Biological variation of Alzheimer’s disease plasma biomarkers in healthy individuals

Abstract

AbstractBackgroundPlasma biomarkers for Alzheimer’s disease (AD) have demonstrated great performance to identify AD pathology in research cohorts, and recent studies also support their potential to monitor effects of disease‐modifying treatments. To properly interpret these biomarkers in research settings and to inform power calculations of future trials using them as surrogate outcomes, information on their physiological variability over time is needed. We conducted a 10‐week biological variation (BV) study to assess the within‐individual (CVI; CV: coefficient of variation), between‐individual (CVG) and analytical variability (CVA) of blood‐based AD biomarkers. These parameters can provide the reference change value (RCV), which determines how much biomarker values must change to represent a significant abnormality‐related change, i.e. exceeding analytical and biological variation.MethodPlasma samples were collected weekly for 10 weeks from 20 healthy individuals from the European Biological Variation Study (n=20; 50% female, median age 46.4). Biomarkers for tau pathology (p‐tau181), brain amyloidosis (Aβ42, Aβ40, Aβ42/40), glial activation (GFAP) and neurodegeneration (NfL) were quantified in duplicate using the Simoa technology. The CV‐ANOVA statistical method was used to compute BV estimates. To evaluate diurnal rhythm of these biomarkers, we also conducted a study with non‐demented older adults (n=24; 58‐82yo), with hourly blood collections during 26h in strictly‐controlled environmental conditions (NCT02091427). P‐tau217 (Lily) analyses are ongoing for both studies.ResultIndividual‐level (Figure 1) and pooled biomarker levels are shown (Figure 2), as well as BV estimates (Table 1). The 10‐week within‐individual physiological variation (CVI) was lower for Aβ42/40 (4.3%), followed by Aβ42 (6.0%), Aβ40 (6.4%), NfL (7.9%), GFAP (9.3%) and p‐tau181 (15.8%). Between‐individual variation (CVG) was lower for Aβ42/40 (8.8%), followed by Aβ42 (13.3%), Aβ40 (17.0%), p‐tau181 (20.5%), NfL (23.0%) and GFAP (31.5%). Analytical variation was low for all biomarkers (CVA range: 2.5‐6.6%). The RCV was higher for p‐tau181 (45.6%), followed by GFAP (31.7%), NfL (27.6%), Aβ40 (19.0%), Aβ42 (18.8%) and Aβ42/40 (15.6%).ConclusionBlood‐based AD biomarkers demonstrate good week‐to‐week stability, but their CVG and RCV’s can be rather high, with implications both for use in clinical routine (misclassification risk) and for future trial designs (high numbers of participants needed). Results for the diurnal variation study will also be presented.