Microglial phenotype during Alzheimer’s Disease (AD) continuum is under debate. At early stages, a protective phenotype with the typical DAM profile would participate in plaque compaction and Aβ degradation. Instead, human AD microglia (HAM) show an enhance aged/degenerative profile, supporting a microglial dysfunction as a central mechanism in AD aetiology. Recent findings from our lab described that peri-plaque microglia are highly reliant on oxygen levels and mitochondrial integrity. Nevertheless, mitochondrial implication in aged microglia during the disease progression remains unclear. Therefore, we aimed to analyse the microglial phenotype in APP-based transgenic mice at different ages and post-mortem human samples of AD patients, focusing on degeneration markers (senescence and ferroptosis), interferon type I pathway and mitochondrial function.Isolated microglia from 18-moth-old APP mice displayed noticeable increases in the expression of main genes related with microglial activation, hypoxia, type I interferon pathway, senescence and ferroptosis. Hippocampal samples from AD individuals confirmed similar rises in the expression of type-I interferon pathway during disease progression. Moreover, immunoblotting analyses of 12-month-old APP/PS1 mice revealed high levels of ferritin+ peri-plaque microglia, which indicated an age-dependent microglial dysfunction associated with oxidative stress and ferroptotic pathway. In this regard, fluorescent probes experiments showed high levels of mitochondrial ROS production in microglia from aged APP mice. Likewise, electron microscopy images exhibited mitochondrial morphological abnormalities in hippocampal microglia from these mice.Altogether, these results suggest that amyloid pathology accumulation triggers a shift towards an aged microglial profile with a special genetic signature associated to mitochondrial abnormalities.