Robustness of CSF Aβ42/40 and Aβ42/P‐tau181 measured using fully automated immunoassays to detect AD‐related outcomes

Abstract

AbstractIntroductionThis study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aβ)42/Aβ40 or Aβ42/phosphorylated tau (p‐tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)‐related outcomes (i.e., Aβ‐positron emission tomography [PET] visual read and AD neuropathology).MethodsWe studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (Aβ‐PET visual read as outcome). Using longitudinal variability in Aβ‐negative controls, we identified a gray zone around cut‐points where the risk of an inconsistent predicted outcome was >5%.ResultsFor Aβ42/Aβ40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For Aβ42/p‐tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was ≈90% for both Aβ42/Aβ40 and Aβ42/p‐tau181 using these cutoffs. Using Aβ‐PET as an outcome, 8.7% of participants fell within a gray zone interval for Aβ42/Aβ40, compared to 4.5% for Aβ42/p‐tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma Aβ42/40, the number of individuals within the gray zone was ≈1.5 to 3 times greater when using plasma Aβ42/40.DiscussionCSF Aβ42/p‐tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys‐based measure in clinical practice and trials.