Diagnostic accuracy of the monocyte Aβ mid‐domain assay for CSF determined brain amyloid deposition. (31st December 2021) - Kirsebom, Bjørn Eivind
Abstract: Background: Cells in the innate immune monocyte‐phagocyte system (MPS), including microglia and monocytes/macrophages are important players in Aβ clearance. MPS‐linked genetic variants are risk factors for Alzheimer's disease, putatively linked to roles in Aβ clearance. The mid‐domain AβX‐34 peptide has recently been suggested as a marker of amyloid clearance. We hypothesize that the mid‐domain AβX‐34 peptides in peripheral blood‐derived monocytes reflect Aβ clearance efficiency and may serve as a biomarker of innate immune brain amyloid deposition. Here, we assess the diagnostic accuracy of blood monocyte derived AβX‐34 levels against an 18F flutemetamol amyloid PET determined CSF Aβ40/42 ratio cut‐off. Method: First, to determine the optimum cut‐off for mesoscale discovery (MSD) CSF Aβ42/40 ratio, n=83 cases and controls from the dementia disease initiation (DDI) cohort with 18F flutemetamol amyloid PET scans were included. Using receiver operating curve (ROC) analysis we determined the optimum cut‐off value for the MSD CSF 42/40 ratio based on visual read of the PET images by a trained radiologist as the standard of truth. Next, AβX‐34 levels were determined using an immunoassay developed on the Quanterix Single Molecule Array (Simoa) platform using a proprietary anti‐mid‐domain sheep monoclonal antibody as capture. The detector is an anticomplex antibody using Bio‐Rad HuCAL technology ensuring optimal Aβ mid‐domain peptide specificity and assay sensitivity (Fladby US patent:9, 625, 474). Lastly, we included n=33 cases and controls and evaluated the diagnostic accuracy of monocyte derived AβX‐34 levels against the PET determined CSF Aβ40/42 ratio cut‐off using a ROC analysis. Result: The MSD Aβ 42/40 ratio obtained an expected high diagnostic accuracy (AUC=.957) against amyloid PET. The monocyte derived AβX‐34 showed a comparatively lower, albeit adequate diagnostic accuracy (AUC=.808) against the Aβ 42/40 ratio cut‐off (see table 1 for details). Conclusion: A new immunoassay quantitating Aβ mid‐domain peptides is a new innovative strategy integrating the innate immune system in the diagnostic armamentarium for AD. The monocyte derived mid‐domain AβX‐34 shows promise as a viable blood‐based biomarker of brain amyloid deposition. However, assessment of diagnostic accuracy in larger samples are warranted.