Citations 1
Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression
Michels, Sebastian, Chen, Chaorong, Ruf, Wolfgang P., Garcia, M. Madhy Garcia, Arnold, Frederick J. , Wu, Zhuoxing, Bennett, Craig L. , Shams, Daniel, Thompson, Leslie M., Dickson, Dennis W., Petrucelli, Leonard, Dorst, Johannes, Li, Wei, Spada, Albert R. La, Walker, Alyssa C. , Bennett, Craig L , Michels, Sebastian , Ruf, Wolfgang Philipp , Thompson, Leslie Michels , Dickson, Dennis W. , Petrucelli, Leonard , Dorst, Johannes , Prudencio, Mercedes , Spada, Albert R. La
Journal of Clinical Investigation | June 1, 2026 | Volume: 136 | Issue: 11 | Pages: No page available
The role of the epigenome in age-related neurodegenerative disorders remains understudied. Here, we analyzed circulating cell-free DNA (cfDNA) from blood to detect methylation changes as a liquid biopsy for Amyotrophic Lateral Sclerosis (ALS). Our study included 20 patients with sporadic ALS, 10 patients with C9orf72-associated ALS, 10 asymptomatic carriers of the C9orf72 repeat expansion mutation, and 21 nondisease control individuals. Following targeted enzymatic methyl-sequencing (EM-seq) of approximately 4 million CpG sites, we detected numerous differentially methylated genes, including several implicated in ALS disease risk and pathogenesis. By integrating multiple epigenetic features, we delineated a distinct epigenetic signature, which achieved an average area under the curve (AUC) of 0.91 ± 0.10 upon receiver operator characteristic (ROC) analysis, which enabled detection of approximately 70% of patients with ALS with close to 100% specificity. Furthermore, we also identified a set of genes whose methylation status significantly correlated with clinical disease progression and cerebrospinal fluid (CSF) neurofilament levels. Our results reveal the potential of cfDNA-based biomarkers to accurately diagnose ALS and potentially predict disease progression.