Alzheimer’s disease is twice more common in women than men. Moreover, women experience faster age-related cognitive decline than men. However, the precise reasons behind these differences in Alzheimer’s disease between women and men are unknown. In this application, we will explore the differential impact of sex on AD pathogenesis. We will employ two emerging technologies to quantify pathological sex-dependent changes in neurons during AD in relevant in vitro models. In preliminary work, these models have been validated to recapitulate the key pathogenic cascades of AD in normal human neurons. This proposal will address the urgent need to address the gap in knowledge of understanding the role of sex differences in AD. Ultimately, it will lead to new insights into AD pathogenesis, which ultimately will result in better interventions to prevent, monitor and treat AD.