How far is the goal of applying β-amyloid in cerebrospinal fluid for clinical diagnosis of Alzheimer’s disease with standardization of measurements?

Cerebrospinal fluid (CSF) β-amyloid (Aβ) is important for early diagnosis of Alzheimer's disease (AD). However, the cohort distributions and cut-off values have large variation across different analytical assays, kits, and laboratories. In this review, we summarize the cut-off values and diagnostic performance for CSF Aβ1-42 and Aβ1-42/Aβ1-40, and explore the important effect factors. Based on the Alzheimer's Association external quality control program (AAQC program), the peer group coefficient of variation of manual ELISA assays for CSF Aβ1-42 was unsatisfied (>20%). Fully automated platforms with better performance have recently been developed, but still not widely applied. In 2020, the certified reference material (CRM) for CSF Aβ1-42 was launched; however, the AAQC 2021-round results did not show effective improvements. Thus, further development and popularization of CRM for CSF Aβ1-42 and Aβ1-40 are urgently required. Standardizing the diagnostic procedures of AD and related status and the pre-analytical protocols of CSF samples, improving detection performance of analytical assays, and popularizing the application of fully automated platforms are also important for the establishment of uniform cut-off values. Moreover, each laboratory should verify the applicability of uniform cut-off values, and evaluate whether it is necessary to establish its own population- and assay-specific cut-off values.