A new blood test could improve how Alzheimer’s disease is diagnosed

By Dr. Liji Thomas, MDReviewed by Lily Ramsey, LLMApr 1 2025

Plasma eMTBR-tau243 shows a strong correlation with tau pathology and cognitive decline, offering a less invasive alternative to tau-PET imaging.

Study: Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer’s disease. Image Credit: Gorodenkoff/Shutterstock.com

Tau protein clumps that form neurofibrillary tangles (NFTs) are a defining feature of Alzheimer’s disease (AD), the leading cause of dementia worldwide. There's growing demand for an affordable, accessible, and less invasive test that can detect tau pathology to aid in diagnosis, guide treatment decisions, and monitor disease progression.

A recent study published in Nature Medicine introduces a blood test targeting a specific insoluble form of tau—offering a potential breakthrough in how we approach Alzheimer's diagnostics.

Introduction

Alzheimer’s disease leads to progressive, irreversible cognitive decline, affecting millions of older adults globally. In the brains of people with AD, two abnormal proteins are consistently found: amyloid-β (Aβ) plaques and tau-based NFTs.

Anti-amyloid immunotherapies have shown promise, slowing cognitive and functional decline by 25%–40%. However, they’re most effective when tau pathology remains limited—highlighting the need for early, accurate detection of tau buildup in the brain.

Identifying a peripheral biomarker that reliably tracks tau pathology could fill this gap. Unlike Aβ accumulation—which can be present in people with no symptoms—tau changes more closely align with disease progression.

This type of marker would not only improve diagnostic accuracy but also support the development of targeted anti-tau treatments, potentially used alongside anti-amyloid therapies for a more comprehensive approach.

Tau-PET imaging vs. fluid biomarkers

Currently, tau-PET scans are the gold standard for assessing tau pathology in symptomatic patients. However, they are expensive and not widely available. Fluid biomarkers, by contrast, offer a more cost-effective and scalable solution—well-suited for routine clinical settings and point-of-care testing.

Existing fluid biomarkers include Aβ42/40 ratios and phosphorylated tau forms such as p-tau181 and p-tau217, measured in both cerebrospinal fluid (CSF) and plasma.

While useful, these markers are more strongly tied to Aβ plaque presence than to tau tangle formation.

In earlier work, researchers used mass spectrometry to detect CSF levels of p-tau205 and MTBR-tau243 (a fragment from tau’s microtubule-binding region containing residue 243). While informative, this approach still relies on lumbar puncture, which is invasive and carries certain risks.

In this new study, the team introduces a blood-based biomarker—endogenously cleaved MTBR-tau243 (eMTBR-tau243)—which avoids those limitations. The researchers conducted two pilot studies and a larger validation study, comparing eMTBR-tau243 levels with cognitive assessments, Aβ-PET, tau-PET, and MRI data.

They also compared its performance with existing plasma biomarkers, specifically %p-tau181 and %p-tau217.

Key findings

The study found that plasma eMTBR-tau243 correlates with both plasma and CSF tau-PET imaging, unlike MTBR-tau243, which aligns only with CSF data.

In the pilot studies, eMTBR-tau243 levels were significantly higher—up to 200-fold—in patients with established AD compared to those with mild cognitive impairment (MCI) or early-stage disease. Notably, this marker did not rise in people who had Aβ plaques but no cognitive symptoms.

In the larger clinical trial, eMTBR-tau243 remained stable in cognitively normal individuals regardless of Aβ status. However, levels increased notably in those with MCI, suggesting the biomarker may help stratify patients by disease stage. It also remained specific to AD, with no elevation in non-AD tauopathies.

Comparatively, plasma %p-tau217 was tracked with AD severity but was also elevated in Aβ-positive individuals without symptoms. A similar but more variable pattern was observed for %p-tau205.

All three markers—eMTBR-tau243, %p-tau217, and %p-tau205—were associated with tau-PET positivity. However, eMTBR-tau243 showed the strongest and most linear relationship, even as disease severity increased.

While %p-tau217 levels tended to plateau, eMTBR-tau243 continued to rise, reflecting a closer link to ongoing tau tangle accumulation.

Among Aβ-positive individuals, 59% tested negative for both tau-PET and eMTBR-tau243, while 30% were positive for both. Discordant results were less common with eMTBR-tau243 (7%) compared to %p-tau217 (41%), further supporting the closer alignment between eMTBR-tau243 and tau-PET findings.

Regionally, eMTBR-tau243 levels strongly correlated with tau-PET positivity in brain areas typically affected later in the disease—suggesting it’s particularly useful for tracking more advanced stages of AD.

Multivariate analysis confirmed that eMTBR-tau243 uniquely captures this later phase of tau pathology, while %p-tau217 aligns more closely with earlier, Aβ-driven changes.

eMTBR-tau243 also had the strongest associations with brain atrophy, early cognitive decline, and global cognitive scores in individuals positive for Aβ or tau-PET.

Implications

If validated in larger populations, this blood test could significantly improve how we diagnose and monitor Alzheimer’s.

By identifying tau pathology earlier and more accurately, clinicians could tailor treatments based on disease stage and potentially improve outcomes.

Researcher Kanta Horie explained the potential shift this brings: 

"We’re about to enter the era of personalized medicine for Alzheimer’s disease. For early stages with low tau tangles, anti-amyloid therapies could be more efficacious. But once dementia sets in and tau tangles accumulate, anti-tau therapies or other experimental approaches may be more appropriate."

Conclusion

This study introduces plasma eMTBR-tau243 as a promising biomarker for detecting and monitoring advanced tau pathology in Alzheimer’s disease.

It outperforms existing markers in predicting tau-PET findings and correlates more strongly with cognitive decline and brain atrophy.

As a potential alternative to tau-PET, eMTBR-tau243 could offer a practical, noninvasive tool for clinical trials and everyday practice, improving diagnostic precision and helping guide treatment decisions based on disease stage.