Sex differences in microglia as a risk factor for Alzheimer’s disease

Abstract Women are known to have a significantly higher lifetime risk of developing Alzheimer’s disease (AD) and recent research shows that they also appear to suffer greater cognitive deterioration than men at the same disease stage. However, the exact mechanisms underlying this prevalence remain elusive. The purpose of this review is to examine the potential role of neuroinflammation and microglia in driving this sex difference in AD. We first introduce the dual role of microglia in AD, describing their transition from being neuroprotective, in reducing amyloid burden during earlier stages of disease, to their pathological role in exacerbating tau pathology in the later stages. We then describe sex differences in the immune system and in microglial maturation and activities as well as how immune activation in early life may modulate brain function later in life. Lastly, sex differences in microglial function are described in the contexts of aging and AD among other neurodegenerative conditions.