Blood Biomarkers for Neurodegeneration

Current State

Blood-based biomarkers are transforming the diagnosis and monitoring of neurodegenerative diseases, particularly Alzheimer's disease (AD). Highly accurate plasma phosphorylated tau 217 (p-tau217) immunoassays are now available, demonstrating significant utility in detecting AD pathology (Ashton et al., 2024). Brain-derived tau (BD-tau) is emerging as a specific blood-based marker for AD-type neurodegeneration, addressing the limitations of total-tau and neurofilament light (NfL) in terms of AD specificity (González-Ortiz et al., 2022). NfL itself is a well-established blood biomarker for general neurodegeneration, showing increased concentrations in AD and other dementias, and correlating with cognitive decline (Mattsson et al., 2017; Byrne et al., 2017). The Alzheimer's Association recommends blood biomarkers as prescreeners for clinical trials evaluating disease-modifying therapies (Hansson et al., 2022).

Strongest Evidence

Plasma p-tau217 has shown high diagnostic accuracy for AD pathology, comparable to CSF and PET imaging markers (Ashton et al., 2024). The NIA-AA Research Framework emphasizes a biological definition of AD, where fluid biomarkers play a crucial role (Jack et al., 2018). Studies have demonstrated the ability of blood-based amyloid-beta (Aβ) ratios, quantified by sensitive methods like SIMOA, to detect cerebral amyloidosis in early stages (Meyer et al., 2020). CSF biomarkers, including Aβ42/40 ratio, total-tau, phosphorylated-tau, and NfL, are already used in clinical practice to support AD diagnosis (Zetterberg et al., 2021).

Unresolved Uncertainties

While significant progress has been made, several challenges persist. The standardization of blood biomarker assays across different platforms and laboratories is crucial for widespread clinical implementation. Establishing clear diagnostic thresholds and cut-off values for various neurodegenerative diseases remains an area of active research. The exact contribution of peripheral sources to blood biomarker levels, particularly for markers like total-tau, needs further elucidation (González-Ortiz et al., 2022). Furthermore, the integration of these biomarkers with neuroimaging and clinical assessments for differential diagnosis and personalized treatment strategies requires more extensive validation.

Why the Topic Matters

Blood biomarkers offer a less invasive, more accessible, and cost-effective approach to diagnosing and monitoring neurodegenerative diseases compared to cerebrospinal fluid (CSF) analysis or neuroimaging (Zetterberg et al., 2021). Their development is critical for early detection, enabling timely interventions and improving patient outcomes. These biomarkers are also invaluable for screening participants for clinical trials, enriching study populations with individuals likely to have specific pathologies, and tracking treatment response (Hansson et al., 2022). Ultimately, advancing blood biomarkers will accelerate drug development and facilitate the translation of research findings into routine clinical practice, revolutionizing the management of neurodegenerative disorders.

Points of Agreement

• Phosphorylated Tau (p-tau) as a Specific AD Biomarker: Plasma p-tau217 is a highly accurate and specific blood biomarker for Alzheimer's disease (AD) pathology, showing strong utility for detecting amyloid-beta (Aβ) and tau pathology (Ashton et al., 2024; Zetterberg et al., 2021). p-tau181 also demonstrates high diagnostic accuracy for AD (Hansson et al., 2022).
• Neurofilament Light (NfL) as a General Neurodegeneration Marker: Plasma NfL is a reliable blood-based biomarker for neuronal damage and neurodegeneration across various conditions, including AD and Huntington's disease, correlating with cognitive decline and imaging evidence of neurodegeneration (Mattsson et al., 2017; Byrne et al., 2017; Zetterberg et al., 2021).
• Blood Biomarkers for Screening and Trial Inclusion: Blood-based markers (BBMs) are recommended as prescreeners to identify individuals likely to have AD pathological changes for inclusion in clinical trials, provided AD status is confirmed by PET or CSF testing (Hansson et al., 2022).
• Correlation with CSF and Imaging Biomarkers: Blood biomarkers for Aβ and p-tau show good diagnostic accuracy and agreement with corresponding CSF and neuroimaging biomarkers within the A/T/(N) framework for AD (González-Ortiz et al., 2022; Zetterberg et al., 2021).

Active Disagreements

• Specificity of Total-Tau: While blood-based p-tau is highly specific for AD, blood total-tau (t-tau) is generally considered less specific to brain-derived pathology, with studies suggesting it originates principally from peripheral, non-brain sources (González-Ortiz et al., 2022; Zetterberg et al., 2021). However, brain-derived tau (BD-tau) is being explored as a more specific blood-based neurodegeneration marker for AD (González-Ortiz et al., 2022).

Uncertain Claims

• Universal Reference Ranges and Cut-offs: While specific cut-offs for plasma p-tau217 have been proposed for abnormal Aβ, the establishment of universal reference ranges and standardized cut-offs for widespread clinical use remains an ongoing area of research (Ashton et al., 2024; Hansson et al., 2022).
• Role in Differential Diagnosis: The full utility of blood biomarkers for differential diagnosis among various neurodegenerative diseases, beyond AD, is still being investigated. While NfL indicates general neurodegeneration, its lack of specificity necessitates further research for distinguishing specific conditions (Mattsson et al., 2017; Zetterberg et al., 2021).

Evidence Gaps

• Integration into Routine Clinical Practice: Despite significant progress, the widespread implementation of blood biomarkers into routine clinical care for early diagnosis, disease progression tracking, and treatment response assessment requires further validation and standardization (Hansson et al., 2022; Zetterberg et al., 2021).
• Impact of Co-pathologies: More research is needed to understand how co-pathologies, such as vascular lesions, TDP-43, and α-synuclein aggregates, influence blood biomarker levels and their diagnostic accuracy in complex neurodegenerative presentations (Thal et al., 2025).
• Longitudinal Studies on Treatment Response: While promising for trial inclusion, more longitudinal studies are needed to evaluate the effectiveness of blood biomarkers in monitoring treatment response to disease-modifying therapies in real-world clinical settings (Hansson et al., 2022).
• Standardization of Assays: Continued efforts are required to standardize high-throughput assays for various blood biomarkers (e.g., Aβ ratios, p-tau, NfL) across different platforms (e.g., ELISA, SIMOA) to ensure comparability and reliability of results across research and clinical settings (Meyer et al., 2020; Zetterberg et al., 2021).

Phosphorylated Tau (p-tau) for Alzheimer's Disease

Evidence Strength: Strong

Plasma p-tau, particularly p-tau217, is a highly specific and accurate blood biomarker for Alzheimer's disease (AD) pathology. A novel, commercially available immunoassay for plasma p-tau217 demonstrated high utility in detecting AD pathology, correlating well with amyloid-beta (Aβ) and tau PET imaging, and showing longitudinal changes across different AD stages (Ashton et al., 2024). This supports earlier findings that p-tau is a robust marker of AD-related tau metabolism (Zetterberg et al., 2021). The Alzheimer's Association recommends the use of blood-based markers like p-tau as prescreeners for clinical trials, provided AD status is confirmed by PET or CSF testing (Hansson et al., 2022).

Neurofilament Light (NfL) as a General Neurodegeneration Marker

Evidence Strength: Moderate to Strong

Plasma NfL is a valuable blood-based biomarker for neurodegeneration, reflecting neuronal damage. It is increased in AD and associated with cognitive decline and neuroimaging evidence of neurodegeneration (Mattsson et al., 2017). NfL has also shown promise as a prognostic marker for neurodegeneration in Huntington's disease, correlating with clinical and MRI findings (Byrne et al., 2017). While NfL is a robust marker of neuronal injury, its lack of specificity to AD pathology means it is not solely indicative of AD, as it can be elevated in various neurodegenerative conditions (Zetterberg et al., 2021; Bos et al., 2019).

Amyloid-beta (Aβ) Ratios for Cerebral Amyloidosis

Evidence Strength: Moderate

Blood-based Aβ ratios, such as Aβ1-42/Aβ1-40, show potential for detecting cerebral amyloidosis in early disease stages (Meyer et al., 2020). However, the diagnostic accuracy can vary depending on the assay used (e.g., ELISA vs. SIMOA), with some assays demonstrating better performance in distinguishing amyloid-positive from amyloid-negative individuals (Meyer et al., 2020). Further standardization and validation of these assays are needed for widespread clinical use.

Brain-Derived Tau (BD-tau) for AD-Type Neurodegeneration

Evidence Strength: Moderate

Brain-derived tau (BD-tau) is a novel blood-based biomarker that aims to specifically detect AD-type neurodegeneration. Unlike total-tau, which can originate from peripheral sources, BD-tau selectively binds to brain-derived tau, showing better correlation with CSF total-tau and AD pathology (González-Ortiz et al., 2022). This marker holds promise for improving the specificity of blood-based neurodegeneration assessment in AD.

Limitations and Future Directions

While significant progress has been made, further research is needed to fully integrate blood biomarkers into routine clinical care (Hansson et al., 2022; Zetterberg et al., 2021). The NIA-AA Research Framework emphasizes the biological definition of AD using biomarkers for research purposes, highlighting the ongoing evolution of diagnostic criteria (Jack et al., 2018). The influence of factors like smoking on CSF biomarkers of neurodegeneration also warrants consideration (Liu et al., 2020). The presence of co-pathologies in AD, such as vascular lesions or α-synuclein aggregates, further complicates biomarker interpretation and necessitates a comprehensive approach (Thal et al., 2025).

Recent trends in blood biomarkers for neurodegeneration are marked by significant advancements, particularly in Alzheimer's disease (AD) diagnostics. A key development is the increasing utility of plasma phosphorylated tau (p-tau) isoforms, with p-tau217 showing high diagnostic accuracy for AD pathology (Ashton et al., 2024). The availability of novel, commercially available immunoassays for plasma p-tau217 is expanding, facilitating wider evaluation and implementation of these blood tests (Ashton et al., 2024).

Another emerging method is the use of brain-derived tau (BD-tau) as a specific blood-based biomarker for AD-type neurodegeneration (González‐Ortiz et al., 2022). This addresses a limitation of traditional blood total-tau, which often originates from peripheral sources and lacks strong correlation with CSF total-tau (González‐Ortiz et al., 2022). Neurofilament light (NfL) remains a valuable, though non-specific, blood-based marker for general neurodegeneration, showing associations with cognitive decline and other AD biomarkers (Mattsson et al., 2017). NfL has also been investigated as a prognostic marker for neurodegeneration in conditions like Huntington's disease (Byrne et al., 2017).

The development of high-throughput immunoassay technologies, such as SIMOA, is crucial for moving fluid biomarkers from research tools to routine clinical diagnostics (Zetterberg et al., 2021; Meyer et al., 2020). These technologies enable non-invasive, cost-effective, and scalable detection of cerebral amyloidosis and other pathologies (Meyer et al., 2020). The Alzheimer's Association has issued appropriate use recommendations for blood biomarkers in AD, suggesting their immediate use as screeners for clinical trials to identify individuals likely to have AD pathological changes (Hansson et al., 2022). This indicates a strong signal for their integration into clinical practice, initially for research purposes, with a view towards broader diagnostic and prognostic applications (Hansson et al., 2022).

While the focus is heavily on AD, research also explores broader aspects of neurodegeneration, including the role of neuroinflammation (Ransohoff et al., 2016) and the impact of lifestyle factors like smoking on CSF biomarkers of neurodegeneration and neuroinflammation (Liu et al., 2020). The NIA-AA Research Framework continues to guide the biological definition of AD, emphasizing the importance of biomarkers in research (Jack et al., 2018). Future trends will likely involve further validation of these blood biomarkers against CSF and imaging markers, and their integration into comprehensive diagnostic algorithms for various neurodegenerative diseases (Thal et al., 2025; Bos et al., 2019).

Synthesis

The field of blood biomarkers for neurodegeneration is rapidly advancing, aiming to replace or supplement invasive cerebrospinal fluid (CSF) collection and expensive positron emission tomography (PET) imaging (Zetterberg et al., 2021). The primary focus has been on Alzheimer's disease (AD), aligning with the A/T/(N) biological framework which defines AD by the presence of amyloid-β (Aβ) plaques, pathologic tau, and neurodegeneration (Jack et al., 2018). Plasma phosphorylated tau (p-tau), particularly p-tau217, has emerged as a highly accurate and specific marker for AD pathology (Ashton et al., 2024). In contrast, neurofilament light (NfL) is a sensitive but non-specific marker of axonal damage, elevated in various neurodegenerative conditions including AD and Huntington's disease (Mattsson et al., 2017; Byrne et al., 2017). Research is also focused on developing more specific markers, such as brain-derived tau (BD-tau), to overcome the limitations of total-tau assays which are confounded by peripheral sources (González‐Ortiz et al., 2022).

Methods/Materials

Progress in this field is driven by technological advancements in immunoassays. Ultrasensitive platforms like Single molecule array (Simoa) have been crucial for detecting the low concentrations of these biomarkers in blood plasma (Meyer et al., 2020). These assays quantify specific proteins, such as the ratio of Aβ42 to Aβ40, various p-tau isoforms (e.g., p-tau217), and NfL. Validation of these blood tests involves correlating their results with established gold standards, including CSF biomarker levels and amyloid- or tau-PET imaging, to ensure they accurately reflect brain pathology (Ashton et al., 2024; Zetterberg et al., 2021).

Applications

Blood biomarkers have significant potential across the clinical spectrum. The Alzheimer's Association recommends their use as prescreening tools in clinical trials to identify individuals with underlying AD pathology, reducing costs and logistical burdens (Hansson et al., 2022). Clinically, they can aid in the early and differential diagnosis of dementia, track disease progression, and potentially monitor therapeutic response. For instance, plasma NfL has been shown to correlate with cognitive decline and neurodegeneration in AD (Mattsson et al., 2017). The availability of commercial assays for markers like p-tau217 is accelerating their integration into clinical practice (Ashton et al., 2024).

Limitations

Despite their promise, several limitations must be addressed. There is a need for standardization across different assay platforms and the establishment of universal, validated cutoffs for clinical decision-making (Hansson et al., 2022). The non-specificity of markers like NfL means they cannot be used for differential diagnosis alone (Mattsson et al., 2017). Furthermore, the influence of co-pathologies (e.g., vascular, TDP-43) and external factors like lifestyle (e.g., smoking) on biomarker levels requires further investigation (Thal et al., 2025; Liu et al., 2020). The transition from research use to routine clinical diagnostics necessitates robust validation and clear guidelines for interpretation (Zetterberg et al., 2021).

Update Triggers

This review will be updated upon the publication of: 1) Large-scale clinical validation studies of new or existing blood biomarkers in diverse populations. 2) Regulatory approval (e.g., by the FDA) of a blood biomarker for routine clinical use in diagnosis or prognosis. 3) Head-to-head comparison studies of different biomarker assays or modalities. 4) Studies demonstrating the utility of blood biomarkers in monitoring the response to novel disease-modifying therapies. 5) The identification of novel biomarkers for other neurodegenerative diseases (e.g., Parkinson's, FTD) or for co-pathologies.

Near-Term Work

The immediate focus is on expanding access to and standardizing highly accurate Alzheimer's disease (AD) biomarkers like plasma phosphorylated tau 217 (p-tau217), which has shown excellent diagnostic performance (Ashton et al., 2024). Concurrently, research should prioritize the discovery and development of novel biomarkers that are more specific to neurodegeneration (N) itself, such as brain-derived tau (BD-tau), to complement the existing amyloid (A) and tau (T) markers and better align with the A/T/(N) framework (González‐Ortiz et al., 2022; Jack et al., 2018).

Validation Needs

Robust validation requires large, longitudinal, and diverse community-based cohorts. Biomarkers must be validated against the gold standards of CSF analysis and PET imaging to establish their accuracy for diagnosis and prognosis. It is crucial to understand biomarker performance across different ethnicities, comorbidities, and disease stages, from preclinical to dementia.

Datasets and Benchmarks

Standardized, multi-center datasets are essential. Benchmarks should be established for diagnostic accuracy (sensitivity/specificity), concordance with CSF/PET, and predictive value for cognitive decline. The NIA-AA Research Framework provides a crucial benchmark for defining AD biologically (Jack et al., 2018).

Translation Barriers

Key barriers include the lack of fully automated, high-throughput, and globally standardized assays. Overcoming regulatory hurdles for clinical approval and establishing clear clinical implementation guidelines, such as the appropriate use recommendations from the Alzheimer's Association, are critical for adoption (Hansson et al., 2022). Reimbursement policies and clinician education also present significant challenges.

High-Value Experiments

1. Head-to-head comparison studies: Directly compare the performance of different blood biomarkers (e.g., p-tau217, p-tau181, BD-tau, NfL) within the same diverse patient cohorts.
2. Clinical trial integration: Use blood biomarkers as pre-screening tools to enrich trial populations and as secondary endpoints to monitor treatment response, accelerating drug development.
3. Primary care utility studies: Evaluate the feasibility and impact of implementing blood biomarker tests in primary care settings to aid in early detection and appropriate referral.