{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:10:39Z","timestamp":1780337439187,"version":"3.54.1"},"reference-count":65,"publisher":"American Society for Clinical Investigation","issue":"11","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R35 NS122140"],"award-info":[{"award-number":["R35 NS122140"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"<jats:p>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 \u00b1 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.<\/jats:p>","DOI":"10.1172\/jci191508","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T17:44:46Z","timestamp":1780335886000},"source":"Crossref","is-referenced-by-count":0,"title":["Multimodal analysis of cell-free DNA identifies epigenetic biomarkers for amyotrophic lateral sclerosis diagnosis and progression"],"prefix":"10.1172","volume":"136","author":[{"given":"Sebastian","family":"Michels","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Ulm, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaorong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang P.","family":"Ruf","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Ulm, Ulm, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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