Sequential plasma biomarker strategy evaluated for Alzheimer's disease

Evidence before this study

We searched PubMed from database inception to May 1, 2025, using the search terms “plasma p-tau217”, “MTBR-tau243”, “eMTBR”, “Alzheimer's disease”, “core biomarkers”, and “tau-PET”. We also used synonyms for p-tau (phosphorylated tau) and Alzheimer's disease (Alzheimer disease, AD). We prioritised studies examining plasma biomarkers for amyloid (Aβ) and tau pathology in symptomatic populations, with biomarker validation using PET or CSF or clinical outcomes as the reference standard. Key findings were that plasma p-tau217 shows high accuracy for detecting Aβ pathology, but lower accuracy for tau-PET positivity. MTBR-tau243 in CSF and plasma are strongly correlated with tau-PET Braak staging but had less sensitivity in early Alzheimer's disease. Core 1 (Aβ and p-tau217) and Core 2 (related to tau aggregates) biomarkers are recognised in revised diagnostic criteria, although no studies have validated a sequential blood-based workflow or systematically tested whether combining p-tau217 with eMTBR-tau243 improves clinical stratification.

Added value of this study

To our knowledge, we report the first large-scale validation of a sequential blood biomarker strategy (plasma %p-tau217 followed by eMTBR-tau243) to distinguish asymptomatic Aβ pathology from established Alzheimer's disease (clinical impairment caused by Alzheimer's disease pathology) in a memory clinic cohort. No previous studies have combined plasma %p-tau217 and eMTBR-tau243 in a staged workflow to reduce the incorrect attribution of observed dementia to Alzheimer's disease neuropathological change. Our approach advances diagnostic precision, since integrating eMTBR-tau243 reduced false positives compared with %p-tau217 alone, while maintaining high sensitivity for established Alzheimer's disease. The relevance of eMTBR-tau243 to clinical staging was supported by strong associations with tau PET burden and cognitive decline, both cross-sectionally and longitudinally. The proposed two-step workflow enables stratification of Aβ-positive individuals into likely asymptomatic Alzheimer's disease pathology (eMTBR-tau243-negative) and established Alzheimer's disease (eMTBR-tau243-positive) categories.

Implications of all the available evidence

Combining Core 1 (%p-tau217) and Core 2 (eMTBR-tau243) plasma biomarkers addresses crucial limitations of current Alzheimer's disease diagnostics. In clinical practice this approach could enable more efficient and cost-effective triaging (replacing many PET or CSF tests) while reducing overdiagnosis in patients with asymptomatic Alzheimer's disease pathology. Furthermore, plasma eMTBR-tau243 could help identify individuals with high tau burden, who might have less benefit from amyloid-targeting therapies, and might be used to stratify participants in clinical trials of tau-targeting and amyloid-targeting therapies.

Source: The Lancet Neurology