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Damaged muscles in ALS patients release proteins previously linked only to brain disease
In a nutshell
- Researchers discovered that phosphorylated tau proteins, long thought to be exclusive Alzheimer’s markers, are also released by damaged muscle tissue in ALS patients
- This unexpected finding challenges the specificity of blood-based Alzheimer’s tests, as elevated tau levels might indicate muscle disorders rather than brain pathology
- The discovery could lead to new diagnostic biomarkers for ALS, while also prompting more cautious interpretation of Alzheimer’s blood test results
HALLE, Germany — A surprising discovery from European researchers raises significant concerns about the accuracy of blood tests designed to detect Alzheimer’s disease (AD). In a surprising twist, the proteins typically used as Alzheimer’s biomarkers have been found at similarly high levels in patients with amyotrophic lateral sclerosis (ALS), originating unexpectedly from muscle tissue rather than the brain alone.
The study discovered elevated levels of these specific tau proteins — phosphorylated tau proteins p-tau 181 and p-tau 217 — in the muscle biopsies of ALS patients. Published in Nature Communications, the findings demonstrate that muscle degeneration could significantly contribute to elevated tau protein levels in blood, challenging the long-held belief that these markers exclusively originate from brain pathology.
“The assumption that these blood markers only originate from the brain is being challenged,” explains Professor Markus Otto, senior author of the study and director at University Medicine Halle. “Our findings limit the potential of p-tau biomarkers as screening tests because of the overlap in the biomarker concentrations between AD and ALS patients.”
Alzheimer’s disease or ALS?
This finding suggests caution when interpreting blood test results for Alzheimer’s, as elevated tau proteins could indicate muscle degeneration instead of or in addition to Alzheimer’s pathology, complicating the diagnostic process. However, it also points toward potential new biomarkers for diagnosing ALS, a disease currently lacking definitive blood tests. The researchers emphasize the urgent need for more specific and validated diagnostic tools to accurately distinguish between these conditions.
“Blood p-tau species could potentially be used to diagnose both ALS and AD,” the researchers conclude in their study—a statement with important implications for early detection strategies for both devastating neurological conditions.
ALS, commonly known as Lou Gehrig’s disease, causes progressive degeneration of motor neurons, leading to muscle weakness, paralysis, and eventually death. Alzheimer’s, meanwhile, primarily affects cognitive function through brain degeneration. The unexpected overlap in these blood biomarkers between such distinct conditions points to previously unknown connections between neuromuscular and neurodegenerative diseases.
The research team made their discovery after analyzing blood samples from 152 ALS patients, 111 Alzheimer’s patients, and 99 disease controls from four different European research centers. They found that both ALS and Alzheimer’s patients had significantly higher levels of p-tau 181 and p-tau 217 in their blood compared to controls without neurodegenerative conditions.
Not content with just measuring blood levels, they directly examined muscle biopsies from ALS patients and controls using both immunohistochemistry (a technique that uses antibodies to visualize specific proteins in tissue) and mass spectrometry (a method that identifies proteins by their molecular weight). Under the microscope, they observed both p-tau 181 and p-tau 217 in the muscle tissues, with ALS patients showing particularly high concentrations in atrophied muscle fibers—those that have begun to waste away due to the disease.
“We have observed that the levels of p-tau 181 were elevated in the blood of ALS patients, but not in their cerebrospinal fluid, as is the case in Alzheimer’s disease patients. In order to uncover the causes of this phenomenon, we launched the largest study on the subject to date,” explains Professor Otto.
This microscopic evidence provides the missing puzzle piece, suggesting that when muscles degenerate in ALS, they release these phosphorylated tau proteins into the bloodstream. This explains why ALS patients show elevated levels despite not having the brain pathology typically associated with Alzheimer’s disease.
From hope to caution
The finding has important implications for the medical field’s growing interest in blood-based biomarkers for neurodegenerative diseases. Recent years have seen extensive research into blood tests for Alzheimer’s, with p-tau 181 and p-tau 217 emerging as particularly promising candidates for early detection. Some researchers have even proposed these blood tests as screening tools for the general population.
“Experts were hoping for a breakthrough that would allow minimally invasive and cost-effective early detection of Alzheimer’s disease in the general population,” explains Professor Otto.
But this new research suggests caution. If these proteins can be elevated due to muscle degeneration rather than brain pathology alone, their specificity as Alzheimer’s biomarkers may be lower than previously thought. A positive blood test might indicate Alzheimer’s—or it might indicate ALS or potentially other conditions involving muscle degeneration.
“Our study confirms that both blood tests for the early detection of AD are not as disease-specific as previously thought,” says Dr. Abu-Rumeileh, first author of the study, senior physician and clinician scientist at University Medicine Halle.
Nevertheless, the study also points to the potential value of these biomarkers in ALS diagnosis and monitoring. Currently, ALS is diagnosed primarily through clinical examination and electromyography (EMG) testing, with no definitive biomarker test available. These tau proteins might help fill that gap.
Importantly, while both proteins were elevated in both conditions, p-tau 217 levels were significantly higher in Alzheimer’s patients than in ALS patients. This suggests that examining the ratio between these two forms of tau might help distinguish between the conditions.
The study also revealed correlations that further support the muscle-origin hypothesis. In ALS patients, blood levels of p-tau 181 and p-tau 217 correlated strongly with blood troponin T, a well-established marker of muscle damage. Additionally, ALS patients with predominantly lower motor neuron involvement—which typically causes more severe muscle atrophy—showed higher levels of these tau proteins than those with predominantly upper motor neuron symptoms.
“[P]-tau 181 and 217 might be potential biomarkers that could be suitable for early diagnosis of ALS or for monitoring disease progression and the effectiveness of new drugs. What at first glance looks like a setback for Alzheimer’s disease diagnostic assessment could help us understand and maybe improve the treatment of ALS and other muscle disorders,” explains Dr. Abu-Rumeileh.
Another interesting disparity was found when researchers examined the relationship between disease duration and tau levels, finding that longer disease duration correlated with higher tau levels in ALS patients. This suggests that these proteins might accumulate as the disease progresses, potentially serving as indicators of disease advancement.
What does this mean for ALS and Alzheimer’s blood testing?
While the findings present exciting possibilities for both ALS and Alzheimer’s research, they also raise challenging questions. If muscle degeneration can elevate these supposedly brain-specific biomarkers, what other peripheral sources might exist? Could other conditions involving muscle damage—from muscular dystrophies to even intense exercise—affect these biomarker levels?
“Other tissues and diseases, in particular neuromuscular diseases, could also influence the p-tau levels,” notes Professor Otto. “These findings raise questions about the current theories of how tau pathology develops in AD patients and will keep scientists looking for answers in the near future.
“It is still possible to detect AD pathology, but not as precisely as one would like or in the way that is often suggested,” he continues. “A positive p-tau test could, for example, prompt the physicians to perform other more informative diagnostic investigations, such as neuropsychological tests, imaging or cerebrospinal fluid analysis.”
The timing of these findings is particularly relevant given the recent approval of new antibody therapies for Alzheimer’s in the U.S. and their expected approval in Europe. Professor Otto notes that this “highlights the importance of research aimed at early disease detection – as only early treatment currently has the potential for success.”
For ALS patients, meanwhile, the findings offer a potential new avenue for diagnosis and disease monitoring. While ALS remains incurable, earlier and more accurate diagnosis could help patients access appropriate care sooner and potentially participate in clinical trials of experimental treatments.
Paper Summary
Methodology
The research team examined blood samples and muscle tissue to determine where tau proteins were coming from. They collected blood from 385 participants across four European research centers, including 152 ALS patients, 111 Alzheimer’s disease patients, and 122 controls (99 disease controls without neurodegenerative conditions and 23 healthy controls). Using highly sensitive technology called Simoa, they measured levels of phosphorylated tau 181 (p-tau 181), phosphorylated tau 217 (p-tau 217), and total tau (t-tau) in the blood samples.
To investigate whether these tau proteins might be coming from muscle tissue, the researchers examined muscle biopsies from 13 ALS patients and 14 disease controls. They used two different approaches: first, they used special antibodies that can detect specific tau proteins under a microscope, allowing them to see where in the muscle these proteins were located. Second, they used mass spectrometry, which can identify the exact chemical makeup of proteins in a sample. This two-pronged approach allowed them to both visualize the tau proteins in muscle tissue and confirm their precise molecular identity.
Results
The study found several important things. First, both ALS and Alzheimer’s patients had much higher levels of p-tau 181 and p-tau 217 in their blood compared to people without these diseases. While p-tau 181 levels were similar between ALS and Alzheimer’s patients, p-tau 217 was significantly higher in Alzheimer’s patients, suggesting it may be more specific to Alzheimer’s disease.
In ALS patients, these elevated tau levels didn’t correlate with markers of brain degeneration but did show strong correlations with markers of muscle damage, particularly a protein called troponin T. This suggested the tau proteins might be coming from damaged muscle rather than the brain.
When they looked at muscle biopsies under the microscope, they found both p-tau 181 and p-tau 217 were present in muscle tissue from both ALS patients and controls. However, ALS samples showed increased concentrations of these proteins specifically in muscle fibers that were wasting away (atrophic).
The mass spectrometry not only confirmed the presence of these phosphorylated tau proteins in muscle but also identified them in regions not typically found in brain tau. ALS patients with more severe muscle wasting showed higher levels of these tau proteins, further supporting the idea that they originate from muscle.
Limitations
The researchers acknowledge several limitations to their study. The sample size for muscle biopsies (13 ALS patients and 14 controls) was relatively small compared to the blood sample group. They also didn’t have paired blood and muscle samples from the same patients, which limited their ability to directly correlate muscle tau content with blood tau levels.
The study didn’t include muscle biopsies from Alzheimer’s patients or healthy controls, making it impossible to compare muscle tau content across all groups. The muscle biopsies came from different muscles in different patients, which could have introduced variability. The researchers also noted limited information on patients’ other medical conditions, which might have influenced results.
While the findings suggest muscle as a source of blood p-tau in ALS, the study cannot definitively rule out contributions from other sources or quantify exactly what percentage of blood p-tau originates from muscle versus other tissues.
Discussion and Takeaways
The findings challenge the assumption that blood p-tau 181 and p-tau 217 come exclusively from the brain. This has important implications for their use as screening tools for Alzheimer’s disease, suggesting they may be less specific than previously thought.
The study proposes that in ALS, damaged muscle fibers release phosphorylated tau proteins into the bloodstream, explaining the elevated blood levels despite normal tau levels in spinal fluid. The researchers suggest that p-tau 217 may still be reasonably specific for Alzheimer’s disease, as its levels were significantly higher in AD patients than in ALS patients.
For ALS research, these tau proteins might potentially serve as biomarkers of disease progression or muscle degeneration. The researchers emphasize that more specific tests need to be developed and validated before these biomarkers can be confidently used as screening tools for Alzheimer’s in the general population. The study opens new avenues for investigating tau proteins not just in ALS but potentially in other muscle diseases as well.
Funding and Disclosures
The research was supported by multiple funding sources, including the Clinician Scientist Programme of the Medical Faculty of the Martin Luther University Halle-Wittenberg, the Federal Ministry of Education and Research (BMBF), and the Thierry Latran Foundation. Several researchers reported receiving consulting fees, advisory board honoraria, or research support from pharmaceutical companies including Biogen, Axon, Roche, Grifols, AveXis, Cytokinetics, Italfarmaco, Novartis, Amylyx, and Zambon, though these relationships were unrelated to the current study. Three co-authors disclosed being co-inventors on a patent application for using beta-synuclein measurement in blood, unrelated to the current research.
Publication Information
The study titled “Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis” was published in Nature Communications (Volume 16, Article number 2019) on March 5, 2025. The research was a collaborative effort led by Samir Abu-Rumeileh and Leila Scholle from the Department of Neurology at Martin-Luther-University Halle-Wittenberg in Germany, with contributions from researchers at multiple institutions across Germany and Italy. The study can be accessed online at https://doi.org/10.1038/s41467-025-57144-7.
