# Epigenetic profiles of tissue informative CpGs inform ALS disease status and progression

## TL;DR

Researchers found that epigenetic changes in cell-free DNA can help detect and track the progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease.

## Contribution

A novel method for analyzing epigenetic cfDNA profiles was developed and applied to ALS and other neurological diseases.

## Key findings

- The method accurately distinguished ALS patients from controls and individuals with other neurological diseases.
- It identified an asymptomatic carrier of a pathogenic C9orf72 variant and correlated with disease progression (Pearson’s R = 0.66).
- DNA methylation signals from multiple tissue types were detected in ALS cfDNA, indicating diverse tissue involvement in the disease.

## Abstract

Cell-free DNA (cfDNA), derived from dying cells, has demonstrated utility across multiple clinical applications. However, its potential in neurodegenerative diseases remains underexplored, with most existing cfDNA technologies tailored to specific disease contexts like cancer or non-invasive prenatal screening.

To address this gap, we developed a novel approach to characterize epigenetic cfDNA profiles by identifying key regions of DNA methylation that reveal the tissues origins undergoing apoptosis or necrosis. We evaluated this method in the largest cfDNA study of amyotrophic lateral sclerosis (ALS) and other neurological diseases (OND) to date, encompassing two independent cohorts (n = 192) from Australia (UQ Ncases = 48, Ncontrols = 32, NOND = 15) and the USA, (UCSF Ncases = 50, Ncontrols = 45)).

Our approach accurately distinguished ALS patients from controls (UQ AUC = 0.82, UCSF AUC = 0.99) and from individuals with other neurological diseases (AUC = 0.91). It also identified an asymptomatic carrier of a pathogenic C9orf72 variant, and strongly correlated with ALS disease progression measures (Pearson’s R = 0.66, p = 3.71 × 10⁻⁹).

We identified DNA methylation signals from multiple tissue types in ALS cfDNA, highlighting diverse tissue involvement in ALS pathology. These findings promote epigenetic cfDNA analysis as a powerful tool for advancing our understanding of neurodegenerative disease.

The online version contains supplementary material available at 10.1186/s13073-025-01542-5.