Oligomerization Partially Explains the Lowering of A beta 42 in Alzheimer's Disease Cerebrospinal Fluid

Background/Objective: The lowering of natively analyzed A beta 42 in cerebrospinal fluid (CSF) is used as a diagnostic tool in Alzheimer's disease (AD). The presence of A beta oligomers can interfere with such analyses causing underestimation of A beta levels due to epitope masking. The aim was to investigate if the lowering of CSF A beta 42 seen in AD is caused by oligomerization. Methods: A beta 42 was analyzed under both denaturing and non-denaturing conditions. An A beta 42 oligomer ratio was calculated from these quantifications. The presence of oligomers leads to A beta 42 epitope masking during non- denaturing assays, resulting in a higher ratio. Results: The A beta 42 oligomer ratio was used for the assessment of oligomerized A beta in human CSF, after being evaluated in transgenic mouse brain homogenates. AD and mild cognitive impairment (MCI) samples displayed the expected decrease in natively measured A beta 42 compared to healthy controls and frontotemporal dementia, but not when analyzing under denaturing conditions. Accordingly, AD and MCI CSF had a higher A beta 42 oligomer ratio in CSF. Conclusion: Combining denaturing and non- denaturing quantifications of A beta 42 into an oligomer ratio enables the assessment of A beta oligomers in biological samples. The increased A beta 42 oligomer ratio for AD and MCI indicates the presence of oligomers in CSF and that the lowering of natively measured A beta 42 is caused by oligomerization. Copyright (C) 2009 S. Karger AG, Basel