The load of amyloid-ß oligomers is decreased in the cerebrospinal fluid of Alzheimer's disease patients.

ABSTRACT

Amyloid-ß (Aß) oligomers are heterogeneous and instable compounds of variable molecular weight. Flow cytometry and fluorescence resonance energy transfer (FRET)-based methods allow the simultaneous detection of Aß oligomers with low and high molecular weight in their native form. We evaluated whether an estimate of different species of Aß oligomers in the cerebrospinal fluid (CSF) with or without dilution with RIPA buffer could be more useful in the diagnosis of Alzheimer's disease (AD) than the measurement of Aß42 monomers, total tau (t-tau), and phosphorylated tau (p-tau). Increased t-tau (p < 0.01) and p-tau (p < 0.01), and decreased Aß42 (p < 0.01), were detected in the CSF of patients with AD (n = 46), compared to patients with other dementia (OD) (n = 35) or with other neurological disorders (OND) (n = 56). In native CSF (n = 137), the levels of Aß oligomers were lower (p < 0.05) in AD than in OD and OND patients; in addition, the ratio Aß oligomers/p-tau was lower in AD than in OD (p < 0.01) and OND (p < 0.05) patients, yielding a sensitivity of 75% and a specificity of 64%. However, in CSF diluted with RIPA (n = 30), Aß oligomers appeared higher (p < 0.05) in AD than in OND patients, suggesting they become partially disaggregated and more easily detectable after RIPA. In conclusion, FRET analysis in native CSF is essential to correctly determine the composition of Aß oligomers. In this experimental setting, the simultaneous estimate of low and high molecular weight Aß oligomers is as useful as the other biomarkers in the diagnosis of AD. The low amount of Aß oligomers detected in native CSF of AD may be inversely related to their levels in the brain, as occurs for Aß monomers, representing a biomarker for the amyloid pathogenic cascade.