Blood‐based quantification of Aβ oligomers indicates impaired clearance from brain in ApoE ε4 positive subjects

Background Quantification of Aβ oligomers in plasma may be useful not only for early diagnosis of Alzheimer’s disease (AD), but particularly to improve our understanding of underlying pathologies. However, quantification necessitates an extremely sensitive and selective technology due to very low concentrations and possible interferences of matrix components. Owing to their central role in AD pathology, oligomers are an attractive therapeutic target to ultimately halt disease progression or even to cure AD. Method In the present study, we developed and validated the surface‐based intensity‐distribution analysis (sFIDA) assay for quantification of Aβ oligomers in plasma. sFIDA is single particle sensitive and completely insensitive to Aβ monomers. Result The blood‐based sFIDA assay delivered a sensitivity of 1.8 fM, an inter‐ and intra‐assay variation below 20% for silica‐nanoparticles (SiNaPs) as calibration standard, and no interference with matrix components. Quantification of Aβ oligomers in 366 plasma samples from the DELCODE cohort, revealed decreased oligomer concentrations in subjective cognitive decline and AD patients compared to healthy controls. Correlation analysis between CSF and plasma oligomer concentrations suggest an impaired clearance of Aβ oligomers depending on ApoE ε4 status. Conclusion sFIDA is able to quantitate Aβ oligomers in plasma samples down to the low fM range. Aβ oligomers in plasma may reveal clearance mechanisms from the brain into blood, and how they are impaired during disease progression.