Microglia-derived extracellular vesicle content as a biomarker for early detection of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta aggregation, tau pathology, synaptic dysfunction, and neuronal loss. While current biomarker frameworks such as the A/T/N classification have advanced diagnosis, they predominantly reflect relatively late stages of disease, limiting opportunities for early intervention. This underscores the urgent need for biomarkers that are not only accessible and sensitive but also specific to the earliest pathogenic mechanisms of AD. Recent work has underscored the pivotal role of disease-associated microglia (DAM) in the onset and progression of AD. DAM exhibit dual roles: they promote protection by phagocytosing amyloid and debris, metabolizing lipids, and remodelling synapses, yet can also drive pathology through excessive cytokine release, chronic inflammatory signalling, and impaired aggregate clearance. DAM release extracellular vesicles (EVs) that encapsulate proteins, nucleic acids, and lipids, reflective of their state. These vesicles reflect microglial (dys)function and can be detected in cerebrospinal fluid and blood, offering a minimally invasive means to monitor early AD pathology. In this review, we examine the emerging evidence that the content of microglia-derived EVs may fulfil the criteria of ideal biomarkers with a focus on the detectability, sensitivity, specificity, and feasibility for longitudinal monitoring. We discuss their potential to overcome limitations of current fluid and imaging biomarkers by offering more stable cargo protection, cell-type specificity, and accessibility in peripheral fluids. Furthermore, we highlight the opportunities and challenges in isolating microglia-derived EVs, identifying reliable surface and cargo markers, and standardizing methodologies for reproducibility across studies. By integrating insights from microglial biology with EV research, we provide evidence for microglia-derived EV content as biomarkers for early detection of AD and propose a roadmap toward DAM-specific EV signatures that could transform early AD diagnosis and disease monitoring. Such advances hold promise not only for AD but also for broader applications in neurodegenerative and neuroinflammatory disorders.