Diurnal variation in brain-derived tau and five other blood-based biomarkers for dementia and their association with cognitive performance

Blood-based biomarkers of dementia are a promising scalable tool for early diagnosis, tracking disease progression, and evaluating therapeutic efficacy. Utility of these biomarkers will not only be dependent on the reliability of their association with pathology but also contingent on their ability to track cognitive status. Previously, we demonstrated diurnal variation in several biomarkers (amyloid beta (Aβ) 42 and 40, 42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated-Tau 217 (p-Tau217)) which has implications for their reliability. Here, we extend these observations to a larger cohort, include brain-derived tau (BD-Tau), which is assumed to be produced exclusively in the brain, and report endocrine measures of circadian rhythmicity. We not only assessed whether these biomarkers vary with time of day, but also whether they associate with daytime function and whether these associations vary with cognitive domain and number of repeated assessments. Data collected in 20 PLWA (72.4±5.9 years, mean±SD) and 19 controls (68.9±9.8 years) were analysed. Participants completed 14 days of home monitoring and one laboratory assessment of sleep and daytime function: mood, daytime sleepiness, reaction time, immediate and delayed memory recall, everyday memory errors. During the 27-hour residential laboratory session, 3-hourly blood samples were collected and analysed for the six blood-based biomarkers of dementia as well as melatonin and cortisol. Rhythmicity of melatonin and cortisol did not differ between groups. P-Tau217 and GFAP (p<0.05) and BD-Tau (p<0.10) were elevated in PLWA. Significant time-of-day variation was observed for BD-Tau as well as the other five biomarkers of dementia, with peak levels coinciding with the sleep period. Group by time-of-day interactions were observed for p-Tau217 and Aβ42. Average BD-Tau, p-Tau217, and GFAP concentration were negatively correlated with memory function when averaged over the 15 assessments, but these correlations became less robust when the number of repeat assessments was smaller. Mood and daytime sleepiness did not correlate with any of the biomarkers. The relationship between p-Tau217 concentration and memory function was strongest for blood samples collected during the sleep period. These data have implications for our understanding of the association between blood-based biomarkers and daytime function and the design of research protocols. The observation that BD-Tau and other plasma biomarkers vary with time of day with highest levels during the sleep period is consistent with sleep or circadian rhythmicity mediated facilitation of overnight clearance of these proteins from brain to blood.