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Abstract

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 selec-
tive decrease in CSF Aβ42 in Alzheimer's disease.