The molecular networks underlying Alzheimer’s disease (AD) are not well-defined. We present temporal profiling of 14,513 proteins and 34,173 phosphosites at the asymptomatic and symptomatic stages of AD, deep proteomics analysis of transgenic mouse models (5xFAD and Tau P301S), and computational algorithms for integrating multi-omics datasets. Network analysis reveals disease stage-correlated modules comprised of 218 proteins and 398 phosphoproteins differentially expressed in AD, as well as Aβ- or phospho-Tau-induced proteomic alterations. Cross-species comparison indicates that the 5xFAD model displays a similar molecular signature to symptomatic AD, but exhibits mouse-specific activation of interferon response, and lacks human-specific events, such as downregulation of neurotrophic factors (e.g. BDNF, VGF, CRH and Neuritin) and deregulation of iron homeostasis. Multi-omics integration prioritizes altered novel molecules and pathways, including inflammation, WNT signaling, TGFβ/BMP signaling, and membrane transport, which are enriched in secreted and cell surface proteins with heparin-binding domains. The top-ranked Aβ-Netrin-UNC5C axis shows a protective feedback in the asymptomatic stage. Thus, the multilayer proteomics and systems biology approaches elucidate disease networks/pathways in AD progression.