Age specific reference intervals for plasma biomarkers of neurodegeneration and neurotrauma in a Canadian population

In this study, we aimed to create reference intervals (RI) using a large Canadian population-based cohort, for plasma protein biomarkers with potential utility to screen, diagnosis, prognosticate and manage a variety of neurological diseases and disorders. RIs were generated for: the ratio of amyloid beta 42 over 40 (Aβ42/40), phosphorylated tau-181 (p-tau-181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). 900 plasma specimens from male and female participants aged 3–79 years old were obtained from the Statistics Canada Biobank, which holds specimens from the Canadian Health Measures Survey. Analysis of Aβ42/40, p-tau-181, NfL and GFAP was performed on the Quanterix Simoa HD-X analyzer using the Neurology 4-plex E and p-tau-181 assays. Discrete RIs were produced according to Clinical Laboratory Standards Institute guidelines (EP28-A3c). Continuous RIs were created using quantile regression. For discrete RIs, significant age partitions were determined for each biomarker. No significant sex partitions were found. The following ranges and age partitions were determined: Aβ42/40: 3–<55y = 0.053–0.098, 55–<80y = 0.040–0.090; p-tau-181: 3–<12y = 1.4–5.6 pg/ml, 12–<60y = 0.8–3.1 pg/ml, 60–<80y = 0.9–4.0 pg/ml; NfL: 3–<40y = 2.6–11.3 pg/ml, 40–<60y = 4.6–17.7 pg/ml, 60–<80y = 8.1–47.1 pg/ml; GFAP; 3–<10y = 47.0–226 pg/ml, 10–<60y = 21.2–91.9 pg/ml, 60–<80y = 40.7–228 pg/ml. Continuous RIs produced smooth centile curves across the age range, from which point estimates for each year of age were calculated. Discrete and continuous RIs for neurological plasma biomarkers will help refine normative cut-offs across the lifespan and improve the precision of interpretating biomarker levels. Continuous RIs are recommended for use in age groups, such as pediatrics and older adults, that experience rapid concentration changes by age.