Blood-based multiplex nanobiosensing of Alzheimer's disease biomarkers: from nanoengineered ınterfaces to clinical translation.

Alzheimer's disease is a progressive neurodegenerative disorder in which molecular and cellular alterations begin years before clinical symptoms, creating a strong need for minimally invasive blood-based tools that can detect disease-related biomarkers with high analytical reliability. This structured narrative review examines recent advances in nanoengineered multiplex biosensors for ultrasensitive profiling of Alzheimer's disease biomarkers in blood-derived matrices. Particular emphasis is placed on amyloid-β 42/40 ratio, phosphorylated tau isoforms, neurofilament light chain, and glial fibrillary acidic protein, which collectively reflect amyloid pathology, tau-associated neurodegeneration, axonal injury, and glial activation. We discuss electrochemical, plasmonic, surface-enhanced Raman scattering, field-effect transistor, nanozyme-assisted, and lab-on-a-chip platforms, focusing on how nanoengineered interfaces improve bioreceptor immobilization, signal amplification, antifouling performance, and low-volume multiplex readout. Although many reported platforms achieve femtomolar to attomolar sensitivity and show potential for point-of-care or near-patient testing, their clinical translation remains constrained by plasma and serum matrix effects, nonspecific adsorption, multiplex channel cross-talk, inconsistent reporting of analytical limits, and batch-to-batch variability in nanomaterial fabrication. We further highlight the importance of matrix-matched calibration, standardized preanalytical workflows, interference testing, reproducibility across independent fabrication batches, and comparison with established clinical reference methods. Overall, nanoengineered multiplex biosensors represent a promising route toward accessible blood-based Alzheimer's disease biomarker profiling, but their implementation in clinical practice will require rigorous analytical validation, scalable manufacturing, and clinically meaningful assay design.