Conformation-Dependent Oligomers in Cerebrospinal Fluid of Presymptomatic Familial Alzheimer’s Disease Mutation Carriers

Abstract

Background/Aims: Oligomerization of amyloid beta (Aβ) is a hypothesized step in the formation of plaques in Alzheimer’s disease (AD) but has been difficult to demonstrate in vivo in humans. As persons destined to develop familial AD (FAD) due to fully penetrant autosomal dominant mutations are essentially certain to develop the disease, they provide the opportunity to identify oligomers during the presymptomatic stage of the disease. Methods: We measured levels of Aβ42 using a conventional immunoassay and prefibrillar, fibrillar, and annular protofibrillar oligomers using polyclonal conformation-dependent antibodies in the cerebrospinal fluid (CSF) of 7 persons at risk for inheriting FAD mutations. Levels of oligomers were compared between FAD mutation carriers and noncarriers. Results: Compared to 2 noncarriers, annular protofibrillar oligomers were elevated, prefibrillar and fibrillar oligomers trended towards elevation and Aβ42 monomer trended towards being decreased in 5 FAD mutation carriers. Conclusion: Our data provide evidence for an identifiable elevation of CSF oligomers during the presymptomatic phase of FAD.

Keywords

• Presymptomatic
• Alzheimer’s disease
• Oligomer
• Aβ
• Aβ42
• Cerebrospinal fluid
• Presenilin-1
• Amyloid precursor protein
• Conformation