GUEST EDITORIAL - Blood-Based Biomarkers to Diagnose and Differentiate Dementias

Neuronal pathology can exist decades before clinical signs of cognitive decline appear. Measuring critical markers, such as phosphorylated tau (e.g., pTau-217), is increasingly feasible in cerebrospinal fluid (CSF), but blood-based diagnostics are essential for routine care.

How can we confidently measure molecules that are 50 times less abundant in blood than in CSF? Furthermore, dementia and neurodegeneration encompass a wide variety of diseases; is a single marker sufficient to assess severity and distinguish between subtypes?

The Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA) from Alamar Biosciences delivers industry-leading protein detection sensitivity with multiplexing, making it the ideal tool for biomarker researchers focused on blood-based diagnosis and differentiation of dementias. Two curated panels—NULISAseq CNS Disease Panel 120 and NULISAseq Inflammation Panel 250—can be processed daily on the automated ARGO HT system with remarkably little hands-on time, facilitating the scalability required for routine clinical care.

Since entering the market less than two years ago, NULISA has already established itself as a valuable asset in neurodegeneration and dementia research, as evidenced by its high-profile peer-reviewed and preprint publications.

Multimodal markers before clinical signs

The ultimate promise of disease-indicative circulating biomarkers is identifying disease development before classical clinical signs appear, when emerging treatments are more effective. In a longitudinal cohort of largely asymptomatic AD participants, Thomas Karikari and colleagues at the University of Pittsburgh reported several proteins in the NULISAseq CNS Disease Panel that correlated with amyloid, tau, or neurodegeneration pathology prior to cognitive impairment. Such signatures can accelerate a personalized medicine approach to AD and related dementias while highlighting novel therapeutic strategies early in the disease's natural history.

Differentiating mild cognitive impairment and various dementias

While AD garners significant attention in biomarker discovery, the noninvasive, blood-based diagnosis of other dementias arising from different underlying biology has important implications for treatment and management. Three preprints from institutions in Sweden, the United Kingdom, and Turkey demonstrated how NULISAseq multiplexing in mixed dementia cohorts enhances the diagnostic accuracy of specific conditions.

• University of Gothenburg in Sweden, led by Henrik Zetterberg
• University of Cambridge in the UK, led by Maura Malpetti
• Istanbul University (Turkey) and University College London (UK), co-led by Haşim Gezegen and Maryam Shoai

Certain neurodegenerative markers, including NfL, CRH, CD276, and S100A12, were predictive of survival outcomes, regardless of the specific type of dementia. Thus, screening a curated battery of proteins can provide insights into condition-specific characteristics and pan-dementia outcomes.

Staging Alzheimer’s disease (AD) and related dementias

In a recent preprint, Sterling Johnson and colleagues at the University of Wisconsin showcased the benefits of multiplexing in the NULISAseq CNS Disease Panel 120. Not only did pTau-217 accurately classify amyloid and tau pathology status (as determined by PET), but pTDP43-409 was also identified as a potential biomarker for detecting non-AD co-occurring pathology. Additional inflammation and oxidative stress markers further illustrate the technology’s ability to reveal novel disease-causing processes in addition to known targets.