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

J Neurol Neurosurg Psychiatry. 2021 Dec;92(12):1289-1295. doi: 10.1136/jnnp-2020-325537. Epub 2021 Jun 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alzheimer Disease / blood*
  • Alzheimer Disease / diagnostic imaging
  • Amyloid beta-Peptides / blood*
  • Biomarkers / blood
  • Brain / diagnostic imaging*
  • Brain / metabolism
  • Cognition / physiology*
  • Databases, Factual
  • Humans
  • Neurofilament Proteins / blood*
  • Phosphorylation
  • Positron-Emission Tomography
  • tau Proteins / blood*


  • Amyloid beta-Peptides
  • Biomarkers
  • Neurofilament Proteins
  • neurofilament protein L
  • tau Proteins

Associated data