valign="middle" style="border-bottom: solid 1px" rowspan="1">Obj-SCD</th> <th colspan="4" align="center" valign="middle" style="border-bottom: solid 1px" rowspan="1">APOE ε4</th> <th colspan="4" align="center" valign="middle" style="border-bottom: solid 1px" rowspan="1">Aβ</th> <th colspan="4" align="center" valign="middle" style="border-bottom: solid 1px" rowspan="1">tau</th> <th colspan="4" align="center" valign="middle" style="border-bottom: solid 1px" rowspan="1">p-tau</th> </tr> <tr> <th align="left" valign="top" style="border-bottom-style: hidden;" rowspan="1" colspan="1"></th> <th align="center" valign="middle" rowspan="1" colspan="1">b</th> <th align="center" valign="middle" rowspan="1" colspan="1">S.E.</th> <th align="center" valign="middle" rowspan="1" colspan="1">p</th> <th align="center" valign="middle" rowspan="1" colspan="1">r</th> <th align="center" valign="middle" rowspan="1" colspan="1">b</th> <th align="center" valign="middle" rowspan="1" colspan="1">S.E.</th> <th align="center" valign="middle" rowspan="1" colspan="1">p</th> <th align="center" valign="middle" rowspan="1" colspan="1">r</th> <th align="center" valign="middle" rowspan="1" colspan="1">b</th> <th align="center" valign="middle" rowspan="1" colspan="1">S.E.</th> <th align="center" valign="middle" rowspan="1" colspan="1">p</th> <th align="center" valign="middle" rowspan="1" colspan="1">r</th> <th align="center" valign="middle" rowspan="1" colspan="1">b</th> <th align="center" valign="middle" rowspan="1" colspan="1">S.E.</th> <th align="center" valign="middle" rowspan="1" colspan="1">p</th> <th align="center" valign="middle" rowspan="1" colspan="1">r</th> <th align="center" valign="middle" rowspan="1" colspan="1">b</th> <th align="center" valign="middle" rowspan="1" colspan="1">S.E.</th> <th align="center" valign="middle" rowspan="1" colspan="1">p</th> <th align="center" valign="middle" rowspan="1" colspan="1">r</th> </tr> </thead> <tbody> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Intercept</td> <td align="left" valign="top" rowspan="1" colspan="1">1.405</td> <td align="left" valign="top" rowspan="1" colspan="1">.088</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.523</td> <td align="left" valign="top" rowspan="1" colspan="1">2.018</td> <td align="left" valign="top" rowspan="1" colspan="1">.122</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.499</td> <td align="left" valign="top" rowspan="1" colspan="1">1.936</td> <td align="left" valign="top" rowspan="1" colspan="1">.138</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.495</td> <td align="left" valign="top" rowspan="1" colspan="1">1.958</td> <td align="left" valign="top" rowspan="1" colspan="1">.137</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.505</td> <td align="left" valign="top" rowspan="1" colspan="1">1.951</td> <td align="left" valign="top" rowspan="1" colspan="1">.139</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.498</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Age</td> <td align="left" valign="top" rowspan="1" colspan="1">.028</td> <td align="left" valign="top" rowspan="1" colspan="1">.013</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.031</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.090</td> <td align="left" valign="top" rowspan="1" colspan="1">.033</td> <td align="left" valign="top" rowspan="1" colspan="1">.018</td> <td align="left" valign="top" rowspan="1" colspan="1">.077</td> <td align="left" valign="top" rowspan="1" colspan="1">.064</td> <td align="left" valign="top" rowspan="1" colspan="1">.016</td> <td align="left" valign="top" rowspan="1" colspan="1">.020</td> <td align="left" valign="top" rowspan="1" colspan="1">.435</td> <td align="left" valign="top" rowspan="1" colspan="1">.033</td> <td align="left" valign="top" rowspan="1" colspan="1">.013</td> <td align="left" valign="top" rowspan="1" colspan="1">.020</td> <td align="left" valign="top" rowspan="1" colspan="1">.537</td> <td align="left" valign="top" rowspan="1" colspan="1">.027</td> <td align="left" valign="top" rowspan="1" colspan="1">.017</td> <td align="left" valign="top" rowspan="1" colspan="1">.020</td> <td align="left" valign="top" rowspan="1" colspan="1">.417</td> <td align="left" valign="top" rowspan="1" colspan="1">.035</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Education</td> <td align="left" valign="top" rowspan="1" colspan="1">−.030</td> <td align="left" valign="top" rowspan="1" colspan="1">.034</td> <td align="left" valign="top" rowspan="1" colspan="1">.373</td> <td align="left" valign="top" rowspan="1" colspan="1">−.037</td> <td align="left" valign="top" rowspan="1" colspan="1">−.066</td> <td align="left" valign="top" rowspan="1" colspan="1">.048</td> <td align="left" valign="top" rowspan="1" colspan="1">.172</td> <td align="left" valign="top" rowspan="1" colspan="1">−.049</td> <td align="left" valign="top" rowspan="1" colspan="1">−.072</td> <td align="left" valign="top" rowspan="1" colspan="1">.055</td> <td align="left" valign="top" rowspan="1" colspan="1">.187</td> <td align="left" valign="top" rowspan="1" colspan="1">−.056</td> <td align="left" valign="top" rowspan="1" colspan="1">−.067</td> <td align="left" valign="top" rowspan="1" colspan="1">.054</td> <td align="left" valign="top" rowspan="1" colspan="1">.211</td> <td align="left" valign="top" rowspan="1" colspan="1">−.053</td> <td align="left" valign="top" rowspan="1" colspan="1">−.065</td> <td align="left" valign="top" rowspan="1" colspan="1">.055</td> <td align="left" valign="top" rowspan="1" colspan="1">.234</td> <td align="left" valign="top" rowspan="1" colspan="1">−.050</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Sex</td> <td align="left" valign="top" rowspan="1" colspan="1">−.486</td> <td align="left" valign="top" rowspan="1" colspan="1">.178</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.007</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.113</td> <td align="left" valign="top" rowspan="1" colspan="1">−.910</td> <td align="left" valign="top" rowspan="1" colspan="1">.253</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.128</td> <td align="left" valign="top" rowspan="1" colspan="1">−.974</td> <td align="left" valign="top" rowspan="1" colspan="1">.287</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.142</td> <td align="left" valign="top" rowspan="1" colspan="1">−1.023</td> <td align="left" valign="top" rowspan="1" colspan="1">.283</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.152</td> <td align="left" valign="top" rowspan="1" colspan="1">−.991</td> <td align="left" valign="top" rowspan="1" colspan="1">.287</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.145</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">GDS</td> <td align="left" valign="top" rowspan="1" colspan="1">.342</td> <td align="left" valign="top" rowspan="1" colspan="1">.066</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.213</td> <td align="left" valign="top" rowspan="1" colspan="1">.356</td> <td align="left" valign="top" rowspan="1" colspan="1">.093</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.135</td> <td align="left" valign="top" rowspan="1" colspan="1">.349</td> <td align="left" valign="top" rowspan="1" colspan="1">.104</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.140</td> <td align="left" valign="top" rowspan="1" colspan="1">.405</td> <td align="left" valign="top" rowspan="1" colspan="1">.103</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.165</td> <td align="left" valign="top" rowspan="1" colspan="1">.381</td> <td align="left" valign="top" rowspan="1" colspan="1">.104</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.153</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">HIS</td> <td align="left" valign="top" rowspan="1" colspan="1">−.059</td> <td align="left" valign="top" rowspan="1" colspan="1">.132</td> <td align="left" valign="top" rowspan="1" colspan="1">.656</td> <td align="left" valign="top" rowspan="1" colspan="1">−.019</td> <td align="left" valign="top" rowspan="1" colspan="1">.249</td> <td align="left" valign="top" rowspan="1" colspan="1">.185</td> <td align="left" valign="top" rowspan="1" colspan="1">.177</td> <td align="left" valign="top" rowspan="1" colspan="1">.048</td> <td align="left" valign="top" rowspan="1" colspan="1">.044</td> <td align="left" valign="top" rowspan="1" colspan="1">.207</td> <td align="left" valign="top" rowspan="1" colspan="1">.833</td> <td align="left" valign="top" rowspan="1" colspan="1">.009</td> <td align="left" valign="top" rowspan="1" colspan="1">.127</td> <td align="left" valign="top" rowspan="1" colspan="1">.204</td> <td align="left" valign="top" rowspan="1" colspan="1">.535</td> <td align="left" valign="top" rowspan="1" colspan="1">.026</td> <td align="left" valign="top" rowspan="1" colspan="1">.135</td> <td align="left" valign="top" rowspan="1" colspan="1">.208</td> <td align="left" valign="top" rowspan="1" colspan="1">.516</td> <td align="left" valign="top" rowspan="1" colspan="1">.027</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">MMSE</td> <td align="left" valign="top" rowspan="1" colspan="1">−.312</td> <td align="left" valign="top" rowspan="1" colspan="1">.064</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.198</td> <td align="left" valign="top" rowspan="1" colspan="1">−.633</td> <td align="left" valign="top" rowspan="1" colspan="1">.086</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.255</td> <td align="left" valign="top" rowspan="1" colspan="1">−.499</td> <td align="left" valign="top" rowspan="1" colspan="1">.098</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.209</td> <td align="left" valign="top" rowspan="1" colspan="1">−.535</td> <td align="left" valign="top" rowspan="1" colspan="1">.096</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.229</td> <td align="left" valign="top" rowspan="1" colspan="1">−.516</td> <td align="left" valign="top" rowspan="1" colspan="1">.097</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">−.218</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">Time</td> <td align="left" valign="top" rowspan="1" colspan="1">.029</td> <td align="left" valign="top" rowspan="1" colspan="1">.003</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.365</td> <td align="left" valign="top" rowspan="1" colspan="1">.033</td> <td align="left" valign="top" rowspan="1" colspan="1">.003</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.326</td> <td align="left" valign="top" rowspan="1" colspan="1">.030</td> <td align="left" valign="top" rowspan="1" colspan="1">.004</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.304</td> <td align="left" valign="top" rowspan="1" colspan="1">.030</td> <td align="left" valign="top" rowspan="1" colspan="1">.004</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.307</td> <td align="left" valign="top" rowspan="1" colspan="1">.030</td> <td align="left" valign="top" rowspan="1" colspan="1">.004</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.299</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">DM</td> <td align="left" valign="top" rowspan="1" colspan="1">.061</td> <td align="left" valign="top" rowspan="1" colspan="1">.334</td> <td align="left" valign="top" rowspan="1" colspan="1">.856</td> <td align="left" valign="top" rowspan="1" colspan="1">.007</td> <td align="left" valign="top" rowspan="1" colspan="1">.577</td> <td align="left" valign="top" rowspan="1" colspan="1">.449</td> <td align="left" valign="top" rowspan="1" colspan="1">.199</td> <td align="left" valign="top" rowspan="1" colspan="1">.044</td> <td align="left" valign="top" rowspan="1" colspan="1">.772</td> <td align="left" valign="top" rowspan="1" colspan="1">.501</td> <td align="left" valign="top" rowspan="1" colspan="1">.124</td> <td align="left" valign="top" rowspan="1" colspan="1">.062</td> <td align="left" valign="top" rowspan="1" colspan="1">1.208</td> <td align="left" valign="top" rowspan="1" colspan="1">.500</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.016</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.098</td> <td align="left" valign="top" rowspan="1" colspan="1">1.118</td> <td align="left" valign="top" rowspan="1" colspan="1">.507</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.028</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.089</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">AD risk</td> <td align="left" valign="top" rowspan="1" colspan="1">.870</td> <td align="left" valign="top" rowspan="1" colspan="1">.188</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.175</td> <td align="left" valign="top" rowspan="1" colspan="1">.953</td> <td align="left" valign="top" rowspan="1" colspan="1">.263</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.125</td> <td align="left" valign="top" rowspan="1" colspan="1">1.502</td> <td align="left" valign="top" rowspan="1" colspan="1">.281</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.212</td> <td align="left" valign="top" rowspan="1" colspan="1">1.356</td> <td align="left" valign="top" rowspan="1" colspan="1">.283</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.193</td> <td align="left" valign="top" rowspan="1" colspan="1">.872</td> <td align="left" valign="top" rowspan="1" colspan="1">.285</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.002</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.124</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">DM × Time</td> <td align="left" valign="top" rowspan="1" colspan="1">.007</td> <td align="left" valign="top" rowspan="1" colspan="1">.011</td> <td align="left" valign="top" rowspan="1" colspan="1">.540</td> <td align="left" valign="top" rowspan="1" colspan="1">.024</td> <td align="left" valign="top" rowspan="1" colspan="1">.021</td> <td align="left" valign="top" rowspan="1" colspan="1">.013</td> <td align="left" valign="top" rowspan="1" colspan="1">.107</td> <td align="left" valign="top" rowspan="1" colspan="1">.057</td> <td align="left" valign="top" rowspan="1" colspan="1">.011</td> <td align="left" valign="top" rowspan="1" colspan="1">.014</td> <td align="left" valign="top" rowspan="1" colspan="1">.446</td> <td align="left" valign="top" rowspan="1" colspan="1">.032</td> <td align="left" valign="top" rowspan="1" colspan="1">.021</td> <td align="left" valign="top" rowspan="1" colspan="1">.014</td> <td align="left" valign="top" rowspan="1" colspan="1">.141</td> <td align="left" valign="top" rowspan="1" colspan="1">.063</td> <td align="left" valign="top" rowspan="1" colspan="1">.018</td> <td align="left" valign="top" rowspan="1" colspan="1">.015</td> <td align="left" valign="top" rowspan="1" colspan="1">.222</td> <td align="left" valign="top" rowspan="1" colspan="1">.052</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">AD risk × Time</td> <td align="left" valign="top" rowspan="1" colspan="1">.034</td> <td align="left" valign="top" rowspan="1" colspan="1">.006</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.210</td> <td align="left" valign="top" rowspan="1" colspan="1">.038</td> <td align="left" valign="top" rowspan="1" colspan="1">.007</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.179</td> <td align="left" valign="top" rowspan="1" colspan="1">.042</td> <td align="left" valign="top" rowspan="1" colspan="1">.008</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.221</td> <td align="left" valign="top" rowspan="1" colspan="1">.034</td> <td align="left" valign="top" rowspan="1" colspan="1">.008</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.177</td> <td align="left" valign="top" rowspan="1" colspan="1">.025</td> <td align="left" valign="top" rowspan="1" colspan="1">.008</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.002</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.129</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">DM × AD risk</td> <td align="left" valign="top" rowspan="1" colspan="1">1.036</td> <td align="left" valign="top" rowspan="1" colspan="1">.664</td> <td align="left" valign="top" rowspan="1" colspan="1">.119</td> <td align="left" valign="top" rowspan="1" colspan="1">.059</td> <td align="left" valign="top" rowspan="1" colspan="1">2.960</td> <td align="left" valign="top" rowspan="1" colspan="1">.906</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.116</td> <td align="left" valign="top" rowspan="1" colspan="1">.310</td> <td align="left" valign="top" rowspan="1" colspan="1">1.004</td> <td align="left" valign="top" rowspan="1" colspan="1">.758</td> <td align="left" valign="top" rowspan="1" colspan="1">.013</td> <td align="left" valign="top" rowspan="1" colspan="1">4.274</td> <td align="left" valign="top" rowspan="1" colspan="1">1.038</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.165</td> <td align="left" valign="top" rowspan="1" colspan="1">3.450</td> <td align="left" valign="top" rowspan="1" colspan="1">.997</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.139</td> </tr> <tr> <td align="left" valign="top" rowspan="1" colspan="1">DM × AD risk × Time</td> <td align="left" valign="top" rowspan="1" colspan="1">.045</td> <td align="left" valign="top" rowspan="1" colspan="1">.022</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.047</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.077</td> <td align="left" valign="top" rowspan="1" colspan="1">.091</td> <td align="left" valign="top" rowspan="1" colspan="1">.026</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong><.001</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.126</td> <td align="left" valign="top" rowspan="1" colspan="1">.017</td> <td align="left" valign="top" rowspan="1" colspan="1">.029</td> <td align="left" valign="top" rowspan="1" colspan="1">.555</td> <td align="left" valign="top" rowspan="1" colspan="1">.025</td> <td align="left" valign="top" rowspan="1" colspan="1">.076</td> <td align="left" valign="top" rowspan="1" colspan="1">.030</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.012</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.108</td> <td align="left" valign="top" rowspan="1" colspan="1">.059</td> <td align="left" valign="top" rowspan="1" colspan="1">.029</td> <td align="left" valign="top" rowspan="1" colspan="1"><strong>.042</strong></td> <td align="left" valign="top" rowspan="1" colspan="1">.086</td> </tr> </tbody> </table></div> <div class="p text-right font-secondary"><a href="table/T2/" class="usa-link" target="_blank" rel="noopener noreferrer">Open in a new tab</a></div> <div class="tw-foot p"><div class="fn" id="TFN2"><p id="P54">FAQ=Functional Activities Questionnaire; DM=Type II diabetes mellitus; AD=Alzheimer’s disease; Obj-SCD=Objectively-defined Subtle Cognitive Decline; APOE ε4=apolipoprotein E ε4; Aβ=β-amyloid; tau=total tau; p-tau=hyperphosphorylated tau; GDS=Geriatric Depression Scale; HIS=Hachinski Ischemia Scale; MMSE=Mini Mental State Exam. Effect size (<em>r</em>-values) interpretation: small=0.10, medium=0.30, large=0.50.</p></div></div></section><p id="P26">Since the three-way interaction that included Aβ was not significant, the two-way interactions involving Aβ were examined. The two-way DM × Aβ interaction was also not significant [<em>F</em>(1, 605.24)=0.10, <em>p</em>=.758 <em>r</em>=.013], suggesting that those participants who had DM and were Aβ+ were not functioning disproportionally worse than those without these risk factors at baseline (i.e., functional decline did not already occur). The two-way Aβ × Time interaction was significant [<em>F</em>(1, 562.54)=28.72, <em>p</em><.001, <em>r</em>=.221], suggesting that, independent of DM status, those who were Aβ+ had a faster decline in everyday functioning compared to those who were Aβ−.</p> <p id="P27">Sensitivity analyses were then conducted to determine to what extent these results can be explained by those who progressed to dementia (n=70) within five years. Therefore, these MLMs were re-run excluding the 70 participants who progressed to dementia. The pattern of findings was largely similar in that the three-way DM × APOE ε4 × Time [<em>F</em>(1, 632.59)=9.61, <em>p</em>=.002, <em>r</em>=.122] and DM × tau × Time [<em>F</em>(1, 417.11)=5.27, <em>p</em>=.022, <em>r</em>=.112] interactions remained significant and the DM × Aβ × Time interaction remained non-significant [<em>F</em>(1, 414.85)=0.15, <em>p</em>=.702, <em>r</em>=.019]. The three-way DM × Obj-SCD × Time [<em>F</em>(1, 1468.13)=3.17, <em>p</em>=.075, <em>r</em>=.046] and DM × p-tau × Time [<em>F</em>(1, 402.92)=2.52, <em>p</em>=.113, <em>r</em>=.079] interactions, which were previously on the cusp of statistical significance, no longer reach significance once those with incident dementia are excluded from analyses.</p></section><section id="S14"><h2 class="pmc_sec_title">DISCUSSION</h2> <p id="P28">Our study demonstrated that cognitively normal participants who had both DM and an AD risk factor had a faster rate of functional decline relative to those with only DM or only an AD risk factor. This was true for the AD risk factors of subtle cognitive decline (Obj-SCD), genetic susceptibility (APOE ε4+), as well as CSF markers of tau pathology and neurodegeneration (i.e., p-tau and tau). However, DM and CSF Aβ positivity did not interact to accelerate functional decline. These preliminary findings extend previous work that has demonstrated that CSF Aβ and p-tau predict decline on functioning in cognitively unimpaired older adults<sup><a href="#R23" class="usa-link" aria-describedby="R23">23</a></sup> by examining the interactive effect of DM. Additionally, DM, in combination with an AD risk factor such as cognitive impairment<sup><a href="#R11" class="usa-link" aria-describedby="R11">11</a>,<a href="#R13" class="usa-link" aria-describedby="R13">13</a></sup> or APOE ε4,<sup><a href="#R14" class="usa-link" aria-describedby="R14">14</a>,<a href="#R40" class="usa-link" aria-describedby="R40">40</a></sup> has been associated with greater atrophy, reduced glucose metabolism,<sup><a href="#R13" class="usa-link" aria-describedby="R13">13</a></sup> greater density of neurofibrillary tangles at autopsy,<sup><a href="#R14" class="usa-link" aria-describedby="R14">14</a></sup> as well as greater cognitive decline<sup><a href="#R12" class="usa-link" aria-describedby="R12">12</a></sup> and increased rates of progression to dementia;<sup><a href="#R11" class="usa-link" aria-describedby="R11">11</a></sup> however, previous work has not examined these interactions as predictors of a continuous functional outcome.</p> <p id="P29">Prior work using ADNI data showed DM has a greater association with tau-related neurodegeneration (CSF tau and p-tau) than Aβ (measured by CSF and PET).<sup><a href="#R10" class="usa-link" aria-describedby="R10">10</a></sup> While the current study did not find significant differences between those with and without DM in the proportions of those considered tau, p-tau, or Aβ positive at baseline using CSF, the interaction of DM with tau and p-tau positivity to predict functional decline is notable. DM<sup><a href="#R26" class="usa-link" aria-describedby="R26">26</a></sup> and tau-related neurodegeneration<sup><a href="#R41" class="usa-link" aria-describedby="R41">41</a>,<a href="#R42" class="usa-link" aria-describedby="R42">42</a></sup> are both risk factors for functional decline. Therefore, it follows that the presence of both risk factors would put one at additive risk for faster decline. Conversely, consistent with our own finding that Aβ predicted functional decline, independent of DM status, Aβ has been shown to predict future functional decline, but its association with DM is less clear.<sup><a href="#R42" class="usa-link" aria-describedby="R42">42</a></sup></p> <p id="P30">The mechanism for the interactive relationship between DM and tau/p-tau, including whether they are unique risk factors for functional decline or whether they share a similar underlying mechanism, is unclear. The moderating effect of DM on tau and p-tau, but not Aβ, provides support for a possible synergistic relationship between DM and tau/p-tau that may be responsible for the accelerated decline, rather than two independent mechanisms. In both DM and AD, there is evidence of alterations in insulin signaling and glucose metabolism, increased oxidative stress and inflammation, and formation of advanced glycation end products.<sup><a href="#R43" class="usa-link" aria-describedby="R43">43</a></sup> One specific mechanism that may be responsible for the relationship between DM and p-tau involves glycogen synthase kinase-3β (GSK3β), which is both activated by insulin resistance and may also lead to insulin resistance. Briefly, insulin resistance activates GSK3β via dephosphorylation, which then activates the phosphorylation of tau.<sup><a href="#R43" class="usa-link" aria-describedby="R43">43</a>,<a href="#R44" class="usa-link" aria-describedby="R44">44</a></sup> One study has shown that when intranasal insulin was administered for four weeks in a rat model of DM and compared to subcutaneous insulin treatment, the intranasal insulin normalized GSK3β activation and reduced hyperphosphorylation of tau.<sup><a href="#R45" class="usa-link" aria-describedby="R45">45</a></sup> This is only one possible mechanism and continued translation of pathologic interactions from animal models to clinical research is needed.</p> <p id="P31">There is a consistent body of literature showing that DM in combination with an APOE ε4 allele puts one at higher risk for worse cognition<sup><a href="#R12" class="usa-link" aria-describedby="R12">12</a>,<a href="#R46" class="usa-link" aria-describedby="R46">46</a></sup> and faster progression to dementia<sup><a href="#R40" class="usa-link" aria-describedby="R40">40</a></sup> than either risk factor alone. Similarly, individuals with both DM and an APOE ε4 allele have been shown to have elevated AD pathology,<sup><a href="#R14" class="usa-link" aria-describedby="R14">14</a>,<a href="#R47" class="usa-link" aria-describedby="R47">47</a></sup> despite consistent evidence showing that a DM diagnosis alone does not result in increased risk for AD neuropathology.<sup><a href="#R4" class="usa-link" aria-describedby="R4">4</a></sup> Our current findings fit well within this existing research and extend the literature to demonstrate that DM moderates the effect of APOE ε4 allele on rate of functional decline; the interaction of DM and APOE had the largest effect relative to the other AD risk factors.</p> <p id="P32">While the differentiation of MCI and dementia is often informed by whether someone’s cognitive impairments are causing functional impairment or not, this is an arbitrary categorization. More likely, functional changes are on a continuum and the determination of functional impairment may vary based on the complexity and nature of the activities that are being attempted. Determining predictors of declining everyday functioning trajectories is critical for several reasons. One key reason is for the individual’s quality of life in that it would be ideal to intervene or develop a scaffolding for maintaining optimal functioning prior to observable everyday impairments and potentially costly errors (e.g., mismanaging finances or medications). Secondly, from a healthcare cost perspective, early interventions (e.g., improving diabetes management or teaching compensatory strategies) may allow individuals to remain independent for longer. One estimation has indicated that a treatment that slows the rate of functional decline by only 10% would reduce the average lifetime costs for an individual by $3,880 in 2015 dollars ($4,122 in 2018 dollars).<sup><a href="#R5" class="usa-link" aria-describedby="R5">5</a>,<a href="#R48" class="usa-link" aria-describedby="R48">48</a></sup></p> <p id="P33">This study is the first to examine Obj-SCD in the context of DM and suggests that the use of Obj-SCD may be a useful method for identifying those at risk for future decline, prior to the development of frank cognitive impairment associated with MCI.<sup><a href="#R15" class="usa-link" aria-describedby="R15">15</a></sup> This Obj-SCD classification is a cost-effective and non-invasive method of early detection that may be particularly beneficial for those with DM given the current finding of accelerated functional decline in individuals with both DM and Obj-SCD, even after adjusting for global cognition. The Obj-SCD criteria likely errs on the side of over-classification such that not everyone identified as Obj-SCD will have accelerated functional decline. Therefore, more work is needed to determine the utility of the Obj-SCD construct in the context of DM, as it will be important not to over-pathologize this classification to the individual. However, identification of Obj-SCD in individuals with DM may have direct clinical importance in that it may be possible to intervene early and develop effective medication management strategies and tools to manage DM prior to future cognitive decline. The Alzheimer’s Association recently showed that if everyone who progresses to Alzheimer’s dementia were diagnosed in the MCI stage rather than in the dementia phase or not at all, approximately $7.9 trillion could be save in medical or long-term care costs.<sup><a href="#R5" class="usa-link" aria-describedby="R5">5</a></sup> Cognitive impairment is a risk factor for poorer DM control, reduced exercise and diet adherence, and greater risk of hypoglycemic events.<sup><a href="#R49" class="usa-link" aria-describedby="R49">49</a>,<a href="#R50" class="usa-link" aria-describedby="R50">50</a></sup> In turn, major hypoglycemic episodes are then a risk factor for dementia in older adults with DM.<sup><a href="#R51" class="usa-link" aria-describedby="R51">51</a></sup> Thus, early detection of subtle cognitive changes may be very useful for sustaining everyday functioning in older adults with DM.</p> <p id="P34">Everyday functioning, including the more complex IADLs that are measured using the FAQ, is associated with a number of cognitive functions, including memory and executive functioning.<sup><a href="#R19" class="usa-link" aria-describedby="R19">19</a></sup> Our previous work examining predictors of functional decline in MCI has shown that individuals with both memory and attention/executive function impairments demonstrated faster everyday functioning decline than those with only a memory or memory plus language impairment.<sup><a href="#R32" class="usa-link" aria-describedby="R32">32</a></sup> In this context, it is possible that the combination of early AD-related changes that may cause subtle memory changes, <em>plus</em> vascular-related changes in the context of DM that may cause early executive functioning changes, are jointly responsible for the accelerated decline in everyday functioning in those with DM plus Obj-SCD, APOE ε4, tau+, or p-tau+.</p> <p id="P35">While ADNI data has a number of advantages, including the CSF biomarkers and longitudinal data, the current study is limited by the low proportions of those with DM as well as other cerebrovascular risk factors. This resulted in a small sample size of participants with DM compared to those without DM. Given the interest in combination of DM and positivity for an AD risk factor in predicting functional decline, the current data are limited as there are some combinations of those with both DM and an AD risk factor that yield very few participants. Therefore, the current findings should be considered preliminary evidence of these relationships, but will need replication in future studies, particularly given the small effect sizes of the three-way interactions. Additionally, more detailed DM-related information such as 8-hour fasting blood glucose levels, hemoglobin A1c values, and age of onset/duration of DM diagnosis were not available, as the primary aims of ADNI are not DM-related. It will be critical for future work to extend these findings in a more representative and diverse population of older adults. Further, there is need to examine the time-course of the transition from pre-DM to DM in the context of AD biomarker changes to further determine if these processes share underlying mechanisms or are unique risk factors for cognitive and functional decline.</p> <p id="P36">Exploratory sensitivity analyses showed that the pattern of results remains largely the same when those individuals who progress to dementia were excluded from the sample; however, the effects of DM plus Obj-SCD and DM plus p-tau on rate of functional change no longer reach statistical significance. It is possible that the participants who progress to dementia were predominately driving the effects for the Obj-SCD and p-tau models. Conversely, given the already small sample size for those with DM, excluding those with incident dementia may have reduced the power to detect the already small effects. The sensitivity analyses, however, also confirm that the significant APOE and tau interactions with DM to predict faster decline are not solely driven by those who progress to dementia. This supports the idea that everyday functioning difficulty is on a spectrum and does not only exist as a dichotomous distinction of those with and without functional dependence; it appears to be important independent of its application to differentiate those with and without dementia. The FAQ had a restricted range, with the majority of participants having little-to-no functional difficulty at baseline. While this is not unexpected in a group of cognitively normal individuals, future studies may consider more sensitive measures or performance-based measures of functioning for use in older adults without notable cognitive impairment.</p> <p id="P37">This longitudinal study offers initial evidence that DM moderates the association between several AD risk factors (except for Aβ positivity) and rate of everyday functioning decline across a five-year period. It extends prior work that has primarily focused on individuals with existing cognitive impairment and demonstrates that cognitively normal older adults can progress from functionally independent to having functional difficulty consistent with mild dementia (e.g., FAQ > 5)<sup><a href="#R34" class="usa-link" aria-describedby="R34">34</a></sup> within five years in the context of having both DM and a positive AD risk factor.</p></section><section id="SM1"><h2 class="pmc_sec_title">Supplementary Material</h2> <section class="sm xbox font-sm" id="SD1"><div class="caption p"> <span>Supplemental Digital Content 1</span><p id="P6">Supplemental Digital Content 1. Table that shows the baseline demographic and clinical variables by AD risk factor status.docx</p> </div> <div class="media p" id="d36e860"><div class="caption"> <a href="/articles/instance/6952586/bin/NIHMS1530734-supplement-Supplemental_Digital_Content_1.docx" data-ga-action="click_feat_suppl" class="usa-link">NIHMS1530734-supplement-Supplemental_Digital_Content_1.docx</a><sup> (162.7KB, docx) </sup> </div></div></section></section><section id="S15" class="ack"><h2 class="pmc_sec_title">Sources of Funding:</h2> <p id="P38">This work was supported by NIH grants R01 AG049810 (M.W.B.), K24 AG026431 (M.W.B.), the Alzheimer’s Association (AARF-17–528918 to K.R.T., AARG-17–500358 to E.C.E., and AARG-18–566254 to K.J.B.), and the U.S. Department of Veterans Affairs Clinical Sciences Research and Development Service (Career Development Award-2 1IK2CX001415 to E.C.E. and 1IK2CX000938 to K.J.B.). Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12–2–0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (<a href="http://www.fnih.org/" class="usa-link usa-link--external" data-ga-action="click_feat_suppl" target="_blank" rel="noopener noreferrer">www.fnih.org</a>). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.</p></section><section id="fn-group1" class="fn-group"><h2 class="pmc_sec_title">Footnotes</h2> <div class="fn-group p font-secondary-light font-sm"><div class="fn p" id="FN2"> <p id="P39">Conflicts of Interest</p> <p id="P40">Dr. Thomas reports no disclosures.</p> <p id="P41">Dr. Bangen reports no disclosures.</p> <p id="P42">Ms. Weigand reports no disclosures.</p> <p id="P43">Dr. Edmonds reports no disclosures.</p> <p id="P44">Dr. Sundermann reports no disclosures.</p> <p id="P45">Dr. Wong reports no disclosures.</p> <p id="P46">Mr. Eppig reports no disclosures.</p> <p id="P47">Ms. Werhane reports no disclosures.</p> <p id="P48">Dr. Delano-Wood reports no disclosures.</p> <p id="P49">Dr. Bondi is a consulting editor for the <em>Journal of the International Neuropsychological Society</em>, and serves as a paid consultant for Novartis, Eisai, and Roche pharmaceutical companies.</p> </div></div></section><section id="ref-list1" class="ref-list"><h2 class="pmc_sec_title">REFERENCES</h2> <section id="ref-list1_sec2"><ul class="ref-list font-sm" style="list-style-type:none"> <li id="R1"> <span class="label">1.</span><cite>Centers for Disease Control. 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