CTAD 2023 – Spotlight on recent advances in blood-based biomarkers for Alzheimer’s disease

By Dr. Nathalie Le Bastard, Fujirebio Europe
 

Both fluid and imaging biomarkers provide biological evidence for the underlying etiology of cognitive impairment. The core fluid biomarkers of Alzheimer’s disease (AD) pathology, i.e. Aβ_1-42/1-40, tTau and pTau₁₈₁ in cerebrospinal fluid (CSF), have long been identified and their clinical diagnostic performance established. In recent years, their implementation in clinical practice has been increasing due to the level of automation of the currently available tests and regulatory clearance in several regions around the world, e.g., Europe, United States and Japan.

However, with the advent of amyloid-targeting disease-modifying treatments for AD comes a great need for easier, less invasive, and more scalable tools to confirm the presence of amyloid (and perhaps also tau) pathology. The emergence of blood-based biomarkers, and sensitive immunoassays to detect these, are becoming a game-changer for the AD field, currently in a transition phase during which blood-based biomarkers are being integrated with “traditional” CSF and positron emission tomography (PET) biomarkers.¹

It seems realistic to assume that certain plasma biomarker assays - currently only used in a research environment - could reach a high agreement with existing biomarker classifications or measurement tools, if used within a specific intended use setting. This is  illustrated by the below examples presented during the latest Clinical Trials in Alzheimer’s Disease (CTAD) meeting.

The work presented by Ashton et al.² (LP048 – The Alzheimer’s Association Global Biomarker Standardization Consortium (GBSC) plasma phospho-tau Round Robin study – S138) reports the results from the largest head-to-head comparison to date including 26 different pTau assays. To estimate the clinical performance, a total of 40 individuals with suspected AD were evaluated and categorized in 25 AD and 15 non-AD cases according to their CSF biomarker profile and the matching plasma samples were measured with each of the participating assays. The discriminative accuracy (represented by the area under the curve (AUC)) as well as the mean fold change between the AD and non-AD group was generally higher for the plasma pTau₂₁₇ assays. Some assays even achieved a perfect (100%) agreement with the CSF biomarker classification, despite the moderate correlation between CSF and plasma pTau which is most likely due to a complete loss of correlation in the AD group. The plasma pTau₁₈₁ assays show a wider range in performance with the best performing pTau₁₈₁ assay achieving an AUC of approximately 0.95, while another cannot distinguish between CSF biomarker positive and negative cases. Other results coming from the current study of significant importance are the strong correlations between the different pTau assays, contrary to the results obtained in similar studies for plasma amyloid in the past.^3,4,5 In conclusion, the results of the current study tend to favor pTau₂₁₇ as the blood-based biomarker of choice over any of the other pTau epitopes.