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Multivariable linear regression analyses were conducted to investigate the main effects and interaction of the <jats:italic>APOE<\/jats:italic> genotype and disease status on the insula functional connectivity (IFC) network. Mediation and moderation analysis were performed to investigate whether IFC strengths regulate the association between <jats:italic>APOE<\/jats:italic> genotype, CSF biomarkers and cognition. Additionally, the support vector machine (SVM) model integrating <jats:italic>APOE<\/jats:italic> genotype, CSF biomarkers, and neuroimaging biomarkers (insula volumes and altered regional IFCs) was used to classify the AD spectrum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The interactive effect of the <jats:italic>APOE<\/jats:italic> genotype and disease on the insula network was found in the left medial superior frontal gyrus (SFGmed.L), right anterior medial prefrontal cortex (aMPFC.R), and bilateral thalamus (THA.B). The functional connectivities (FCs) in the left insula (LIns) connecting with the left posterior middle temporal gyrus (pMTG.L), SFGmed.L, and right lingual gyrus (LING.R) were correlated with cognition. LIns\u2010SFGmed.L and LIns\u2010pMTG.L FCs could moderate the effects of Tau on cognition. Furthermore, LIns\u2010SFGmed.L FC may suppress the association between <jats:italic>APOE<\/jats:italic> genotype and cognition. More importantly, the integrated biomarkers from the SVM model yielded strong powers for classifying the AD spectrum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Insula functional connectivity regulated the association between <jats:italic>APOE<\/jats:italic> genotype, CSF Tau and cognition and provided stage\u2010dependent biomarkers for early differentiation of the AD spectrum. The present study used a cross\u2010sectional design. Follow\u2010up studies are needed to validate the relationship.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.14401","type":"journal-article","created":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T09:10:00Z","timestamp":1692004200000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The relationship between <i>APOE<\/i> genotype, <scp>CSF<\/scp> Tau and cognition across the Alzheimer's disease spectrum, moderation and mediation role of insula network connectivity"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9426-088X","authenticated-orcid":false,"given":"Yao","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine University of Science and Technology of China  Hefei 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