Dementia is a term for several diseases that affect memory, thinking, and daily activity performance. The most prevalent form of dementia is Alzheimer’s disease (AD), which explains 60-70% of dementia cases (World Health Organization [WHO], 2023). AD is a neurodegenerative disorder characterized by brain atrophy, gliosis, Abeta and tau proteinopathies, and vascular dysfunction. Previously, our group has described that a non-productive angiogenesis (NPA) phenomenon occurs around Abeta plaques, giving rise to disassembled, low-perfused vascular structures, which we have called vascular scars (VaS). We have also observed that microglia are not only reactive to Abeta deposits but also to nearby endothelial cells (EC), which could contribute to the VaS formation (Álvarez-Vergara, M.I., et al., Nat. Commun., 2021). As microglia get exhausted during the progression of AD (March-Díaz, R., et al., Nat. Aging, 2021), we wonder whether the vascular dysfunction could be exacerbated when the microglia activity is reduced in the brain of AD models. We are studying the vascular consequences of inhibiting microglial phagocytosis using a pharmacological approach based on PLX3397 diet. Our preliminary results show an efficient microglial depletion, which has a potential effect on amyloid pathology, mainly in female mice. Strikingly, we have not been able to completely deplete microglia around Abeta deposits, therefore, we are planning to use a genetic tool with reduced microglial activity (Trem-/- ). While work is in progress, our preliminary data suggests potential resistance of microglia to CSF1R inhibition in the Abeta context, prompting us to explore alternative approaches.