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We evaluated the influence of <jats:italic>APOE<\/jats:italic> \u03b54\u00a0allele on synaptic density and investigated the effects of \u03b54 genotype on the associations of synaptic density with Alzheimer's disease (AD) biomarkers. The mediation effects of AD biomarkers on \u03b54\u2010associated synaptic density loss were analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Compared with non\u2010carriers, <jats:italic>APOE<\/jats:italic> \u03b54 allele carriers exhibited significant synaptic loss in the medial temporal lobe. Amyloid beta (A\u03b2) and tau pathology mediated the effects of <jats:italic>APOE<\/jats:italic> \u03b54 on synaptic density to different extents. The associations between synaptic density and tau pathology were regulated by the <jats:italic>APOE<\/jats:italic> \u03b54 genotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>The <jats:italic>APOE<\/jats:italic> \u03b54 allele was associated with decreased synaptic density in CI individuals and may be driven by AD biomarkers.<\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.13775","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T08:15:06Z","timestamp":1710317706000},"page":"3157-3166","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["<i>APOE<\/i> \u03b54 is associated with decreased synaptic density in cognitively impaired participants"],"prefix":"10.1002","volume":"20","author":[{"given":"Kun","family":"He","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine &amp; PET Center Huashan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binyin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology &amp; 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