Primary cilia–extracellular vesicle crosstalk in Alzheimer's disease: Emerging mechanisms and biomarker potential

Alzheimer's disease (AD) is a neurodegenerative condition marked by cognitive decline and synaptic issues. Recent studies show primary cilia (PCs), sensory organelles present on the surface of most mammalian cells, act as a critical regulators of brain homeostasis and signaling. PCs act as a signaling hubs for pathways like G protein-coupled receptor, Hedgehog, Wnt, and neuroinflammation. When PCs are depleted or dysfunctional, they impair the processing of amyloid precursor protein, tau phosphorylation, synaptic signaling, and neuron-glia communication, leading to tau tangles, neuroinflammation, and amyloid beta plaques that drive AD progression. Beyond their role in signal transduction, PCs also regulate the biogenesis, release, and cargo selection of extracellular vesicles (EVs), and dysfunctional EV-PC crosstalk may contribute to AD progression. Examining PC-derived EVs offers pathway-specific insights into early ciliary and neuroinflammatory issues. This review consolidates evidence on PCs' multifaceted role in AD pathogenesis and suggests their potential as an early biomarker.