REVIEW OF: Horie K et al, Nature Medicine 2025;31(6):2044–2053

STUDY TYPE: Multi-cohort, observational biomarker validation study

Detecting Alzheimer’s disease (AD) tau tangles once required expensive imaging or invasive lumbar punctures. Tau pathology directly correlates with AD clinical symptoms. This study examines how a simple blood test performs, introducing plasma eMTBR-tau243, a novel biomarker for tau tangle pathology.

Researchers developed an assay for eMTBR-tau243, a blood-based tau form targeting a fragment in the microtubule-binding region. They validated this biomarker in a pair of pilot groups (n = 108 and 55) and a large validation cohort (n = 739) from the Swedish BioFINDER-2 study. Participants ranged from cognitively unimpaired to AD dementia and underwent amyloid and tau positron emission tomography (PET) imaging, cognitive testing, and MRI-based atrophy measures.

This study compared plasma eMTBR-tau243 with blood biomarkers p-tau217 and p-tau205. Participants provided blood samples and completed imaging and cognitive assessments (Mini-Mental State Examination and modified Preclinical Alzheimer’s Cognitive Composite). Investigators examined how each marker correlated with tau PET, brain atrophy, and cognitive decline to determine which best reflected tau pathology and disease severity.

Plasma eMTBR-tau243 levels increased with clinical progression and were highly specific to tau pathology. In the validation cohort, this biomarker outperformed p-tau217 and p-tau205 in predicting tau PET positivity, particularly as pathology spreads to the temporal lobes and neocortex. eMTBR-tau243 showed stronger correlation with global tau PET signal (beta = 0.68, R² = 0.45) and cognitive performance (beta = 0.60, R² = 0.40), meaning it explained 40%–45% of the variation in these outcomes—a moderate-to-strong relationship indicating that higher eMTBR-tau243 levels reliably track greater tau burden and worse cognition. Unlike p-tau217, eMTBR-tau243 levels did not rise in cognitively normal individuals with amyloid plaques, suggesting better specificity for symptomatic AD. It was not elevated in non-AD tauopathies like progressive supranuclear palsy or frontotemporal dementia, reinforcing disease specificity.

CARLAT TAKE
Plasma eMTBR-tau243 is a promising blood biomarker closely reflecting tau PET imaging, but it is currently limited to research settings. Unlike p-tau217, eMTBR-tau243 doesn’t rise in cognitively normal individuals with amyloid plaques, making it more specific for symptomatic AD and useful for tracking progression. The only FDA-cleared blood test is the Lumipulse G p-tau217/beta-amyloid 1-42 plasma ratio, which rises earlier—even in amyloid-positive, cognitively normal individuals. For now, continue relying on standard tools, but expect plasma tau biomarkers to soon help distinguish AD from non-AD cognitive disorders, guide therapy based on tau burden, and serve as trial endpoints for disease-modifying therapies.