The immune response within Alzheimer's disease: from the lense of peripheral monocyte-derived macrophages

Alzheimer's disease (AD) is the most significant form of dementia characterized by neurodegeneration and higher-order cognitive decline affecting over 6.9 million Americans age 65 and older. Emerging evidence for AD pathogenesis has expanded mechanistic investigation from focusing on the central nervous system (CNS), to including the peripheral immune system. Microglia in CNS and their counterpart peripheral monocyte-derived macrophages (MDMs) share fundamental functions as innate cells that contribute to the inflammatory response, phagocytosis of debris, and tissue repair after injury. As recently recognized in AD pathogenesis, MDMs have distinct origins and respond differently to environmental cues relative to microglia, presenting unique potentials for therapeutic targeting outside of the blood-brain barrier. In this review, we will diverge from the previously highlighted primary immune regulator in the CNS, the microglia, to explore the significance of MDMs as a peripheral-origin contributor to the pathogenesis of AD.