Abstract Microglial dysfunction is believed to play a pathogenic role in Alzheimer’s disease (AD). Here, we characterize the amyloid-β related pathology and microglial responses in an engineered APP knock-in mouse model of familial AD. This model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered glial responses and neurodegeneration. Leveraging multi-omics approaches, we found lipid accumulation and an exacerbated disease-associated transcriptomic response in methoxy-X04-positive, phagocytic microglia. Together, these findings highlight the potential of this novel, open-access mouse model to investigate AD pathogenesis and demonstrate that fibrillar Aβ triggers lipid dysregulation and immuno-metabolic perturbations in phagocytic microglia. Highlights Novel open-access APP KI mouse model shows salient AD pathological features Deep phenotyping of sorted microglia reveals profound lipidomic perturbations in line with Alois Alzheimer’s original descriptions of glial adipose inclusions Immunometabolic perturbations are exacerbated in microglia accumulating fibrillar Aβ

Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse model