Impact of cerebrospinal fluid matrix on the detection of Alzheimer's disease with Aβ42 and influence of disease on the total‐Aβ42/Aβ40 ratio

The 42-amino acid fragment of amyloid β (Aβ1-42) in cerebrospinal fluid has continued to be important for detecting cerebral β-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) e4 genotype. This study investigated matrix interference as a contributing factor for detecting AD in APOE e4-negative patients by comparing total extractable Aβ1-42 to free Aβ1-42. It also examined the ratio of total Aβ1-42 to Aβ1-40, since changes relative to other Aβ peptides may provide a measurement of cerebral β-amyloidosis that is neutral to changes in APP metabolism. Total Aβ1-42 lost the diagnostic power for detecting AD, confirming a role for matrix in the diagnostic. However, when total Aβ1-42/Aβ1-40 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 Aβ1-42/Aβ1-40 ratio when matrix interference is small. It may be preferable to employ a total Aβ1-42/Aβ1-40 measurement, since this could minimize variability because of matrix and compensate for across patient differences. Aβ1-42 measurement in CSF has provided an important tool for early detection of AD. However, it appears that most assays measure a free fraction of Aβ1-42. This study examined total extracted Aβ1-42, since this would provide a more accurate assessment of Aβ1-42 in AD CSF. Total Aβ1-42 measurements alone were not good for detecting AD but total Aβ1-42/Aβ1-40 performed well.