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The APOE-\u03b54 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the \u03b54 allele. Yet, no study has assessed APOE-\u03b54 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. We assessed the impact of APOE-\u03b54 on rsFC in a sample of 429 cognitively unimpaired individuals hosting a high number of \u03b54 homozygotes (n\u2009=\u200958), which enabled testing different models of genetic penetrance. We used independent component analysis and found a reduced rsFC as a function of the APOE-\u03b54 allelic load in the temporal default-mode and the medial temporal networks, while recessive effects were found in the extrastriate and limbic networks. Some of these results were replicated in a subsample with negative amyloid markers. Interaction with cognitive data suggests that such a network reorganization may support cognitive performance in the \u03b54-homozygotes. Our data indicate that APOE-\u03b54 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation.<\/jats:p>","DOI":"10.1093\/cercor\/bhac239","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T19:42:27Z","timestamp":1656272547000},"page":"2748-2760","source":"Crossref","is-referenced-by-count":20,"title":["Genotypic effects of\n                    <i>APOE<\/i>\n                    -\u03b54 on resting-state connectivity in cognitively intact individuals support functional brain compensation"],"prefix":"10.1093","volume":"33","author":[{"given":"Raffaele","family":"Cacciaglia","sequence":"first","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center (BBRC), Pasqual Maragall Foundation , Wellington 30, 08005 Barcelona, Spain"},{"name":"Hospital del Mar Medical Research Institute (IMIM) , 08005 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) , 28089 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gr\u00e9gory","family":"Operto","sequence":"additional","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center (BBRC), Pasqual Maragall Foundation , Wellington 30, 08005 Barcelona, Spain"},{"name":"Hospital del Mar Medical Research Institute (IMIM) , 08005 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) , 28089 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carles","family":"Falc\u00f3n","sequence":"additional","affiliation":[{"name":"Barcelona\u03b2eta Brain Research Center (BBRC), Pasqual Maragall Foundation , Wellington 30, 08005 Barcelona, Spain"},{"name":"Hospital del Mar Medical Research Institute (IMIM) , 08005 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Bioingenier\u00eda, Biomateriales y 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