BD-Tau as a Plasma Biomarker of Neurodegeneration in Alzheimer’s Disease

The landscape of biomarker research is continually evolving, with technological advancements reshaping our understanding and capabilities. In the pursuit to enhance Alzheimer's disease (AD) diagnostics, researchers are exploring blood biomarkers capable of identifying individuals at risk of cognitive decline by staging amyloid-beta (Aβ) pathophysiology alongside neurodegeneration intensity. While phosphorylated tau (p-Tau) in blood has been shown to track with Aβ pathology, a definitive biomarker for AD-type neurodegeneration has remained elusive. A recent multicenter study sheds light on a promising candidate: brain-derived tau (BD-Tau) in blood¹.

Exploring the Role of BD-Tau as a Blood-Based Neurodegeneration Biomarker in Alzheimer's Disease

Significant strides have been made in identifying blood biomarkers for Aβ pathophysiology in AD. However, tracking neurodegenerative changes specific to AD itself remains a critical gap. AD is pathologically characterized by Aβ plaques, tau neurofibrillary tangles, and brain atrophy. Although clinical symptoms of cognitive impairment may take several years to appear, the molecular alterations preceding symptom onset can be detected using biomarkers. As a result, there are continuous efforts to incorporate biomarkers into programs for early disease detection, treatment, and the subgrouping of participants in clinical therapeutic trials.

Advancements over the last few years have led to the development and validation of blood-based biomarkers, including Aβ42/Aβ40 ratio, p-Tau 181, p-Tau 217, and p-Tau 231, which demonstrate high accuracy in identifying Aβ pathophysiology and monitoring longitudinal changes in clinical trials. However, there is still an unmet need for a blood biomarker that tracks AD-specific neurodegeneration. Such a biomarker would help identify Aβ-positive individuals at higher risk for rapid disease progression, enabling prioritization for immediate treatment with anti-Aβ drugs. This differentiation is crucial as many Aβ-positive cognitively normal (CN) older adults do not develop cognitive decline for years, making it essential to identify those at higher risk of future cognitive decline and brain atrophy.

Recent research has highlighted BD-Tau as a promising blood-based biomarker. Studies from the University of Gothenburg have shown that BD-Tau levels are elevated in Alzheimer's disease (AD) compared to non-AD dementia and controls, with validation across diverse cohorts and autopsy-confirmed diagnoses². Building on this foundation, a new multicenter study¹ examines the association of blood BD-Tau with longitudinal cognition and AD-signature atrophy rates across the preclinical, MCI, and dementia phases of AD. This study evaluates whether BD-Tau levels increase with combined A+ and N+ abnormalities in the AD continuum and explores the potential of using blood-based biomarkers to identify those at short-term risk for cognitive decline and atrophy. Additionally, the study assesses the impact of genetic risk, comorbid conditions, and demographic factors, including racial self-identity, on plasma BD-Tau concentrations and clinical performance. This research marks a significant advancement in addressing the unmet need for AD-specific neurodegeneration biomarkers, potentially transforming AD diagnosis and treatment strategies.

Analytic Approach for BD-Tau Assessment

Utilizing a multi-cohort design, this study employed Simoa® technology to measure plasma biomarkers across four AD cohorts (n = 1076). Biomarker analyses were conducted using the HD-X™ Automated Immunoassay Analyzer, with BD-Tau measured using a Homebrew Custom Assay. Plasma p-Tau 181, t-tau and NfL were also measured using Simoa® assay kits.

Key Findings

Here, we summarize key findings of this study that underscore the importance of plasma BD-Tau across different stages of AD, underscoring its potential diagnostic and prognostic value:

• Plasma BD-Tau levels show a distinct association with amyloid-β (Aβ) pathology across the clinical AD continuum. BD-Tau concentrations are notably higher in individuals with Aβ positivity (A+) compared to those without (A-), indicating its potential as an AD-associated marker even in early stages of the disease.

• Across multiple cohorts, a strong correlation between plasma BD-Tau and cerebrospinal fluid (CSF) total tau (t-tau) levels has been observed. This correlation strengthens in the presence of both Aβ and neurofibrillary tangles (N) abnormalities, further supporting BD-Tau's role in reflecting AD-related neurodegeneration.

• Plasma BD-Tau demonstrates significant associations with future AD-related atrophy and cognitive decline. Higher BD-Tau levels are linked to increased rates of brain atrophy and poorer cognitive performance over time, highlighting its potential as a predictive biomarker.

• Integrating plasma p-Tau and BD-Tau allows for operationalizing the Aβ and neurodegeneration (A/N) classification in blood. This combination helps in stratifying individuals into different risk groups, facilitating personalized treatment strategies and disease management.

Impact on AD Pathology Research

These findings are crucial for AD pathology research, highlighting the importance of early and accurate diagnosis in managing dementia's global impact. Blood-based biomarkers such as BD-Tau show promise in detecting neurodegenerative changes, potentially revolutionizing AD management. The study's validation across multiple cohorts enhances the reliability of these biomarkers in clinical settings. Addressing the challenge of distinguishing disease stages and predicting cognitive decline, this study demonstrates that plasma BD-Tau, alongside biomarkers like p-Tau 181, provides nuanced insights into disease progression. Elevated levels of both biomarkers correlate with steeper cognitive decline, emphasizing their combined predictive power in AD.

The advancements in using BD-Tau as a plasma biomarker underscore the continuous innovation in biomarker detection technologies. Quanterix's Simoa® platform exemplifies the cutting-edge tools available to researchers, enabling them to push the boundaries in AD research. As our understanding of AD complexities evolves, integrating reliable biomarkers like BD-Tau will be crucial in combating this challenging disease.

Explore Quanterix's new commercially available BD-Tau assay to enhance your research capabilities in neurodegenerative diseases.

Powering Neuropathology Research with Quanterix Simoa® Technologies

Simoa® digital technology has played an instrumental role in advancing neuropathology research. With its ultra-sensitivity, full automation, and compatibility across various assays, the HD-X™ Automated Immunoassay Analyzer is an invaluable tool for detecting low-abundance biomarkers.

Explore our full menu of Simoa® assays and discover how they can transform your research in neurodegenerative diseases

References

1. Gonzalez-Ortiz F, Kirsebom BE, Contador J, et al. Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease. Nat Commun. 2024;15(1):2908. Published 2024 Apr 4. doi:10.1038/s41467-024-47286-5

1. Gonzalez-Ortiz F, Turton M, Kac PR, et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration [published correction appears in Brain. 2023 Oct 3;146(10):e89-e90. doi: 10.1093/brain/awad208]. Brain. 2023;146(3):1152-1165. doi:10.1093/brain/awac407

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