Specific amyloid-beta oligomers in-human cerebrospinal fluid.

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a long preclinical stage, during which pathological changes and biomarker abnormalities, such as elevations of tau proteins in the cerebrospinal fluid (CSF), occur in the absence of cognitive impairment. Research on the etiology of AD in cell culture and animals have suggested that soluble oligomers of amyloid-β (Aβ), such as Aβ*56, trimers, and dimers, are the synaptotoxic species in AD and are thought to be responsible for initiating the cognitive impairment associated with the early stages of disease. These studies also suggest that tau pathology develops downstream of Aβ and may mediate the detrimental effects of Aβ on learning and memory. However, the whether these Aβ oligomers exist in humans and are associated with disease processes of AD is still unknown. To address this question, we developed a sensitive method to detect Aβ*56, trimers, and dimers in lumbar CSF, enabling the study of these oligomers in clinically characterized living subjects. Biochemical study of CSF from cognitively intact subjects and impaired subjects with clinical diagnosis of AD and mild cognitive impairment (MCI) showed that these oligomers were present in the CSF of both the unimpaired and impaired subjects.Within the unimpaired group, subjects at a higher risk of having preclinical AD had elevated levels of Aβ oligomers. Furthermore, Aβ*56, dimers, and trimers were positively correlated with total or abnormally phosphorylated tau in the CSF of unimpaired subjects, suggesting that these oligomers are associated with disease processes and may induce tau abnormalities in the preclinical phase of disease. Study of CSF from subjects enrolled in a longitudinal study showed that Aβ*56 was negatively correlated with memory in unimpaired subjects who converted to MCI/AD during follow-up. However, baseline Aβ oligomer levels were not predictive of conversion to MCI/AD from cognitive normality. Further exploratory analysis revealed significant associations between high levels of baseline total tau or low Aβ*56 levels and a faster rate of memory decline. The results of these studies are consistent with the hypothesis that Aβ oligomers may trigger tau abnormalities in preclinical AD, and that Aβ*56 may play a pathological role in preclinical AD but is not sufficient to trigger disease progression. A hypothetical model describing the characteristics of Aβ*56 and tau during the preclinical phase of AD was generated from this data and awaits further evaluation.