Advances in Alzheimer Diagnosis: Coming to a Lab Near You?

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The amyloid-β_42/40 (Aβ_42/40) ratio should be included as a cerebrospinal fluid (CSF) biomarker for Alzheimer disease (AD) and may be appropriate for use in the clinical diagnostic setting, according to a team of researchers affiliated with the University Medical Center Goettingen in Goettingen, Germany.¹ CSF plays and important role in the differential diagnosis of AD, but lack of standardization compromises use in clinical laboratories, presenting risk of over- and underdiagnosis. The findings suggest that analysis of Aβ₄₀ as well as Aβ₄₂ concentrations may provide greater sensitivity and specificity.

The researchers explained that Aβ₄₀ is the most abundant C-terminal Aβ-variant in CSF and correlates well with the total Aβ concentration; thus, it has the ability to serve as a surrogate-marker for total CSF Aβ. They pointed to studies showing that the Aβ₄₂ to Aβ₄₀ concentration ratio can to improve diagnostic accuracy in patients who appear to have either unusually low or high overall Aβ. To assess whether assessment of the Aβ_42/40 ratio is feasible in a clinical diagnostic setting, the researchers compared parallel CSF biomarker measurement results of 2 different certified clinical laboratories. They also confirmed findings in a subset (n=10) of patients using amyloid positron emission tomography/computed tomography.

Parallel aliquots of CSF samples from 114 subjects were sent to 2 independent laboratories for analysis of t-Tau, p-Tau, Aβ₄₂, and Aβ₄₀ and concentrations and Aβ_42/40 concentration ratios, with measurements done in accordance with each laboratory’s specific standard operating procedures and cut-off points. Mean age of study subjects was 66.5 years, and 52% of the cohort were men. Biomarker levels and corresponding diagnostic classifications were compared, and the degree of agreement between results of the different laboratories was assessed.

The Aβ₄₂ and Aβ₄₀ measurements performed by the 2 laboratories showed statistically significant correlations, with R² = 0.5078 for Aβ₄₂ and R² = 0.4308 for Aβ_42/40, respectively (P < .0001 for both parameters). Statistically significant correlations for p-Tau and t-Tau measurements (P < .0001 for both parameters) and CSF Aβ₄₀ (R² = 0.5739; P < .0001) also were seen. Not surprisingly, though, substantial discrepancies in regard to the Aβ₄₂ concentrations and Aβ_42/40 ratios were noted, likely owing to use of different assay kits (IBL vs Fujirebio).

Discrepancies were not seen for Aβ₄₀ or t-Tau and p-Tau measures; however, diagnostic interpretations between laboratories were often discordant for Aβ₄₂ as well as t-Tau and p-Tau, as cut-off points differed between laboratories. Of note, however, is that, when subjects were diagnostically classified via interpretation of Aβ₄₂ levels (normal vs pathological range), a discordance was cited in 32% of cases whereas, when the classification was based on the Aβ_42/40 ratio, discordance was reduced by nearly half (17% of cases).

According to the study, these findings lend support to the argument that Aβ_42/40 ratio may represent a better neurochemical biomarker of pathologic Aβ deposition than Aβ₄₂ concentration alone. They added that their findings illustrate the importance of improving and standardizing CSF marker interpretation in the clinical diagnostic laboratory setting to reduce false-negative and false-positive AD diagnoses.

Disclosures:

1. Vogelgsang J, Wedekind D, Bouter C, et al. Reproducibility of Alzheimer's disease cerebrospinal fluid-biomarker measurements under clinical routine conditions. J Alzheimers Dis. 2018;62:203-212.