Researchers at Universitätsmedizin Halle have developed an optimized two-step blood test procedure to detect Alzheimer’s disease more reliably by isolating brain-derived tau proteins and avoiding false positives caused by muscle or nerve disorders like ALS, according to findings published in Nature Communications.
Isolating Brain Tau to Prevent False Positives
Blood tests for Alzheimer’s disease rely heavily on measuring the phosphorylated tau protein, specifically pTau217.
However, elevated pTau217 levels do not exclusively point to Alzheimer's disease. Damaged muscle tissue, alongside central nervous system changes, contributes to these elevated readings. The tau protein appears in different forms: a smaller variant found primarily in the brain, and a larger variant present in nerves, muscles, and other tissues. Standard blood assays fail to reliably distinguish between these forms, causing non-Alzheimer conditions to mimic Alzheimer biomarkers.
The Two-Step Assay and Multi-Center Trial Results
Before running the actual biomarker measurement, the procedure isolates brain-specific small tau from the blood sample using a targeted antibody. Comparative analyses of brain, spinal cord, and muscle tissue via mass spectrometry confirmed that the brain-specific small pTau217 form is practically absent in muscle tissue.
The research team evaluated the new method against conventional testing using blood samples from 315 individuals across neurological centers in Halle, Mannheim, and Milan. While conventional assays returned elevated pTau217 levels for both Alzheimer's and ALS cohorts, the new two-step enrichment procedure yielded elevated readings exclusively in Alzheimer's samples, leaving ALS and control groups unaffected.
Improving Diagnostic Accuracy Using Specialized Antibody
- Targeted Biomarkers: Traditional blood tests measure pTau217 to flag Alzheimer’s early, but they can pick up unrelated proteins released by damaged muscles or nerves.
- The Two-Step Fix: The newly developed assay filters out non-brain proteins using a specialized antibody before testing, sharpening diagnostic accuracy.
- Clinical Utility: This method serves as a secondary check when initial blood test results do not match a patient’s physical symptoms, helping prevent misdiagnoses.
Future Integration into Clinical Practice
Researchers suggest integrating the two-step procedure as a secondary verification tool alongside existing blood assays. Standard pTau217 tests can still provide the initial screening indicator. If a result contradicts a patient’s clinical presentation or if underlying neuromuscular conditions threaten to skew the data, the two-step protocol can provide clarity.
Beyond Alzheimer’s diagnostics, the findings offer substantial value for ALS research. Before routine clinical implementation can occur, the assay requires formal standardization and validation across larger, independent patient cohorts.
| Cohort Group | Sample Size (N) | Conventional pTau217 Outcome | Two-Step Assay Outcome |
|---|---|---|---|
| Alzheimer’s Disease | 101 | Elevated | Elevated |
| Amyotrophic Lateral Sclerosis (ALS) | 139 | Elevated | Normal / Baseline |
| Healthy Controls | 75 | Normal | Normal |
Limitations of Biomarker Assays in Definitive Diagnosis
Because standard blood biomarkers can be influenced by peripheral nerve damage, muscular disorders, or comorbid conditions, biomarker assays alone cannot establish a definitive diagnosis.
References
- Abu-Rumeileh S et al. (2026) Tau isoform mapping across tissues and biofluids reveals a signature distinguishing Alzheimer’s disease from amyotrophic lateral sclerosis. Nature Communications. DOI: 10.1038/s41467-026-78390-3
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