Evaluating the potential of salivary biomarkers in amyotrophic lateral sclerosis: a promising frontier for early diagnosis and disease monitoring

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons and is associated with a poor prognosis due to the absence of effective disease-modifying treatments. Diagnosis remains challenging, as early symptoms are subtle and may overlap with other neurological conditions. Current diagnostic methods—clinical evaluation, electrophysiology, neuroimaging, and exclusion of alternative etiologies—are frequently applied only after significant disease progression. Although current and emerging biomarkers improve diagnostic accuracy, most require invasive collection of cerebrospinal fluid or blood. This review explores the potential of saliva as a reliable, accessible and non-invasive biofluid for ALS biomarker discovery. Saliva reflects systemic physiological states through its diverse molecular constituents, including proteins, metabolites, nucleic acids, and inflammatory markers. Specific candidates show promise: salivary chromogranin A may correlate with disease severity, while salivary cortisol reflects the emotional and physiological stress associated with ALS. Additionally, proteomic profiling, spectroscopic analyses, and extracellular vesicle characterization may reveal broader molecular signatures with diagnostic and prognostic value. Despite these promising findings, significant challenges remain, including the lack of standardized collection and analysis protocols, inherent variability in salivary composition, and limited large-scale clinical validation. Further research is needed to establish salivary biomarkers as a robust component of the ALS diagnostic and monitoring framework, with the potential to improve early detection and long-term patient outcomes.