{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T11:24:15Z","timestamp":1768821855165,"version":"3.49.0"},"reference-count":53,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC3605200"],"award-info":[{"award-number":["2023YFC3605200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005089","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["JQ21022"],"award-info":[{"award-number":["JQ21022"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81901181"],"award-info":[{"award-number":["81901181"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071212"],"award-info":[{"award-number":["82071212"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471449"],"award-info":[{"award-number":["82471449"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Evidence from observational and Mendelian randomization (MR) studies suggested that insulin resistance (IR) was associated with Alzheimer's disease (AD). However, the causal effects of different indicators of IR on AD remain inconsistent. Here, we aim to assess the causal association between the insulin sensitivity index (ISI), a measure of post\u2010prandial IR, and the risk of AD. We first conducted primary and secondary univariable MR analyses. We selected 8 independent genome\u2010wide significant (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20095E\u201008, primary analyses) and 61 suggestive (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20091E\u201005, secondary analyses) ISI genetic variants from large\u2010scale genome\u2010wide association studies (GWAS;\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200953\u2009657), respectively, and extracted their corresponding GWAS summary statistics from AD GWAS, including IGAP2019 (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u200963\u2009926) and FinnGen_G6_AD_WIDE (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009412\u2009181). We selected five univariable MR methods and used heterogeneity, horizontal pleiotropy test, and leave\u2010one\u2010out sensitivity analysis to confirm the stability of MR estimates. Finally, we conducted a meta\u2010analysis to combine MR estimates from two non\u2010overlapping AD GWAS datasets. We further performed multivariable MR (MVMR) to assess the potential mediating role of type 2 diabetes (T2D) on the association between ISI and AD using two MVMR methods. In univariable MR, utilizing 8 genetic variants in primary analyses, we found a significant causal association of genetically increased ISI with decreased risk of AD (OR\u2009=\u20090.79, 95% CI: 0.68\u20130.92,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003). Utilizing 61 genetic variants in secondary analyses, we found consistent findings of a causal effect of genetically increased ISI on the decreased risk of AD (OR\u2009=\u20090.89, 95% CI: 0.82\u20130.96,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003). Heterogeneity, horizontal pleiotropy test, and leave\u2010one\u2010out sensitivity analysis ensured the reliability of the MR estimates. In MVMR, we found no causal relationship between ISI and AD after adjusting for T2D (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&gt;\u20090.05). We provide genetic evidence that increased ISI is significantly and causally associated with reduced risk of AD, which is mediated by T2D. These findings may inform prevention strategies directed toward IR\u2010associated T2D and AD.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16254-fig-0004-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16254","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T04:55:07Z","timestamp":1730350507000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Causal association between insulin sensitivity index and Alzheimer's disease"],"prefix":"10.1111","volume":"169","author":[{"given":"Fang","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Neurology Xuanwu Hospital, National Center for Neurological Disorders, Capital Medical University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiyang","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders Capital Medical University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shan","family":"Gao","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders Capital Medical University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders Capital Medical University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Huang","sequence":"additional","affiliation":[{"name":"Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine Macau University of Science and Technology  Taipa, Macao SAR China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics School of Public Health, Wannan Medical College  Wuhu Anhui 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