Central Nervous System-Derived Extracellular Vesicles as Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) has emerged as a global health threat that demands early detection to seize the optimal intervention opportunity. Central nervous system (CNS)-derived extracellular vesicles (EVs), lipid-bilayer nanoparticles released by CNS cells, carry key biomolecules involved in AD pathology, positioning them as a promising source of biomarkers for early detection. Current breakthroughs in EV-based isolation and detection technologies have opened up the possibility of early, accurate AD diagnosis. This review summarizes their multifaceted roles in AD pathogenesis, including amyloid-β (Aβ) aggregation, tau propagation, neuroinflammation, and synaptic dysfunction, and highlights neuron- and glia-derived EV biomarkers with translational potential. We further outline recent advances in EV isolation techniques-including density-, size-, charge/dielectric-, immunoaffinity-, and acoustics-based approaches-and emerging detection platforms such as fluorescence, surface plasmon resonance (SPR), surface-enhanced Raman spectroscopy (SERS), electrochemical, and nanomechanical sensors for sensitive, multiplex AD diagnostics. Finally, we discuss key challenges, including standardization, sensitivity, and high-throughput adaptation, and explore future directions such as automated microfluidics and single-vesicle analysis. CNS-derived EVs hold significant promise as minimally invasive, next-generation tools for early AD detection and precision medicine.