BackgroundAlzheimer’s disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD.MethodsWe integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP)viamultiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes. The expression patterns and functional relevance of the top sex-specific network driver of AD were further investigated using postmortem human brain samples and gene perturbation experiments in AD mouse models.ResultsGene expression changes in ADversuscontrol were identified for each sex. Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex. Key network regulators were further identified as potential drivers of sex differences in AD development.LRP10was identified as a top driver of the sex differences in AD pathogenesis and manifestation. Changes of LRP10 expression at the mRNA and protein levels were further validated in human AD brain samples. Gene perturbation experiments in EFAD mouse models demonstrated thatLRP10differentially affected cognitive function and AD pathology in sex- and APOE genotype-specific manners. A comprehensive mapping of brain cells inLRP10over-expressed (OE) female E4FAD mice suggested neurons and microglia as the most affected cell populations. The female-specific targets ofLRP10identified from the single cell RNA-sequencing (scRNA-seq) data of theLRP10OE E4FAD mouse brains were significantly enriched in theLRP10-centered subnetworks in female AD subjects, validatingLRP10as a key network regulator of AD in females. Eight LRP10 binding partners were identified by the yeast two-hybrid system screening, and LRP10 over-expression reduced the association of LRP10 with one binding partner CD34.ConclusionsThese findings provide insights into key mechanisms mediating sex differences in AD pathogenesis and will facilitate the development of sex- and APOE genotype-specific therapies for AD.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13024-023-00624-5.