Microglia, tissue-resident macrophages of the brain, are strongly involved in the maintenance of brain homeostasis. Genome-wide association studies have established their critical role in the pathogenesis of Alzheimer’s disease (AD) but their precise contribution is not yet clarified. Most AD preclinical studies are performed in transgenic mouse models. However murine and human microglia have different transcriptomic profiles with aging. Interestingly, induced pluripotent stem cells (iPSCs) – derived models enable studying human-like cells. Our project aims to generate human iPSCs-derived microglia-like cells (iMGLs) from both non-demented controls and AD patients to study the roles of microglia in AD.iPSCs were generated from non-demented individual (ND), patient with sporadic or autosomal dominant (PSEN1 mutation) forms of AD. Then, iPSCs were differentiated into iMGLs and characterized using in vitro assays and transcriptomic studies.Our protocol allows the generation of iMGLs expressing microglial markers, such as P2RY12 or TMEM119, and exhibiting typical microglial functions, including phagocytosis and cytokines secretion in response to inflammatory stimuli. Further, iMGLs can integrate into 2D or 3D neural networks. AD-iMGLs present distinct transcriptomic profiles from ND-iMGLs with more than 4400 deregulated genes. Pathway enrichment analyses are ongoing. AD-iMGLs exhibit also several functional alterations compare to ND-iMGLs. Notably they tend to form clusters in culture and display increased secretion of pro-inflammatory cytokines in basal condition and decreased phagocytosis capabilities.Our model provides an unprecedent approach to better understand the roles of human microglia in the early stages of AD. Such knowledge is a required step to design innovative therapeutic strategies.