{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:07:50Z","timestamp":1778479670338,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,11]]},"group-title":"In Review","reference-count":0,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,17]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  Background\n Mild cognitive impairment (MCI) is a critical prodromal stage of progressive cognitive decline. As a core cognitive brain network, the default mode network (DMN) exhibits structural alterations in MCI that are closely associated with cognitive impairment.\n                  <italic>Apolipoprotein E \u03b54 (APOE \u03b54)<\/italic>\n                  , the strongest genetic risk factor for pathological cognitive decline, has been shown to disrupt the structural integrity of the DMN\u2019s three core subsystems: the Midline Core, Medial Temporal Lobe (MTL), and Dorsomedial Prefrontal Cortex (DMPFC) subsystems. However, the subsystem-specific effects of\n                  <italic>APOE \u03b54<\/italic>\n                  and the cognitive mechanisms through which they operate in MCI remain unclear.\nMethods\n We enrolled 176 participants from the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI), including 116 patients with MCI and 60 cognitively normal (CN) individuals, with balanced APOE \u03b54 carrier status within each diagnostic group. Standardized volumes of eight DMN regions were analyzed using permutational multivariate analysis of variance (PERMANOVA) to test diagnosis-by-genotype interactions, followed by false discovery rate (FDR)-corrected univariate analyses and multiple linear regression to identify regional volume differences. Bootstrap-based mediation analysis and receiver operating characteristic (ROC) analysis were further performed to examine clinical relevance.\nResults\n A significant diagnosis-by-\n                  <italic>APOE \u03b54<\/italic>\n                  interaction was observed in the global structural pattern of the DMN, primarily driven by the DMPFC and MTL subsystems. Among patients with MCI,\n                  <italic>APOE \u03b54<\/italic>\n                  carriers exhibited selective atrophy within the DMPFC subsystem, specifically in the gyrus rectus (REC) and superior temporal pole (TPOsup), relative to non-carriers. Critically, TPOsup atrophy mediated 30.43% of the negative effect of\n                  <italic>APOE \u03b54<\/italic>\n                  on global cognition, as measured by the Mini-Mental State Examination (MMSE), and was significantly associated with impaired orientation.\nConclusion\n The TPOsup may represent a key neural hub linking\n                  <italic>APOE \u03b54<\/italic>\n                  to cognitive decline in MCI and may serve as a specific imaging marker for risk stratification in this population.\n                <\/p>","DOI":"10.21203\/rs.3.rs-9447482\/v1","type":"posted-content","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T05:08:12Z","timestamp":1778476092000},"source":"Crossref","is-referenced-by-count":0,"title":["APOE \u03b54-related structural vulnerability in mild cognitive impairment: a subsystem-based analysis of the default mode network"],"prefix":"10.21203","author":[{"given":"Xiaoming","family":"Yang","sequence":"first","affiliation":[{"name":"Second Affiliated Hospital of Xi'an Jiaotong University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Lyu","sequence":"additional","affiliation":[{"name":"Second Affiliated Hospital of Xi'an Jiaotong University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jubo","family":"Wang","sequence":"additional","affiliation":[{"name":"Second Affiliated Hospital of Xi'an Jiaotong University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Quan","sequence":"additional","affiliation":[{"name":"Second Affiliated Hospital of Xi'an Jiaotong University"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9447482\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9447482\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T05:08:12Z","timestamp":1778476092000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-9447482\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,11]]},"references-count":0,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-9447482\/v1","relation":{},"subject":[],"published":{"date-parts":[[2026,5,11]]},"subtype":"preprint"}}