Ratios of CSF Proteins Reflect Cognitive Function in ALS

Background Cognitive impairment is a recognised feature of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Despite advances in understanding cognitive impairment in ALS, no fluid biomarkers reliably predict these changes. Prior research in Alzheimer disease (AD) has demonstrated that CSF protein ratios enhance biomarker accuracy by mitigating inter-individual variability, improving diagnostic precision. Specifically, studies in AD have identified protein pairs reflecting key pathological processes, including synaptic dysfunction. Methods Building on findings from the AD field, we analysed 47 CSF proteins, suggested to be associated to neurodegeneration, in 66 patients with ALS and explored protein ratios to evaluate their utility in detecting cognitive impairment, hypothesising shared mechanisms between neurodegenerative diseases. Elastic net regression identified the most predictive protein pairs associated with cognitive impairment, assessed with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Results We identified seven single proteins and eight protein pairs associated with cognitive impairment in ALS. The selected protein pairs showed stronger associations with ECAS scores compared to the individual proteins, indicating an enhanced ability to capture cognitive changes. Several of the proteins in the most predictive pairs have previously been implicated to associate to cognitive impairment in AD. Conclusion Our findings indicate that protein ratios outperform single-protein analyses in detecting associations with cognitive impairment, aligning with advancements in AD research. By extending the concept of CSF protein ratios from AD to ALS, this study highlights shared pathological mechanisms and suggests that similar proteins are linked to cognitive dysfunction in both diseases.