Neuron-derived Extracellular Vesicles As a Liquid Biopsy for Brain Insulin Dysregulation in Alzheimer's Disease and Related Disorders

Extracellular vesicles (EVs) have emerged as novel blood-based biomarkers for various pathologies. The development of methods to enrich cell-specific EVs from biofluids has enabled us to monitor difficult-to-access organs, such as the brain, in real time without disrupting their function, thus serving as liquid biopsy. Burgeoning evidence indicates that the contents of neuron-derived EVs (NDEs) in blood reveal dynamic alterations that occur during neurodegenerative pathogenesis, including Alzheimer's disease (AD), reflecting a disease-specific molecular signature. Among these AD-specific molecular changes is brain insulin-signaling dysregulation, which cannot be assessed clinically in a living patient and remains an unexplained co-occurrence during AD pathogenesis. This review is focused on delineating how NDEs in the blood may begin to close the gap between identifying molecular changes associated with brain insulin dysregulation reliably in living patients and its connection to AD. This approach could lead to the identification of novel early and less-invasive diagnostic molecular biomarkers for AD. HIGHLIGHTS: Neuron-derived extracellular vesicles (NDEs) could be isolated from peripheral blood. NDEs in blood reflect the molecular signature of Alzheimer's disease (AD). Brain insulin-signaling dysregulation plays a critical role in AD. NDEs in blood could predict brain insulin-signaling dysregulation. NDEs offer novel early and less-invasive diagnostic biomarkers for AD.