Plasma N-terminal tau fragment is an amyloid-dependent biomarker in Alzheimer's disease.

Introduction: Novel fluid biomarkers for tracking neurodegeneration specific to Alzheimer's disease (AD) are greatly needed.

Methods: Using two independent well-characterized cohorts (n = 881 in total), we investigated the group differences in plasma N-terminal tau (NT1-tau) fragments across different AD stages and their association with cross-sectional and longitudinal amyloid beta (Aβ) plaques, tau tangles, brain atrophy, and cognitive decline.

Results: Plasma NT1-tau significantly increased in symptomatic AD and displayed positive associations with Aβ PET (positron emission tomography) and tau PET. Higher baseline NT1-tau levels predicted greater tau PET, with 2- to 10-year intervals and faster longitudinal Aβ PET increases, AD-typical neurodegeneration, and cognitive decline. Plasma NT1-tau showed negative correlations with baseline regional brain volume and thickness, superior to plasma brain-derived tau (BD-tau) and neurofilament light (NfL) in Aβ-positive participants.

Discussion: This study suggests that plasma NT1-tau is an Aβ-dependent biomarker and outperforms BD-tau and NfL in detecting cross-sectional neurodegeneration in the AD continuum.

Highlights: Plasma N-terminal tau (NT1-tau) was specifically increased in the A+/T+ stage. Plasma NT1-tau was positively associated with greater amyloid beta (Aβ) and tau PET (positron emission tomography) accumulations. Higher plasma NT1-tau predicted greater tau burden and faster Aβ increases. Plasma NT1-tau was more related to neurodegeneration than plasma brain-derived tau (BD-tau) and neurofilament light (NfL).