# Ratios of CSF proteins reflect cognitive function in ALS

## TL;DR

This study finds that ratios of certain proteins in cerebrospinal fluid better predict cognitive impairment in ALS than single proteins, suggesting shared mechanisms with Alzheimer's disease.

## Contribution

The study introduces CSF protein ratios as a novel approach to detect cognitive impairment in ALS, extending methods from Alzheimer's disease research.

## Key findings

- Protein ratios outperformed single proteins in detecting cognitive impairment in ALS patients.
- The PTPRN2/GAP43 ratio showed the strongest association with cognitive scores.
- Several proteins in the predictive ratios are also linked to cognitive impairment in Alzheimer's disease.

## Abstract

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. In AD, ratios involving synaptic markers have shown stronger associations with cognitive outcomes than single proteins, motivating evaluation of a similar ratio-based approach in ALS.

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).

Elastic net identified seven single proteins (NEFM, NPTX2, GAP43, IGFBP4, IGFBP7, SPP1, CDH8) and eight protein pairs associated with ECAS total score. Ratios were generally more informative than individual proteins, with PTPRN2/GAP43 showing the strongest association with ECAS scores, 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.

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.

The online version contains supplementary material available at 10.1186/s13195-026-01976-y.