Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in Alzheimer's Disease

Abstract

Background: Decreased concentrations of amyloid-β 1-42 (Aβ42) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer's disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone.

Objective: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status and analyzed the distribution of cases with discordant CSF-PET results.

Methods: CSF obtained from a mixed cohort (n = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n = 150 PET-negative, n = 50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar's test for paired proportions.

Results: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p < 0.0001) and a larger AUC (0.936 versus 0.814, respectively, p < 0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases.

Conclusion: The CSF Aβ42/40 ratio is superior to Aβ42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ.

Keywords: Alzheimer’s disease; amyloid-β; biomarker; cerebrospinal fluid; positron emission tomography.

Fig.1

Scatterplots of cortical amyloid PET load using [¹¹C] PiB and concentrations of CSF Aβ₄₂ (A), the Aβ_42/40 ratio (B), and Aβ₄₀ (C). Solid vertical line represents the a priori dichotomous cut-off for PiB positivity as published previously [28]. Dashed horizontal lines on panels A and B represent the best-performing cut-offs of the respective CSF biomarkers calculated in the present study.

Fig.2

Receiver operating characteristic (ROC) curves of the CSF Aβ₄₂ concentration and Aβ_42/40 ratio. Values for areas under the ROC curves (AUC) correspond to mean±95% CI. Open circles represent the combinations of the sensitivities and the specificities at the maximal Youden Indices.