Biological variation estimates of Alzheimer’s disease plasma biomarkers in healthy individuals
Authors: Brum Wagner S. , Ashton Nicholas J. , Simrén Joel , di Molfetta Guiglielmo , Karikari Thomas K. , Benedet Andrea L. , Zimmer Eduardo R. , Lantero-Rodriguez Juan , Montoliu-Gaya Laia , Jeromin Andreas , Aarsand Aasne K. , Bartlett William A. , Calle Pilar Fernández , Coşkun Abdurrahman , Díaz–Garzón Jorge , Jonker Niels , Zetterberg Henrik , Sandberg Sverre , Carobene Anna , Blennow Kaj 
Published: August 2023

AbstractIntroductionBlood biomarkers have proven useful in Alzheimer’s disease (AD), but little is known about their biological variation (BV), which plays a crucial role in the interpretation of individual patient data.MethodsWe measured plasma amyloid-β (Aβ42, Aβ40), phosphorylated tau (p-tau181, p-tau217, p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in fasting plasma samples collected weekly over 10 weeks from 20 participants aged 40-60y from the European Biological Variation Study. We determined within- (CVI) and between-subject (CVG) BV, analytical variation (CVA) and reference change values (RCV).ResultsBiomarkers presented considerable variability in CVIand CVG. Aβ42/Aβ40 had the lowest CVI(∼3%) and p-tau181 the highest (∼16%), while the others ranged from 6-10%. Most RCVs ranged from 20-30% (decrease) and 25-40% (increase).InterpretationWe provide BV estimates for AD plasma biomarkers, which can potentially refine their clinical and research interpretation. RCVs might be useful for detecting significant changes between serial measurements when monitoring early disease progression or interventions.Highlights·Plasma Aβ42/Aβ40 presents the lowest between- and within-subject biological variation, but also changes the least in AD patients vs controls.·Plasma p-tau variants significantly vary in their within-subject biological variation, but their substantial fold-changes in AD likely limits the impact of their variability.·Plasma NfL and GFAP demonstrate high between-subject variation, the impact of which will depend on clinical context.·Reference change values can potentially be useful in monitoring early disease progression and the safety/efficacy of interventions on an individual-level.·Serial sampling revealed that unexpectedly high values in heathy invidivuals can be observed, which urges caution when interpreting AD plasma biomarkers based on a single test result.Research in ContextSystematic ReviewWe reviewed PubMed for articles and conference abstracts that evaluated the biological variation (BV) of novel Alzheimer’s disease (AD) blood biomarkers. Two previous studies had reported BV estimates for serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL). Thus, we aimed to provide the first robust BV estimates for plasma amyloid-β (Aβ) and phosphorylated tau (p-tau) biomarkers, and also for plasma GFAP and NfL in in the same population.InterpretationPlasma biomarkers of key pathological features of AD demonstrate heterogeneity in their within- and between-subject variation. Plasma Aβ42/Aβ40 generally shows lower variability but also changes very modestly in AD patients vs controls. While plasma p-tau variants demonstrate higher variability, its clinical impact is likely limited due to large fold-increases in AD. Plasma NfL and GFAP had the largest between-subject variability, which may impact upon their application in certain contexts. Most research on blood biomarkers so far has been done using either single measurements or repeated measurements over longer (e.g., yearly) time frames; the weekly serial sampling in our study revealed that unexpected outlier values may occur, urging caution in clinical and research interpretation.Future directionsFuture studies should evaluate the potential clinical impact of the application of BV knowledge upon clinical and research interpretation of AD plasma biomarkers, especially in disease monitoring and in the evaluation of safety and efficacy of novel therapeutic interventions.