Associations of longitudinal plasma p-tau181 and NfL with tau-PET, Aβ-PET and cognition

Abstract

Objective: To explore if changes over time of plasma phosphorylated tau (p-tau)181 and neurofilament light chain (NfL) predict future tau and amyloid β (Aβ) PET load and cognitive performance, we studied a subsample of the Alzheimer's disease (AD) neuroimaging cohort with longitudinal blood peptide assessments.

Methods: Eight hundred and sixty-five AD Neuroimaging Initiative participants were included. Using established AD cut-points for the cerebrospinal fluid concentrations of Aβ42, total-tau and p-tau181, subjects were classified according to the National Institute on Aging-Alzheimer's Association research framework, grouping markers into those of Aβ deposition (A), tau pathology (T) and neurodegeneration (N). Analysis of variance was used to compare the plasma biomarker data between the ATN groups. The rate of change over time of p-tau181 and NfL was obtained from linear mixed effects models and compared between the ATN groups. Linear regression analysis was used to investigate the association of baseline plasma biomarker concentrations and rates of change with future PET tau and Aβ load and cognitive performance.

Results: P-tau181 and NfL plasma concentrations increased along the AD spectrum, but only NfL showed greater rates of change in AD patients versus controls. Cognitive performance was associated cross-sectionally with NfL in all subgroups, and with p-tau181 only in AD spectrum individuals. The baseline concentrations of both plasma markers predicted PET Aβ and tau load and cognitive performance. The rate of change of NfL predicted future PET tau and cognitive performance.

Conclusions: P-tau and NfL behave differently within the same individuals over time and may therefore offer complementary diagnostic information.

Trial registration number: NCT02854033, NCT01231971.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Longitudinal trajectories of plasma p-Tau181 and plasma NfL concentrations in the different ATN groups (A) log10 plasma p-Tau181 (B) log10 plasma NFL. Rate of change over time (slope) obtained using a LMEM (C) plasma p-Tau181 (normalised) and (D) plasma NfL concentrations (normalised) comparing the ATN groups. A+/−, amyloid-β positive/negative; ATN, Aβ deposition, tau pathology and neurodegeneration; LMEM, linear mixed effects model; NfL, neurofilament light protein, picogram per millilitre; p-Tau181, tau phosphorylated at threonine 181; TN+/−, tau/neurodegeneration.

Figure 2

Associations between (A) log10 plasma p-Tau181 baseline concentration (B) plasma p-Tau181 rate of change (slope) (C) log10 plasma NfL baseline concentration and (D) plasma NfL rate of change (slope) and ADNI-mem after a mean of 5.8 (SD=1.6) Years in the different ATN groups. ADNI-mem, composite memory score. A+/−, amyloid-β positive/negative; ADNI, Alzheimer’s Disease Neuroimaging Initiative; bL, baseline; Fu, follow-up; NFL, neurofilament light protein; p-Tau181, tau phosphorylated at threonine 181; TN+/−, Tau/Neurodegeneration positive/negative.

Figure 3

Association of plasma biomarkers with flortaucipir uptake after approximately 5 years time. (A) Log10 plasma p-Tau181 (B) plasma NfL rate of change (slope) (C) log10 plasma NfL baseline in the whole study cohort and within the ATN groups. Left: linear regression between biomarker and SUVR PET uptake in a meta ROI*. Right: Vertex-wise Pearson correlations adjusted for age, sex and the time difference between plasma sampling and flortaucipir PET (tfce FWE corrected p<0.05). AV45, 18F-florbetapir amyloid-β PET. *Flortaucipir meta ROI: entorhinal, amygdala, parahippocampal, fusiform, inferior temporal and middle-temporal-ROIs. A+/−, Aβ positive/negative; ATN, Aβ deposition, tau pathology and neurodegeneration; FWE, family-wise error corrected; NfL, neurofilament light chain; p-Tau181, tau phosphorylated at threonine 181; ROI, region of interest; SUVR, standardised uptake value; tfce, threshold free cluster enhancement; TN+/−, Tau/Neurodegeneration.

Figure 4

Association of plasma biomarkers with florbetapir uptake after approximately 5 years time. (A) Log10 plasma p-Tau181 B) log10 plasma NfL baseline. Left: linear regression between biomarker and SUVR PET uptake in a meta ROI*. Right: Vertex-wise Pearson correlations adjusted for age, sex and the time difference between plasma sampling and florbetapir PET (tfce FWE corrected p<0.05). *Florbetapir meta ROI: frontal, anterior/posterior cingulate, lateral parietal, lateral temporal regions. bL, baseline; FWE, family-wise error corrected; NFfL, neurofilament light protein; ROI, region of interest; SUVR, standardised uptake value; tfce, threshold free cluster enhancement;