AbstractRecent multi‐omics analyses paved the way for a comprehensive understanding of pathological processes. However, only few studies have explored Alzheimer’s disease (AD) despite the possibility of biological subtypes within these patients. For this study, unsupervised classification of four datasets (genetics, miRNA transcriptomics, proteomics, and blood‐based biomarkers) using Multi‐Omics Factor Analysis+ (MOFA+), along with systems‐biological approaches following various downstream analyses are performed. New subgroups within 170 patients with cerebral amyloid pathology (Aβ+) are revealed and the features of them are identified based on the top‐rated targets constructing multi‐omics factors of both whole (M‐TPAD) and immune‐focused models (M‐IPAD). The authors explored the characteristics of subtypes and possible key‐drivers for AD pathogenesis. Further in‐depth studies showed that these subtypes are associated with longitudinal brain changes and autophagy pathways are main contributors. The significance of autophagy or clustering tendency is validated in peripheral blood mononuclear cells (PBMCs; n = 120 including 30 Aβ‐ and 90 Aβ+), induced pluripotent stem cell‐derived human brain organoids/microglia (n = 12 including 5 Aβ‐, 5 Aβ+, and CRISPR‐Cas9 apolipoprotein isogenic lines), and human brain transcriptome (n = 78). Collectively, this study provides a strategy for precision medicine therapy and drug development for AD using integrative multi‐omics analysis and network modelling.