The diurnal variation of Alzheimer’s disease plasma biomarkers: a 25h study with hourly sampling

Abstract

AbstractBackgroundNovel plasma biomarkers can accurately reflect key pathological features of Alzheimer’s disease (AD). To ensure their safe clinical implementation in the near future, determining whether they present a diurnal rhythm is a key pending task in the field. This would help to elucidate whether the time of day in which blood samples are collected could influence blood biomarker results in clinical trials, research studies and clinical practice. Thus, we aimed to determine the diurnal rhythm of novel AD plasma biomarkers.MethodIn this study, we included n = 24 cognitively unimpaired older adults (median age [IQR]: 73 [64‐83] years). After overnight fasting and refraining from exhaustive physical activities for 2 days, volunteers were restricted to a standardized experimental environment from 8:30AM to 9:30AM on the following day (NCT02091427). Plasma‐EDTA samples were collected hourly (n = 26 time points), and we quantified biomarkers of tau pathology (p‐tau181), amyloid‐β (Aβ42, Aβ40, Aβ42/Aβ40), glial activation (glial fibrillary acidic protein, GFAP) and neurodegeneration (neurofilament light, NfL) with Simoa HD‐X instruments (UGOT assay: p‐tau181; Quanterix Neurology‐4‐Plex‐E for others). For visualization, biomarker concentrations were CV‐transformed, a standard procedure in which each measurement corresponds to the percent variation from each individual’s mean value over a day.ResultBiomarkers generally demonstrated stable values during a day’s period (Figure 1). When evaluating CV‐transformed concentrations, the observed 5th and 95th quantiles of within‐individual variation over a day were: Aβ42, ‐18.4% to 15.4%; Aβ40, ‐13.7% to 14.4%; Aβ42/Aβ40, ‐9.4% to 8.7%; P‐tau181, ‐15.7% to 21.5%; GFAP, ‐24.0% to 26.8%; NfL, ‐16.2% to 19.9%. Plasma Aβ42 and Aβ40 increased during the day, reaching a peak during sleep (2:00AM), with a similar pattern but much smaller in magnitude for Aβ42/Aβ40 (Figure 2A‐C). P‐tau181 presented a peak in the morning, while GFAP and NfL also presented a peak during sleep (Figure 2D‐F).ConclusionNovel AD plasma biomarkers seem to present a diurnal rhythm. A night‐time biomarker peak, such as observed for plasma Aβ42 and Aβ40, could be explained by sleep‐related clearance of certain proteins from the brain. Nevertheless, the clinical impact of our findings will depend on the analyte of interest and clinical context of their application.