Impact of cerebrospinal fluid matrix on the detection of Alzheimer's disease with Aß42 and influence of disease on the total-Aß42/Aß40 ratio.

ABSTRACT

The 42-amino acid fragment of amyloid ß (Aß1-42) in cerebrospinal fluid has continued to be important for detecting cerebral ß-amyloidosis in Alzheimer's disease (AD). However, there are impediments to our ability to fully understand this measurement, including matrix interference and changes linked to apolipoprotein E (APOE) ε4 genotype. This study investigated matrix interference as a contributing factor for detecting AD in APOE ε4-negative patients by comparing total extractable Aß1-42 to free Aß1-42. It also examined the ratio of total Aß1-42 to Aß1-40, since changes relative to other Aß peptides may provide a measurement of cerebral ß-amyloidosis that is neutral to changes in APP metabolism. Total Aß1-42 lost the diagnostic power for detecting AD, confirming a role for matrix in the diagnostic. However, when total Aß1-42/Aß1-40 was examined, the separation between groups was reestablished. This result was confirmed in a second sample set of unknown APOE status. These results confirmed that matrix interference in some cerebrospinal fluid samples appears to contribute to identifying AD patients and this can be compensated by using a total extracted Aß1-42/Aß1-40 ratio when matrix interference is small. It may be preferable to employ a total Aß1-42/Aß1-40 measurement, since this could minimize variability because of matrix and compensate for across patient differences. Aß1-42 measurement in CSF has provided an important tool for early detection of AD. However, it appears that most assays measure a free fraction of Aß1-42. This study examined total extracted Aß1-42, since this would provide a more accurate assessment of Aß1-42 in AD CSF. Total Aß1-42 measurements alone were not good for detecting AD but total Aß1-42/Aß1-40 performed well.