ALS blood test detects early signs years before symptoms

A new blood test for ALS detects early signs years before symptoms appear, researchers report.

By 2040, experts estimate that nearly 400,000 people worldwide will be living with amyotrophic lateral sclerosis, or ALS, commonly known as Lou Gehrig’s disease.

This degenerative nervous system disease damages nerve cells responsible for controlling voluntary muscle movement, leading to progressive muscle weakness, loss of muscle mass, and, eventually, difficulty breathing. Current ALS diagnosis relies on neurological evaluations and the presence of symptoms; at present, there is no definitive diagnostic test.

Researchers at the Johns Hopkins University School of Medicine and the National Institutes of Health, in collaboration with the UK Biobank and the University of Turin, Italy, have identified a distinct set of proteins in blood that can detect ALS with remarkable accuracy up to a decade before symptoms appear.

Results of the new study in Nature Medicine lay the foundation for a much-needed diagnostic test for ALS.

Using an advanced platform that measured nearly 3,000 neurological and skeletal muscle proteins in blood samples from more than 600 participants, researchers applied machine learning to isolate a protein signature predictive of ALS. The protein they eventually modeled was more than 98% accurate in distinguishing patients with ALS from healthy individuals and those with other neurological diseases.

“We see the light at the end of the tunnel here, and that target is an approved and available blood test for ALS,” says co-investigator Alexander Pantelyat, associate professor of neurology at the Johns Hopkins University School of Medicine and director of the Johns Hopkins Atypical Parkinsonism Center.

“With a test that allows for earlier detection of ALS, we have opportunities to enroll people in observational studies, and by extension, offer promising disease-modifying—and hopefully disease-stopping—medications, before ALS becomes debilitating.”

The study examined not only patients with active ALS, but also individuals who had donated blood samples years before developing the disease. Among these pre-symptomatic individuals, the researchers observed previously unknown (before this study) changes in blood proteins before the patients later developed symptoms. These protein shifts point to early dysfunction in skeletal muscle, nerve signaling, and energy metabolism, suggesting ALS may affect the body long before traditional clinical signs emerge.

The team confirmed the test’s accuracy across multiple independent groups, including a 23,000-participant cohort from the UK Biobank. Within this group, blood samples from 110 individuals—collected 10 to 15 years before they developed ALS—showed changes in the protein signature identified in the study. These findings suggest the biological markers of ALS can be detected up to a decade before clinical symptoms appear.

“We had always assumed that ALS was a rapid disease that starts 12 to 18 months before symptom onset,” Pantelyat says.

“But when we look at our findings, we see this has been a process that goes on for a decade or so before the patient ever steps into the doctor’s office or clinic.”

In every validation group, the model demonstrated a strong ability to detect ALS while minimizing false positives caused by other neurological conditions like Parkinson’s disease or neuropathy.

Notably, the study confirmed that these protein changes were not driven by inherited genetic mutations, meaning the blood-based signature could be applied broadly, even in patients with no family history of ALS.

“It’s crucial for patients and their families to be able to discern between ALS and other conditions for diagnostic clarity, prognostic understanding, and eligibility to enroll into the appropriate clinical trials,” Pantelyat says.

Further research is underway to explore how this protein-based signature could help monitor ALS progression, evaluate treatment effectiveness in clinical trials, and inform diagnostic tools for other neurodegenerative diseases. The research team also has made their data publicly available to accelerate progress in ALS biomarker development.

“Fifteen years of cross-institutional collaboration went into this work,” Pantelyat says. “Large-scale partnerships are the lifeblood of research. They’re what will lead to effective diagnostics and ultimately effective treatments for devastating diseases like ALS.”

Funding for this research came from the Intramural Research Program of the National Institutes of Health; the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Division of Intramural Research (DIR) of the National Institute of Allergy and Infectious Diseases, and Merck Sharp & Dohme Corporation, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Coauthor Bryan J. Traynor received additional support from the Centers for Disease Control and Prevention, the Muscular Dystrophy Association, Microsoft Research, the Packard Center for ALS Research at Johns Hopkins, the ALS Association, and Cerevel Therapeutics.

This work was also partly supported by the Italian Ministry of Health; the Progetti di Rilevante Interesse Nazionale program of the Ministry of Education, University and Research; the Horizon 2020 Programme; the Horizon Europe Programme. This study was performed under the Department of Excellence grant of the Italian Ministry of University and Research to the “Rita Levi Montalcini” Department of Neuroscience, University of Torino, Italy.

Additional contributors to the research are from The Johns Hopkins University, the National Institutes of Health, and the University of Turin and Azienda Ospedaliero Universitaria Città della Salute e della Scienza in Italy.

Bryan Traynor and others have a patent pending (US Patent Application No. 63/717,807) on diagnostic testing for ALS based on the proteomic panel. Bryan J. Traynor holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Bryan J. Traynor and Sonja W. Scholz receive research support from Cerevel Therapeutics. Sonja W. Scholz serves on the Scientific Advisory Committee of the Lewy Body Dementia Association, Mission MSA, and the GBA1 Canada Initiative. All other authors declare that they have no conflicts of interest.

Source: Johns Hopkins University

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