Plasma eMTBR-tau as a marker of clinical stage and progression across the Alzheimer’s disease continuum

Importance

Plasma biomarkers of neurodegeneration may help characterise progression across the Alzheimer’s disease (AD) continuum. Plasma eMTBR-tau243 has been associated with tau pathology and cognitive decline. Whether plasma eMTBR-tau levels differ across subjective cognitive decline (SCD), mild cognitive impairment (MCI) and AD dementia, between MCI subtypes, or best discriminate subsequent clinical progression in brain health and memory clinic populations remains unclear.

Objective

To compare plasma eMTBR-tau and selected biomarkers of neurodegeneration, neuropathology, and neuroinflammation across the AD continuum by pTau217 and APOE ε4 status, and explore their associations with clinical progression over two years.

Design

Observational cohort study with longitudinal follow-up in a subset of participants.

Setting

Healthy Brain Ageing (HBA) brain health and memory clinic, Sydney, Australia. Participants underwent assessment between October 2018 and April 2026.

Participants

Cross-sectional analysis included 436 participants; 166 were followed up approximately two years later.

Exposures

Plasma biomarker quantification using the NULISAseq ^TM Neuro 220 Panel, clinical classification by multidisciplinary memory clinic assessment, plasma pTau217 status (SIMOA ALZpath), and APOE ε4 carrier status.

Main Outcomes and Measures

Fasting blood was collected on the morning of assessment. Plasma was analysed using the NULISAseq ^TM Neuro 220 panel. Relative biomarker abundance was compared across clinical and biomarker-defined groups. BD-pTau217 and eMTBR-tau levels at the preceding assessment were modelled individually and jointly to assess SCD-to-MCI progression and MCI-to-AD conversion over approximately two years of follow-up.

Results

Among 436 participants (mean [SD] age, 70.2 [8.0] years; 67.2% female), 186 had SCD, 228 MCI, and 22 AD dementia. Among 221 biomarkers, phosphorylated tau analytes (pTau181/T205/T212/217/231) dominated clinical group differences, while eMTBR-tau showed the largest adjusted differences: 1.69-fold higher in MCI than SCD, 6.55-fold higher in AD than SCD and 3.88-fold higher in AD than MCI (all FDR-adjusted P < .001). eMTBR-tau was higher in multidomain amnestic MCI than in SCD, and in pTau217-positive than in pTau217-negative individuals. In the exploratory MCI-to-AD analysis (6/40 converted over 2 years), eMTBR-tau at the preceding assessment showed higher cross-validated discrimination of MCI-to-AD conversion than BD-pTau217 (AUC, 0.936 vs. 0.882).

Conclusions and Relevance

Clinical stages across the AD continuum are defined by a tau-dominant pattern. eMTBR-tau showed prominent stage-related differences, supporting its further evaluation as a marker of clinical progression.

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