Longitudinal trajectory of plasma p-tau217 in cognitively unimpaired subjects

Abstract

Background: The advent of Alzheimer's disease-modifying drugs requires accurate biological diagnosis to identify candidates for these therapies. So far, the most promising single plasma biomarker is phosphorylated tau at threonine 217 (p-tau217). To understand its biological features, it is essential to know its longitudinal trajectory and factors influencing it in cognitively unimpaired subjects with no brain pathology.

Methods: We analyzed longitudinal plasma p-tau217 values (mean follow-up time = 768.3 days) in a cohort of 209 healthy volunteers. We have studied factors associated with plasma p-tau217 changes by using different linear mixed-effects models.

Results: In amyloid-negative cognitively healthy subjects (n = 151) carriers of ApoE ε4 allele had significantly higher p-tau217 values than non-carriers (0.85 pg/mL; p-value < 0.001) and also a greater rate of change (0.01 pg/mL/year; p-value < 0.001). In the overall sample, including subjects with amyloid and tau pathology we have seen that amyloid positive subjects had higher predicted baseline plasma p-tau217 values than amyloid negative subjects (0.16 pg/mL; p-value < 0.001) and a greater rate of change (0.00004 pg/mL/day; p-value < 0.001). Subjects considered tau positive also showed a greater rate of change of p-tau217 with respect to tau negative (0.00005 pg/mL/day; p-value < 0.001). A + T + N + participants showed a higher baseline p-tau217 levels than A-T-N- subjects (0.2 pg/mL; p-value < 0.001) and also a greater rate of change (0.00006 pg/mL/day; p-value = 0.002). ApoE ε4 carriers had a greater rate of change than non-carriers (0.00003 pg/mL/day; p-value = 0.03).

Conclusion: In amyloid-negative cognitively unimpaired subjects, ApoE4 status influenced both baseline levels and rate of change of plasma p-tau217. Other factors such as age, sex or glomerular filtration rate have not shown significant influence on plasma p-tau217 levels in this group.

Keywords: Alzheimer’s Disease; Biomarkers; Early diagnosis; Healthy controls; Longitudinal; Plasma p-tau217.

Fig. 1

Longitudinal trajectory of plasma p-tau217 in CU A- subjects according to ApoE4 status. Interaction plot derived from LMM of plasma p-tau217 in healthy controls. Estimates come from the interaction effects of the best model for plasma p-tau217. Predicted plasma p-tau217 values are on the y-axis. X-axis represents age in years. P-tau217 measurements of each subject are shown in blue (ApoE ε4 non-carriers) and orange (ApoE ε4 carriers) and linked with a dashed gray line. Coloured lines are regression lines of ApoE ε4 carriers (orange)and non-carriers (blue), and the shaded area represents 95% confidence interval. Age-related longitudinal trajectory was higher in ApoE ε4 carriers

Fig. 2

Longitudinal trajectories of plasma p-tau217. Longitudinal trajectories of plasma p-tau217 concentrations over time (days) by different factors adjusted by sex and age at baseline. The plots correspond to a linear mixed model. Dots represent each individual value, and the lines between the dots show the trajectories of each subject. Thick lines are the regression line of the different groups, and the shaded area represents the 95% confidence interval. Y axis represents plasma p-tau217 values in pg/mL. X axis shows the number of days between samples. Figure 2A shows the trajectories of amyloid-negative (left) and amyloid-positive subjects (right). Amyloid-positive group had higher baseline levels of p-tau217 (Estimate = 0.16 pg/mL; p-value < 0.001) and a greater rate of change (Estimate = 0.00004 pg/mL/day; p-value = 0.01). Figure 2B shows the different trajectories of tau-negative (left) and tau-positive subjects (right). Those participants considered as tau-positive had both higher baseline p-tau217 levels (Estimate = 0.17 pg/mL; p-value < 0.001); and greater rate of change (Estimate = 0.00005 pg/mL/day; p-value = 0.004). Figure 2C shows the differences between ATN groups, being the A-T-N- represented in red, the A + T-N- in brown, A + T + N- in purple, A + T + N + in green, and A-T + N- in blue. A + T + N + participants showed a higher baseline p-tau217 levels than A-T-N- subjects (0.2 pg/mL; p-value < 0.001) and a higher growth rate than A-T-N- (Estimate = 0.00006 pg/mL/day; p-value = 0.003). Figure 2D represents the differences between ApoE4 carriers (right) and non-carriers (left). ApoE4 carriers had a higher rate of change of p-tau217 than non-carriers (Estimate = 0.00003 pg/mL/day; p-value = 0.03)