Plasma eMTBR-tau as a marker of clinical stage and progression across the Alzheimer's disease continuum
Abstract
ImportancePlasma biomarkers of neurodegeneration may help characterise progression across the Alzheimers 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.
ObjectiveTo compare plasma eMTBR-tau and selected biomarkers of neurodegeneration, neuropathology, and neuroinflammation across the AD continuum by pTau217 and APOE {varepsilon}4 status, and explore their associations with clinical progression over two years.
DesignObservational cohort study with longitudinal follow-up in a subset of participants.
SettingHealthy Brain Ageing (HBA) brain health and memory clinic, Sydney, Australia. Participants underwent assessment between October 2018 and April 2026.
ParticipantsCross-sectional analysis included 436 participants; 166 were followed up approximately two years later.
ExposuresPlasma biomarker quantification using the NULISAseqTM Neuro 220 Panel, clinical classification by multidisciplinary memory clinic assessment, plasma pTau217 status (SIMOA ALZpath), and APOE {varepsilon}4 carrier status.
Main Outcomes and MeasuresFasting blood was collected on the morning of assessment. Plasma was analysed using the NULISAseqTM 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.
ResultsAmong 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 RelevanceClinical 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.
KEY POINTSO_ST_ABSQuestionC_ST_ABSHow do plasma biomarkers of neurodegeneration vary across clinical and biomarker-defined groups along the Alzheimers disease (AD) continuum, and are eMTBR-tau levels associated with clinical progression over approximately two years of follow-up?
FindingsIn a brain health and memory clinic cohort of 436 participants, plasma eMTBR-tau showed the largest adjusted biomarker difference between subjective cognitive decline, mild cognitive impairment (MCI) and AD dementia groups. Amongst 166 participants followed up after 2 years, plasma eMTBR-tau levels at the preceding assessment best discriminated MCI-to-AD conversion (6/40; AUC=0.936).
MeaningPlasma eMTBR-tau is a potential biomarker of clinical progression across the AD continuum.
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BibTeX
@misc{michaelian2026plasma,
title = {{Plasma eMTBR-tau as a marker of clinical stage and progression across the Alzheimer's disease continuum}},
author = {J. C. Michaelian and R. Yu and A. Lee and T. K. Karikari and L. Shi and E. Drummond and S. L. Naismith},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.26366056},
url = {https://www.medrxiv.org/content/10.64898/2026.10.21.26366056v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Plasma eMTBR-tau as a marker of clinical stage and progression across the Alzheimer's disease continuum
AU - J. C. Michaelian
AU - R. Yu
AU - A. Lee
AU - T. K. Karikari
AU - L. Shi
AU - E. Drummond
AU - S. L. Naismith
PY - 2026
DA - 2026/10/21
PB - medRxiv
DO - 10.64898/2026.10.21.26366056
UR - https://www.medrxiv.org/content/10.64898/2026.10.21.26366056v1
AB - ImportancePlasma biomarkers of neurodegeneration may help characterise progression across the Alzheimers 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. ObjectiveTo compare plasma eMTBR-tau and selected biomarkers of neurodegeneration, neuropathology, and neuroinflammation across the AD continuum by pTau217 and APOE {varepsilon}4 status, and explore their associations with clinical progression over two years. DesignObservational cohort study with longitudinal follow-up in a subset of participants. SettingHealthy Brain Ageing (HBA) brain health and memory clinic, Sydney, Australia. Participants underwent assessment between October 2018 and April 2026. ParticipantsCross-sectional analysis included 436 participants; 166 were followed up approximately two years later. ExposuresPlasma biomarker quantification using the NULISAseqTM Neuro 220 Panel, clinical classification by multidisciplinary memory clinic assessment, plasma pTau217 status (SIMOA ALZpath), and APOE {varepsilon}4 carrier status. Main Outcomes and MeasuresFasting blood was collected on the morning of assessment. Plasma was analysed using the NULISAseqTM 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. ResultsAmong 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 RelevanceClinical 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. KEY POINTSO_ST_ABSQuestionC_ST_ABSHow do plasma biomarkers of neurodegeneration vary across clinical and biomarker-defined groups along the Alzheimers disease (AD) continuum, and are eMTBR-tau levels associated with clinical progression over approximately two years of follow-up? FindingsIn a brain health and memory clinic cohort of 436 participants, plasma eMTBR-tau showed the largest adjusted biomarker difference between subjective cognitive decline, mild cognitive impairment (MCI) and AD dementia groups. Amongst 166 participants followed up after 2 years, plasma eMTBR-tau levels at the preceding assessment best discriminated MCI-to-AD conversion (6/40; AUC=0.936). MeaningPlasma eMTBR-tau is a potential biomarker of clinical progression across the AD continuum.
ER -