Detection and quantification of Aβ-3-40 (APP669-711) in cerebrospinal fluid

Neurochemical biomarkers can support the diagnosis of Alzheimer's disease and may facilitate clinical trials. In blood plasma, the ratio of the amyloid-β (Aβ) peptides Aβ-3-40/Aβ1-42 can predict cerebral amyloid-β pathology with high accuracy (Nakamura et al., 2018). Whether or not Aβ-3-40 (aka. amyloid precursor protein (APP) 669-711) is also present in cerebrospinal fluid (CSF) is not clear. Here, we investigated whether Aβ-3-40 can be detected in CSF and to what extent the CSF Aβ-3-40/Aβ42 ratio is able to differentiate between individuals with or without amyloid-β positron emission tomography (PET) evidence of brain amyloid. The occurrence of Aβ-3-40 in human CSF was assessed by immunoprecipitation followed by mass spectrometry. For quantifying the CSF concentrations of Aβ-3-40 in 23 amyloid PET-negative and 17 amyloid PET-positive subjects, we applied a sandwich-type immunoassay. Our findings provide clear evidence of the presence of Aβ-3-40 and Aβ-3-38 in human CSF. While there was no statistically significant difference in the CSF concentration of Aβ-3-40 between the two diagnostic groups, the CSF Aβ-3-40/Aβ42 ratio was increased in the amyloid PET-positive individuals. We conclude that Aβ-3-40 appears to be a regular constituent of CSF and may potentially serve to accentuate the selective decrease in CSF Aβ42 in Alzheimer's disease.