A blood-testing approach that selectively enriches brain-derived tau improved discrimination between Alzheimer’s disease and amyotrophic lateral sclerosis, according to a multicenter study published in Nature Communications.
Blood phosphorylated tau 217 (p-tau217) is widely studied as a marker of Alzheimer’s disease pathology. However, elevated concentrations have also been reported in patients with amyotrophic lateral sclerosis (ALS). This may partly reflect the release of a larger tau isoform, known as big tau, from damaged or denervated muscle rather than Alzheimer’s-related changes in the brain.
Samir Abu-Rumeileh of Martin Luther University Halle-Wittenberg and colleagues examined whether separating brain-derived tau from peripheral tau could improve diagnostic specificity.
The researchers first measured serum brain-derived tau and p-tau217 directly using commercial single-molecule array immunoassays. The multicenter cohort included 139 patients with ALS, 101 with Alzheimer’s disease, and 75 disease controls.
Direct testing showed increased serum brain-derived tau and p-tau217 in both Alzheimer’s disease and ALS compared with controls. This indicated that the commercial assays did not fully distinguish tau originating in the central nervous system from related peripheral isoforms.
The team then introduced a preanalytical immunoprecipitation step using antibody-coated magnetic beads to selectively capture brain-derived tau. After the enriched tau was released from the beads, brain-derived tau and brain-derived p-tau217 were measured on the same immunoassay platform.
This two-step analysis was performed in a subgroup of 60 patients with Alzheimer’s disease, 50 with ALS, and 39 disease controls. After enrichment, brain-derived tau and brain-derived p-tau217 were elevated in Alzheimer’s disease but not in ALS.
For distinguishing Alzheimer’s disease from ALS, the area under the receiver operating characteristic curve for p-tau217 increased from 0.729 with direct testing to 0.900 after brain-derived tau enrichment. A ratio of brain-derived tau to brain-derived p-tau217 produced an area under the curve of 0.961.
Targeted mass spectrometry provided biological support for the assay findings. Brain-derived tau predominated in frontal cortex samples, while big tau was most abundant in skeletal muscle. Spinal cord samples showed an intermediate profile. Following p-tau217 immunoprecipitation, muscle samples contained big p-tau217 but no detectable brain-derived p-tau217.
The findings suggest that peripheral tau released from muscle can confound blood tau measurements, particularly in ALS and potentially other conditions involving muscle damage. A selective enrichment step could therefore help laboratories clarify elevated or borderline p-tau217 results when the clinical presentation is atypical.
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