Cerebrospinal Fluid A beta(42/40) Corresponds Better than A beta(42) to Amyloid PET in Alzheimer's Disease

Background: Decreased concentrations of amyloid-beta 1-42 (A beta(42)) in cerebrospinal fluid (CSF) and increased retention of A beta 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 A beta metabolism. The CSF A beta(42/40) ratio seems to be a more accurate biomarker of clinical AD than CSF A beta(42) alone. Objective: We tested whether CSF A beta(42) alone or the A beta(42/40) 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 A beta(42) and A beta(40) 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 A beta(42/40) corresponded better than A beta(42) 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 A beta(42/40) ratio is superior to A beta(42) 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 A beta.