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Shared genetic signatures between LOAD and longevity were frequently hypothesized, likely characterized by distinctive epistatic and pleiotropic interactions. Here, we applied a multidimensional reduction approach to detect gene\u2013gene interactions affecting LOAD in a large dataset of genomic variants harbored by genes in the insulin\/IGF1 signaling, DNA repair, and oxidative stress pathways, previously investigated in human longevity. The dataset was generated from a collection of publicly available Genome Wide Association Studies, comprising a total of 2,469 gene variants genotyped in 20,766 subjects of Northwestern European ancestry (11,038 LOAD cases and 9,728 controls). The stratified analysis according to <jats:italic>APOE<\/jats:italic>*4 status and sex corroborated evidence that pathways leading to longevity also contribute to LOAD. Among the significantly interacting genes, <jats:italic>PTPN1<\/jats:italic>, <jats:italic>TXNRD1<\/jats:italic>, and <jats:italic>IGF1R<\/jats:italic> were already found enriched in gene\u2013gene interactions affecting survival to old age. Furthermore, interacting variants associated with LOAD in a sex\u2010 and <jats:italic>APOE<\/jats:italic>\u2010specific way. Indeed, while in <jats:italic>APOE<\/jats:italic>*4 female carriers we found several inter\u2010pathway interactions, no significant epistasis was found in <jats:italic>APOE<\/jats:italic>*4 negative females; conversely, in males, significant intra\u2010 and inter\u2010pathways epistasis emerged according to <jats:italic>APOE<\/jats:italic>*4 status. These findings suggest that interactions of risk factors may drive different trajectories of cognitive aging. Beyond helping to disentangle the genetic architecture of LOAD, such knowledge may improve precision in predicting the risk of dementia and enable effective sex\u2010 and <jats:italic>APOE<\/jats:italic>\u2010stratified preventive and therapeutic interventions for LOAD.<\/jats:p>","DOI":"10.1111\/acel.13938","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T05:40:45Z","timestamp":1692942045000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Sex\u2010 and <i>APOE<\/i>\u2010specific genetic risk factors for late\u2010onset Alzheimer's disease: Evidence from gene\u2013gene interaction of longevity\u2010related loci"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2589-7929","authenticated-orcid":false,"given":"Serena","family":"Dato","sequence":"first","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences University of 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