Next-generation optical biosensors for ultra-early detection of Alzheimer's and Parkinson's diseases: Recent advances, challenges, and future perspectives.

Alzheimer's disease (AD) and Parkinson's disease (PD) are considered among the most difficult neurodegenerative diseases because they are progressive, and there are no reliable tools to make early diagnoses. Traditional diagnostic approaches, such as neuroimaging and CSF analysis, are not ideal for rapid clinical screening and are often invasive and costly. Optical biosensors have become attractive platforms for detecting neurodegenerative markers in recent years, offering ultra-sensitivity and minimal invasiveness. Recent advances in optical biosensing technologies for the early detection of key AD and PD biomarkers, such as amyloid-β, tau protein, α-synuclein, dopamine, and neurofilament light chain (NFL), are highlighted. Several photonic techniques, including fluorescence-based assays, surface plasmon resonance (SPR), surface-enhanced Raman scattering (SERS) and whispering-gallery-mode (WGM) microcavity sensors, are critically described, highlighting their sensing mechanisms, analytical performance, and clinical applications. Significant focus is placed on nanostructured SERS substrates, microfluidically integrated platforms, paper-based optical chips, and WGM microlaser-assisted immunosensors for femtomolar-to-attomolar detection in clinically relevant biofluids. Moreover, the use of sophisticated nanomaterials and artificial intelligence-based data analysis is discussed as an effective approach to developing multiplexed, portable, and point-of-care diagnostics. Finally, the challenges and future directions in translating next-generation optical biosensors for the diagnosis of neurodegenerative diseases are discussed.