Promising Biomarkers for Alzheimer’s Diagnosis Less Specific Than Hoped

For the early detection of Alzheimer's disease, so-called p-tau proteins in the blood are not as disease-specific as previously assumed: the biomarkers in the blood are also elevated in people with amyotrophic lateral sclerosis (ALS). For effective Alzheimer's screening of the general population, more precise tests must first be developed and validated. These are the results of a multicenter study with 385 test subjects led by the University Medical Center Halle in cooperation with the neurological centers of the universities of Milan (Italy), Mannheim and Ulm. The work was published in the journal "Nature Communications". 

The tau protein variants p-tau 181 and 217 are considered early warning signals for Alzheimer's when they occur in increased numbers in the cerebrospinal fluid. The procedure, which is now part of the diagnostic criteria, is a stressful procedure for patients, including a lumbar puncture. Recent work has shown that p-tau proteins can also be detected in the blood of people with Alzheimer's using highly sensitive methods, which would make diagnosis much easier.

"The experts were expecting a breakthrough that could enable minimally invasive and cost-effective early detection of Alzheimer's for the general population," explains Prof. Dr. Markus Otto, Director of the University Clinic and Polyclinic for Neurology at Halle University Medical Center.

In addition to Alzheimer's disease, he is researching the early detection of other neurological diseases before clinical symptoms appear. These include, for example, amyotrophic lateral sclerosis (ALS), a degenerative neuromuscular disease of the motor nervous system.

"We noticed that the concentrations of p-Tau 181 were increased in the blood of ALS patients, but not in the cerebrospinal fluid, as is known from people with Alzheimer's. To get to the bottom of the phenomenon, we initiated the largest study to date on this topic," explains neurologist Otto. In collaboration with colleagues from the universities of Milan, Mannheim and Ulm, 111 Alzheimer's patients and 152 ALS sufferers were examined and compared with 122 control subjects with no signs of Alzheimer's or ALS disease.

p-Tau: Not as Alzheimer-specific as hoped, but still relevant

The suspicion was confirmed and the research team made further discoveries: "In ALS, the levels of p-tau 181 in the blood are at least as high as in Alzheimer's. We were also able to show for the first time that p-tau 217 is also increased in ALS cases. Our study confirms, on the one hand, that the two hoped-for blood tests for early detection of Alzheimer's are not as specific as originally assumed. On the other hand, we have obtained possible biomarkers for ALS that could be suitable for early and follow-up diagnostics or for monitoring the effectiveness of new medications. What at first glance looks like a setback for Alzheimer's diagnostics could help us further in understanding and treating ALS and other muscle diseases," explains Dr. Samir Abu Rumeileh, lead author of the study and senior physician and clinician scientist in neurology at the University Medical Center Halle.

The p-tau proteins remain valuable candidates for early diagnosis of Alzheimer's disease using a blood test, according to the authors of the study. "It can still be used to detect Alzheimer's pathology, but not as precisely as one would like and as is often propagated. If the test is positive, one would have the option of checking more closely using neuropsychological and imaging procedures or a cerebrospinal fluid analysis, for example. However, we fear that such a screening procedure is only of limited use, as the disease parameters overlap considerably in these early phases," explains Prof. Otto. In view of new antibody therapies against Alzheimer's disease, which have already been approved in the USA and are expected for Europe, it remains an enormously important goal of research to identify those affected early and efficiently - because only early treatment is currently promising.

Contrary to previous assumption: Brain is not the only possible p-tau source

Mass spectrometry analyses and immunohistochemical procedures from tissue showed that the muscle tissue of ALS patients is capable of producing p-tau itself. "The assumption that these blood markers can only come from the brain is apparently not correct," summarizes Prof. Otto. 

It is possible that other tissues and diseases, particularly neuromuscular diseases, could influence the values. These findings challenge established theories on the development of tau in Alzheimer's disease and will continue to occupy scientists in the near future. 

Reference: 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. 2025;16(1):2019. doi: 10.1038/s41467-025-57144-7

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