The cerebrospinal fluid biomarker ratio Aβ42/40 identifies amyloid positron emission tomography positivity better than Aβ42 alone in a heterogeneous memory clinic cohort.

Background: Cerebrospinal fluid (CSF) analysis for detecting amyloid positivity may be as reliable as positron emission tomography (PET). We evaluated the performance of the amyloid beta (Aβ)42/40 ratio for predicting amyloid positivity by PET, compared with Aβ42 alone, and phosphorylated tau 181 (pTau181)/Aβ42 and total tau (tTau)/Aβ42 ratios, using fully automated CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) in a heterogeneous cohort of patients with a range of cognitive disorders reflecting the typical population of a memory clinic.

Methods: CSF samples from 103 patients with known amyloid PET status (PET positive = 54; PET negative = 49) were retrospectively selected from one site in Germany; 71 patients were undergoing treatment for mild cognitive impairment (n = 44) or mild-to-moderate dementia (n = 27) due to Alzheimer's disease (AD), and 32 patients were undergoing treatment for non-AD-related cognitive disorders. Aβ42, pTau181, and tTau concentrations were measured in CSF samples using the respective Elecsys CSF immunoassays modified for use on the cobas e 411 analyzer; Aβ40 concentrations were measured using a non-commercially available robust prototype assay. Sensitivities/specificities for amyloid positivity cut-offs (Youden-derived and pre-defined) were calculated, and receiver operating characteristic analyses determined area under the curve (AUC) versus amyloid PET status. Limitations include a small sample size, use of a pre-analytical protocol not in accordance with the Elecsys CSF immunoassay method sheets, and the lack of a pre-defined cut-off for Aβ42/40.

Results: Point estimates for sensitivity and specificity of CSF biomarkers and biomarker ratios versus amyloid PET were 0.93 and 0.57 for Aβ42, 0.96 and 0.69 for pTau181/Aβ42, 0.92 and 0.69 for tTau/Aβ42, and 0.94 and 0.82 for Aβ42/40. For AUCs, point estimates (95% confidence intervals) versus amyloid PET were 0.78 (0.68-0.88) for Aβ42, 0.88 (0.81-0.95) for pTau181/Aβ42, 0.87 (0.80-0.95) for tTau/Aβ42, and 0.90 (0.83-0.97) for Aβ42/40.

Conclusions: CSF Aβ42/40 ratio can predict PET amyloid positivity with high accuracy in patients with a range of cognitive disorders when evaluating Aβ pathology independent of tau and neurodegeneration for research purposes. The performance of Aβ42/40 was comparable with pTau181/Aβ42 and tTau/Aβ42 used in clinical practice and better than Aβ42 alone.