Harmonization and standardization of biofluid‐based biomarker measurements for AT(N) classification in Alzheimer's disease

Abstract

Fluid biomarkers are currently measured in cerebrospinal fluid and blood for Alzheimer's disease diagnosis and are promising targets for drug development and for patients’ follow‐up in clinical trials. These biomarkers have been grouped in an unbiased research framework, the amyloid (Aβ), tau, and neurodegeneration (AT[N]) biomarker system to aid patients’ early diagnosis and stratification. Metrological approaches relying on mass spectrometry have been used for the development of reference materials and reference measurement procedures. Despite their excellent performances as clinical tools, fluid biomarkers often present an important between‐laboratory variation. Standardization efforts were carried out on the biomarkers currently included in the AT(N) classification system, involving the collaboration of national metrology institutes, clinicians, researchers, and in vitro diagnostic providers. This article provides an overview of current activities towards standardization. These reference methods and reference materials may be used for recalibration of immunoassays and the establishment of standardized cutoff values allowing a better stratification of Alzheimer's disease patients.Highlights The AT(N) biomarker system allows stratifying AD patients on the basis of biomarker profiles. Fluid biomarker measurements often present an important between‐laboratory variation preventing the establishment of standardized cutoff values. Overview on the standardization initiatives involving the fluid biomarkers currently included in the AT(N) framework.

The CentiMarker Project: Standardizing Quantitative Alzheimer’s disease Fluid Biomarkers for Biologic Interpretation

“…These standardization projects typically take years to complete, and some of the biomarkers may be hard to standardize due to molecular heterogeneity of the analyte to be standardized, which may result in non-commutable reference materials. 19 In contrast, the goal of the CentiMarker standardization is to have a biologically relevant scale that relates to the disease stage from normal to abnormal to facilitate biologic interpretation. Thus, these multiple standardization approaches are useful in different contexts: comparing the same measure across labs, harmonizing across runs and labs, and comparing the magnitude of biological effects across biomarker measures in an easy-to-understand scale.…”

Advances in Blood Biomarkers for Alzheimer’s Disease: Ultra-Sensitive Detection Technologies and Impact on Clinical Diagnosis

“…Patients negative for A are considered non-AD, whereas being positive for N, regardless of T status, is classified as non-AD neurodegenerative changes. 106 Although diagnosing AD accurately using only plasma biomarkers remains challenging, the combination of various blood biomarkers can identify potential AD patients from control groups, promising to become an effective method for pre-screening AD ( Table 2 ).…”