Biological variation estimates of Alzheimer's disease plasma biomarkers in healthy individuals

Abstract

INTRODUCTIONBlood biomarkers have proven useful in Alzheimer's disease (AD) research. However, little is known about their biological variation (BV), which improves the interpretation of individual‐level data.METHODSWe measured plasma amyloid beta (Aβ42, Aβ40), phosphorylated tau (p‐tau181, p‐tau217, p‐tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in plasma samples collected weekly over 10 weeks from 20 participants aged 40 to 60 years from the European Biological Variation Study. We estimated within‐ (CVI) and between‐subject (CVG) BV, analytical variation, and reference change values (RCV).RESULTSBiomarkers presented considerable variability in CVI and CVG. Aβ42/Aβ40 had the lowest CVI (≈ 3%) and p‐tau181 the highest (≈ 16%), while others ranged from 6% to 10%. Most RCVs ranged from 20% to 30% (decrease) and 25% to 40% (increase).DISCUSSIONBV estimates for AD plasma biomarkers 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 amyloid beta (Aβ42/Aβ40) presents the lowest between‐ and within‐subject biological variation, but also changes the least in Alzheimer's disease (AD) patients versus controls. Plasma phosphorylated 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 neurofilament light chain and glial fibrillary acidic protein 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 individuals can be observed, which urges caution when interpreting AD plasma biomarkers based on a single test result.

Neuron loss in the brain starts in childhood, increases exponentially with age and is halted by GM-CSF treatment in Alzheimer’s disease

“…To identify biomarkers of neuronal cell loss or damage during brain aging, we focused on UCH-L1 and NfL because of numerous reports that their plasma concentrations are well correlated with neuronal damage in, for example, neurodegenerative disease and traumatic brain injury (TBI) [24][25][26][27][28][29] . Although UCH-L1 was initially discovered and named as a ubiquitin C-terminal hydrolase, it is likely that this is not its primary function, especially in neurons, as cells and animals lacking UCH-L1 are not defective in the ubiquitin proteosome system 25,30 .…”

Influence of Physiological Variables and Comorbidities on Plasma Aβ40, Aβ42, and p-tau181 Levels in Cognitively Unimpaired Individuals

“…On the one hand, there are laboratory factors that influence them in different ways. P-tau181 presents a significant inter-subject variability (≈18%), while the Aβ42/Aβ40 ratio presents the lowest intra-and inter-subject variability (≈3%) [6]. Moreover, AD has been related in the literature to several pathologies, especially cardiovascular risk factors, and previous studies have evaluated the influence of different physiological variables and comorbidities on plasma levels of Aβ and p-tau [7][8][9].…”