Molecular biomarkers of neurodegeneration in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disease. However, definitive diagnosis can be delayed by up to 12 months due to the lack of specific and sensitive biomarkers for ALS. In our study, conducted for the first time on a large cohort of ALS patients (n = 100) within the Russian population, we assessed key biomarkers of neurodegenerative pathology, including β-amyloids (Aβ40 and Aβ42) and tau proteins (Tau-total and Tau-p181), as well as other pathogenetically relevant, promising biomarkers such as FGF-21, Kallikrein-6 (KLK-6), NCAM-1, Neurogranin (NRGN), TDP-43, Apolipoprotein E4, Clusterin (Apo J), Complement Factor H, Fetuin-A, α2-Macroglobulin, Apo AI, Apo CIII, Apo E, Complement C3, GDNF, sRAGE, and S100B protein. Significant differences between ALS patients and the control group were observed for Aβ40 (p = 0.044), Aβ42 (p < 0.001), FGF-21 (p < 0.001), Tau-total (p = 0.001), Tau-pT181 (p = 0.014), Clusterin (p < 0.001), Complement C3 (p = 0.001), and S100B (p = 0.024). A significant direct correlation was found between ALSFRS-R score and the concentrations of Aβ40 and Aβ42. Alterations in the complement system (Complement C3 and Complement Factor H) were identified, highlighting the critical role of neuroinflammatory processes in ALS pathogenesis. Additionally, increased levels of FGF-21 were observed in patients with the bulbar onset of ALS. The significant elevation in concentration of the chaperone protein clusterin in patients with rapid disease progression suggests its potential as a prognostic biomarker for motor neuron disease. Furthermore, its role in maintaining proteostasis could provide novel therapeutic targets for intervention.