Alzheimer's disease (AD) exhibits sex-specific prevalence rates, yet the molecular mechanisms underlying these differences remain elusive. Neuroinflammation, specifically the microglia response, is thought to have a prominent role in AD pathogenesis. This study seeks to understand how sex chromosomes influence human microglia response to amyloid accumulation and how this may contribute to sexual dimorphisms in AD pathology. Inducible pluripotent stem cells (iPSCs) were generated from a donor with Klinefelter’s syndrome (XXY) and modified to express one or 2 sex chromosomes (XX, XY, XO). Microglia progenitors derived from these isogenic lines were grafted into AppNL-G-F mice to determine the effects of amyloid pathology on male and female microglia using single-cell transcriptomics and immunohistochemistry. This chimeric system offers a powerful tool to study how human microglia respond to amyloid pathology in a physiologically relevant environment and allows in an unprecedented way to evaluate the contribution of the X and the Y chromosome to microglia behaviour in the context of AD. Transplanted XX, XY and XO derived microglia show similar levels of chimerism and have no impact onto amyloid plaques burden. However, our findings reveal distinct microglial responses driven by the sex chromosome composition. This innovative approach sheds light on the role of sex chromosomes in modulating microglial function in AD, offering insights into sex-specific disease mechanisms and potential therapeutic targets.