The Load of Amyloid-β Oligomers is Decreased in the Cerebrospinal Fluid of Alzheimer's Disease Patients

Amyloid-beta (A beta) 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 A beta oligomers with low and high molecular weight in their native form. We evaluated whether an estimate of different species of A beta 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 A beta(42) monomers, total tau (t-tau), and phosphorylated tau (p-tau). Increased t-tau (p < 0.01) and p-tau (p < 0.01), and decreased A beta(42) (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 A beta oligomers were lower (p < 0.05) in AD than in OD and OND patients; in addition, the ratio A beta 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), A beta 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 A beta oligomers. In this experimental setting, the simultaneous estimate of low and high molecular weight A beta oligomers is as useful as the other biomarkers in the diagnosis of AD. The low amount of A beta oligomers detected in native CSF of AD may be inversely related to their levels in the brain, as occurs for A beta monomers, representing a biomarker for the amyloid pathogenic cascade.