P-tau217 and other blood biomarkers of dementia: variation with time of day

Abstract

Plasma biomarkers of dementia, including phosphorylated tau (p-tau217), offer promise as tools for diagnosis, stratification for clinical trials, monitoring disease progression, and assessing the success of interventions in those living with Alzheimer's disease. However, currently, it is unknown whether these dementia biomarker levels vary with the time of day, which could have implications for their clinical value. In two protocols, we studied 38 participants (70.8 ± 7.6 years; mean ± SD) in a 27-h laboratory protocol with either two samples taken 12 h apart or 3-hourly blood sampling for 24 h in the presence of a sleep-wake cycle. The study population comprised people living with mild Alzheimer's disease (PLWA, n = 8), partners/caregivers of PLWA (n = 6) and cognitively intact older adults (n = 24). Single-molecule array technology was used to measure phosphorylated tau (p-tau217) (ALZpath), amyloid-beta 40 (Aβ40), amyloid-beta 42 (Aβ42), glial fibrillary acidic protein, and neurofilament light (NfL) (Neuro 4-Plex E). Analysis with a linear mixed model (SAS, PROC MIXED) revealed a significant effect of time of day for p-tau217, Aβ40, Aβ42, and NfL, and a significant effect of participant group for p-tau217. For p-tau217, the lowest levels were observed in the morning upon waking and the highest values in the afternoon/early evening. The magnitude of the diurnal variation for p-tau217 was similar to the reported increase in p-tau217 over one year in amyloid-β-positive mild cognitively impaired people. Currently, the factors driving this diurnal variation are unknown and could be related to sleep, circadian mechanisms, activity, posture, or meals. Overall, this work implies that the time of day of sample collection may be relevant in the implementation and interpretation of plasma biomarkers in dementia research and care.

Fig. 1. Levels of plasma biomarkers (deviation from the mean LS-means ± SE) across a 24-h period: p-tau217, Aβ40, Aβ42, Aβ42/Aβ40, NfL, and GFAP.

The grey shading indicates the habitual sleep episode.

Fig. 2. Levels of plasma p-tau217 (LS-means ± SE) across a 24-h period in PLWA, their study partners, and cognitively intact older adults.

Blue symbols represent cognitively intact older adults, green symbols represent study partners, and orange symbols represent PLWA. The grey shading indicates the habitual sleep episode. ***Indicates a significant (p < 0.0001) difference in levels between the indicated time points in PLWA. The data for the Study partners and the cognitively intact older adults are displaced by 15 min so that the variance indicators of the various groups are visible.