Abstract: Brain insulin resistance (BIR) is a prevalent detrimental feature of Alzheimer’s disease (AD) and all-cause dementia. Therapies designed to activate insulin signaling and enhance insulin receptor sensitivity have proven beneficial for cognitive enhancement in pre-clinical models, non-human primates, and humans. BIR encompasses dysregulated brain insulin signaling, which is either due to insulin receptor resistance, reduced insulin receptor levels, or reduced levels of insulin in the brain, affecting processes involved in AD development and progression. While prior work has shown BIR is a nexus between metabolic dysfunction and neurodegenerative disease, a recent work by Chen et al. (2025) re-emphasizes a role of BIR in AD, highlighting microglia as a key mediator. This recent work is a great step forward in answering many of these questions and shows how central insulin receptor resistance of microglia can result in altered cellular metabolism, neuroinflammation, altered mood and social behavior, and accelerated AD pathogenesis