Time of the day at sampling affects amyloid‐beta levels in CSF and plasma

Abstract

AbstractBackgroundStudies suggest that cerebrospinal fluid (CSF) levels of Alzheimer’s disease (AD) biomarkers, amyloid‐β (Aβ) and tau, follow a circadian rhythm. However sustained sampling of CSF with indwelling intrathecal catheter used in most of these studies might have affected the observed fluctuations in the biomarker levels.MethodsWe included 38 individuals with either normal (N = 18) or abnormal (N = 20) CSF Aβ42/40 status. CSF and plasma were collected, at the same occasion, at two different visits separated by an average of 53 days with lumbar punctures and venepunctures performed either in the morning or evening. At the first visit, collection was performed in the morning for 17 participants and the order was reversed (evening collection first) for the remaining 21 participants. CSF and plasma samples were analyzed for Aβ42, Aβ40, GFAP, NfL, p‐tau181, p‐tau217 and p‐tau231. CSF samples were also tested for a battery of synaptic and lysosomal proteins.ResultsCSF Aβ42 (mean difference [MD] = 0.208ng/ml; p = 0.043), CSF Aβ40 (MD = 1.85ng/ml; p<0.001), plasma Aβ42 (MD = 1.65pg/ml; p = 0.002) and plasma Aβ40 (MD, 0.011ng/ml, p = 0.003) levels were increased in the evening samples compared with morning samples by 4.2%‐17.0% (Figures 1‐2). However, changes between morning and evening samples were not significant for either CSF or plasma Aβ42/40. Additional proteins in CSF, APP, STX1B, NPTXR and NPTX1, were also found increased in the evening samples (MDrange, 0.087–0.243; p<0.048) by 4.7%‐12.15% (Figure 3). No significant differences were found between morning and evening levels for any of the other biomarkers, including p‐tau’s, NfL and GFAP. There were no significant interactions between time of day at sample collection and either Aβ status or order in which samples were obtained.ConclusionOur findings provide further evidence for diurnal fluctuations in Aβ peptides, which is observed in both CSF and plasma. Additionally, CSF levels of some synaptic proteins followed circadian rhythm. Importantly, CSF and plasma Aβ42/40 ratios remained unaltered, suggesting that increased production or decreased clearance of Aβ peptides during daytime similarly affect the CSF and plasma levels of both Aβ42 and Aβ40. Thus, these ratios are more suitable for implementation as biomarkers of AD as they are not influenced by diurnal fluctuations.