Alzheimer’s disease, a neurodegenerative disorder characterized by progressive cognitive decline and accumulation of amyloid-plaques and neurofibrillary-tangles[1], begins with microstructural damage 10-20 years before cognitive symptoms appear[2]; developing novel non-invasive approaches to characterize early Alzheimer-specific patterns has great potential to improve diagnosis. Neuroinflammation accompanies plaque formation and is a potential target for early detection[2]. Here, we aimed to test advanced MRI-based inflammation biomarkers to capture microstructural differences between APP/PS1 mice and age-matched controls.A cohort of APP/PS1 and age-matched controls (12 and 20) were scanned on a 7T Bruker scanner at four timepoints (3, 4.5, 6 and 12 months). Gray matter microstructure was characterized by conventional and advanced diffusion-weighted MRI to extract markers of microglia and astrocyte morphology. An Elastic-Net statistical model was employed to highlight regions and parameters better discriminating APP/PS1 and controls (Figure1). To validate the advanced MRI biomarkers observed alterations, MRI was complemented with immunohistochemistry to detect plaques, degeneration and inflammation: immunostaining of Iba1 (microglia), DAPI (nuclei) and 6E10 (amyloid plaques) in APP/PS1 confirms presence of plaques and periplaque reactive microglia in cortex and hippocampus.Conventional and advanced biomarkers were significantly altered at 12 months old (Figure1) in regions pathologically active like hippocampus and cortex. Markers associated to process density were the ones that best discriminate APP/PS1 from controls. Interestingly, such markers are already different between groups as early as at 3 months. Overall, this framework holds great potential as non-invasive, in-vivo screening to detect early microglial alterations associated to Alzheimer’s disease-specific microstructural alterations.