CSF and plasma Aß42/40 across Alzheimer's disease continuum: comparison of two ultrasensitive Simoa® assays targeting distinct amyloid regions

Objectives: Decreased cerebrospinal fluid (CSF) amyloid beta 42/40 ratio (A ss 42/40) is one of the core Alzheimer ' s disease (AD) biomarkers. Measurement of A ss 42/40 in plasma has also been proposed as a surrogate marker for amyloidosis, however the validity and the diagnostic performance of this biomarker is still uncertain. Here we evaluated two immunoassays targeting distinct regions of the amyloid peptides by (a) performing a method comparison in both CSF and plasma, and (b) assessing the diagnostic performance across the AD continuum. Methods: We used N4PE and N3PA Simoa((R)) assays to measure A ss 42/40 in CSF and plasma of 134 patients: preclinical AD (pre-AD, n=19), mild cognitive impairment due to AD (MCI-AD, n=41), AD at the dementia stage (AD-dem, n=35), and a control group (CTRL, n=39). The N4PE includes a detector antibody targeting the amyloid N-terminus, while the N3PA uses a detector targeting amyloid mid-region. Results: Method comparison of N4PE and N3PA assays revealed discrepancies in assessment of plasma A ss 42/A ss 40. While the diagnostic performance of the two assays did not significantly differ in CSF, in plasma, N4PE assay provided better accuracy for AD discrimination than N3PA assay (AUC AD-dem vs. CTRL 0.77 N4PE, 0.68 N3PA). Conclusions: While both A ss 42/40 assays allowed for an effective discrimination between CTRL and different AD stages, the assay targeting amyloid N-terminal region provided the best diagnostic performance in plasma. Differences observed in technical and diagnostic performance of the two assays may depend on matrix-specific amyloid processing, suggesting that further studies should be carried to standardize amyloid ratio measurement in plasma.