Objective:

To assess whether selectively enriching brain-derived tau improves the ability of blood tests to distinguish Alzheimer’s disease from amyotrophic lateral sclerosis (ALS).

Approach:

• Direct testing: Researchers measured serum brain-derived tau and p-tau217 with commercial single-molecule array immunoassays in 139 patients with ALS, 101 with Alzheimer’s disease, and 75 disease controls.
• Tau enrichment: In a subgroup of 60 patients with Alzheimer’s disease, 50 with ALS, and 39 disease controls, antibody-coated magnetic beads were used to enrich brain-derived tau before measurement.
• Biological assessment: Targeted mass spectrometry examined tau isoforms in frontal cortex, spinal cord, and skeletal muscle samples.

Key Findings:

• Direct testing found elevated serum brain-derived tau and p-tau217 in both Alzheimer’s disease and ALS compared with 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 p-tau217 area under the ROC curve increased from 0.729 with direct testing to 0.900 after enrichment; the brain-derived tau-to-brain-derived p-tau217 ratio had an area under the curve of 0.961.
• Mass spectrometry found brain-derived tau predominated in frontal cortex, big tau in skeletal muscle, and an intermediate profile in spinal cord. Muscle samples contained big p-tau217 but no detectable brain-derived p-tau217 after immunoprecipitation.

Interpretation:

The authors’ findings suggest that tau released from muscle can contribute to elevated blood tau measurements, including in ALS, and that selectively enriching brain-derived tau may improve diagnostic discrimination.

Limitations:

• The enrichment analysis was conducted in a subgroup of the multicenter cohort.
• The provided article context does not report confidence intervals, external validation, or performance in other muscle-damaging conditions.

Sources:

• Article context; Nature Communications study