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

Abstract

The 42-amino acid fragment of amyloid b (Ab1-42) in cerebrospinal fluid has continued to be important for detecting cerebral b-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 Ab1-42 to free Ab1-42. It also examined the ratio of total Ab1-42 to Ab1-40, since changes relative to other Ab peptides may provide a measurement of cerebral b-amyloidosis that is neutral to changes in APP metabolism. Total Ab1-42 lost the diagnostic power for detecting AD, confirming a role for matrix in the diagnostic. However, when total Ab1-42/Ab1-40 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 Ab1-42/Ab1-40 ratio when matrix interference is small. It may be preferable to employ a total Ab1-42/Ab1-40 measurement, since this could minimize variability because of matrix and compensate for across patient differences.

Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer’s disease dementia in mild cognitive impairment

“…In fact, in the multicenter study by Dumurgier et al [ 29 ] the mean Aβ42/40 ratio was comparable across centers, despite the significant inter-center differences in reported CSF Aβ40 and Aβ42 levels. Therefore, this ratio seems to be less sensitive to preanalytical and analytical sources of variability both intra-laboratories [ 73 – 75 ] and inter-laboratories [ 29 ].…”

Plasma Levels of Aβ42 and Tau Identified Probable Alzheimer’s Dementia: Findings in Two Cohorts

“…However, studies of sporadic AD subjects were not consistent, reporting Aβ42 levels as being unchanged, decreased, or increased (Mehta et al, 2000; Blennow et al, 2009; Lui et al, 2010; Chiu et al, 2012; Wu et al, 2012; Toledo et al, 2013; Janelidze et al, 2016; Lovheim et al, 2016; Poljak et al, 2016). Factors that affect Aβ42 results include platform-associated limitations such as matrix effect, interference, and epitope masking (Bibl et al, 2004; Toledo et al, 2011; Slemmon et al, 2012, 2015; Blennow and Zetterberg, 2015b). Although both ELISA assays and IMR assays are based on antigen-antibody reactions, IMR assays appears to have unique capability of detecting modest alterations in plasma Aβ42 levels possibly due to minimal matrix effect.…”

Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta

“…The Aβ42:38 ratio is a potential readout of γ-secretase carboxypeptidase-like cleavage efficiency [10] and the Aβ38:40 has been used to compare the theorised Aβ49 versus Aβ48 dependent pathways [5]. The Aβ42:40 ratio has been shown to effectively distinguish fAD and sAD from healthy controls in CSF samples, improving diagnostic accuracy and prediction of AD [11][12][13][14][15][16]. However, few studies have explored these dynamics in human neurons and at endogenous expression levels.…”