The development of blood-based biomarkers (BBMs) for early detection of Alzheimer’s disease (AD) pathology is transformative for research and drug development. Historically, diagnosis relied on symptomatic presentation with costly confirmatory imaging. Today, the field is shifting toward a biologically defined framework for earlier detection and trial stratification. BBMs are central to this change, offering scalable and less invasive screening methods. Among them, phosphorylated tau (pTau217) has emerged as a frontrunner, while panels including pTau181, pTau231, Aβ42/40 ratios, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are proving valuable. In combination with imaging, these markers enable a multimodal diagnostic approach that could accelerate the development of disease-modifying therapies.

The Rise of pTau217 and Beyond

Large-scale initiatives such as the Bio-Hermes trials are testing these markers across diverse populations and comparing them to gold standard imaging. pTau217 has demonstrated high accuracy in distinguishing AD from other dementias, reporting strong correlations with amyloid status and tau PET burden biomarkers. However, its diagnostic performance does not perfectly align with amyloid PET, particularly in individuals near the threshold of amyloid positivity.

To address this, dual-threshold approaches are being explored; In this model, BBMs provide rapid, efficient first-line screening, while individuals with indeterminate results undergo confirmatory imaging. Imaging can then deliver second-stage confirmation, staging, and identification of co-pathologies. This staged workflow reduces costs and participant burden while ensuring trials enrol individuals with biologically confirmed AD.

Ultimately, clinical trials will likely rely on a “biomarker toolbox,” combining plasma assays with imaging to maximize diagnostic precision. Importantly, pTau217 and other BBMs have also been shown to correlate with long-term disease progression, opening opportunities for their use not only in screening but also as efficacy markers in clinical trials, alongside traditional imaging endpoints for an enriched multimodal view of the population.

Considerations Before Integrating to Clinical Trials

Before widescale adoption, several factors must be addressed. Assay reproducibility across laboratories and platforms remains a priority, as does the definition of validated cut-offs for trial inclusion and exclusion. Workflows must be designed so that plasma and imaging provide complementary, rather than redundant, information. Equally critical is the validation of biomarker performance across diverse populations to ensure equitable trial access and reliable interpretation across different clinical and demographic backgrounds.

Key Challenges Identified
Despite progress, challenges remain. Plasma markers are subject to biological variability and can be influenced by comorbidities, vascular disease, or pre-analytical handling. Studies such as Bio-Hermes are increasingly incorporating MRI to assess vascular pathology, which remains a key confounder and an area of active research. While BBMs reduce upfront costs, advanced imaging remains indispensable for confirmation and staging, and access to PET or MRI is limited in some regions. Regulatory frameworks are also evolving, with agencies still defining how BBMs will be incorporated into trial endpoints, enrichment strategies, and eventual clinical use.

Conclusion
The integration of plasma biomarkers with imaging represents the next frontier in AD clinical research. While pTau217 remains the strongest candidate for early AD detection, complementary plasma markers such as pTau181, pTau231, Aβ42/40, GFAP, and NfL are expanding the toolkit. When combined with imaging, they enable biologically precise, cost-efficient, and scalable approaches to trial enrolment and staging.

At IXICO, we partner with biotech and pharmaceutical organizations to design and deliver multimodal biomarker and imaging strategies in Alzheimer’s disease clinical trials. To explore how we can support your programs with efficient plasma and imaging biomarkers, please visit our AD Content portal

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