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The early diagnosis of Alzheimer’s disease (AD) through the detection of p-tau proteins in the blood is less disease-specific than assumed since these biomarkers are also elevated in the blood of people with amyotrophic lateral sclerosis (ALS). Therefore, more specific tests should be developed and validated as screening tests for AD in the general population. These were the findings of a multi-center study with 385 subjects led by the University Medicine Halle in cooperation with the departments of Neurology at the Universities of Milan (Italy), Mannheim and Ulm. The paper is published in “Nature Communications”.
Elevated levels of p-tau 181 and 217 in cerebrospinal fluid are considered to reflect early Alzheimer’s disease pathology. However, biomarker detection, which is now part of the diagnostic criteria, requires a lumbar puncture that can be invasive for patients. Recent studies have shown that p-tau proteins can also be detected in the blood of AD patients through highly sensitive assays, which would make diagnosis much easier. “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 Markus Otto, director of the University Clinic and Outpatient Clinic for Neurology at University Medicine Halle. In addition to AD, he is investigating the early detection of other neurological diseases before clinical symptoms appear. One such disease is ALS, a degenerative disease of the motor nervous system.
“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 AD patients. In order to uncover the causes of this phenomenon, we launched the largest study on the subject to date,” explains the neurologist Professor Otto. In collaboration with colleagues from the universities of Milan, Mannheim and Ulm, 111 Alzheimer’s patients and 152 patients with ALS were examined and compared with 122 control subjects who had no signs of AD or ALS.
Blood p-tau: not as Alzheimer’s-specific as hoped, but still significant
Not only were the researchers’ suspicions confirmed, they also made further discoveries: “The levels of p-tau 181 in the blood of ALS patients are just as high as in patients with AD. We were able to show for the first time that also blood p-tau 217 is elevated in ALS patients. Our study confirms that both blood tests for the early detection of AD are not as disease-specific as previously thought. However, in this study we have also discovered that 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 AD diagnostic assessment could help us understand and maybe improve the treatment of ALS and other muscle disorders,” explains Dr. Samir Abu Rumeileh, first author of the study, senior physician and clinician scientist at University Medicine Halle.
P-tau proteins continue to play a significant role in the blood detection of early AD. “It is still possible to detect AD pathology, but not as precisely as one would like or in the way that is often suggested. 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. However, our findings limit the potential of p-tau biomarker as screening tests because of the overlap of disease parameters in the asymptomatic or early stages of AD and ALS given the overlap in the biomarker concentrations between the two diseases,” concludes Professor Otto.
The approval of new antibody therapies for Alzheimer’s in the U.S., and their expected approval in Europe, highlights the importance of research aimed at early disease detection – as only early treatment currently has the potential for success.
Contrary to previous assumptions, the brain is not the only possible source of p-tau
Mass spectrometry and immunohistochemical tissue analyses have shown that the muscle of ALS patients is capable of producing and expressing p-tau. “The assumption that these blood markers only originate from the brain is being challenged,” explains Professor Otto.
Other tissues and diseases, in particular neuromuscular diseases, could also influence the p-tau levels. 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.
Background
Researchers around the world are searching for simple and reliable methods for the early detection of AD. Here the tau protein, which normally supports the long pathways of nerve cells, plays a key role. The protein is pathologically altered in AD patients, detaching from the nerve cells and clumping together. This results in the deposit of neurofibrillary tangles of phosphorylated tau (p-tau) that are typical for the disease, which disrupt cell communication and cause nerve cells to die. Characteristic symptoms like cognitive impairment only appear once the disease has progressed.
The study was supported by 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.
University Medicine Halle
University Clinic and Outpatient Clinic for Neurology
Professor Markus Otto, Director
Dr. Samir Abu Rumeileh, Senior Physician
neurologie@uk-halle.de
Abu-Rumeileh, S., Scholle, L., Mensch, A. et al. Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis. Nat Commun 16, 2019 (2025). https://doi.org/10.1038/s41467-025-57144-7
http://www.umh.de/neurologie University Clinic and Outpatient Clinic for Neurology at University Medicine Halle
Professor Markus Otto at the microscope: In a study, he and his colleagues showed that p-tau protein ...
University Medicine Halle
Professor Markus Otto at the microscope: In a study, he and his colleagues showed that p-tau protein ...
University Medicine Halle
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