Association Between Plasma N-Terminal Tau, Cognitive Decline, and Neurodegeneration in the ADNI Cohort

Blood-based biomarkers offer a cost-effective, minimally invasive alternative to neuroimaging and CSF biomarkers. Newly developed fluid biomarkers, including the N-terminal tau fragment (NT1), show promise for identifying individuals at risk for Alzheimer disease (AD) and for monitoring disease progression. Here, we determine whether NT1 levels are associated with key clinical and biomarker measures in a large, well-characterized cohort.

Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort with available plasma NT1, β-amyloid (Aβ)-PET, MRI, and clinical measures (Clinical Dementia Rating) were included in this observational study. NT1 was measured using the Quanterix Simoa HD-X platform. PET, MRI, clinical, and other plasma measures were obtained using established ADNI procedures. A subset also had NULISA-based plasma measures of amyloid and tau and tau-PET assessed. Linear regression and linear mixed-effects models were used to assess cross-sectional and longitudinal associations between NT1 and clinical or biomarker measures, adjusting for relevant covariates. Multivariable-adjusted Cox regression was performed to evaluate the association between baseline NT1 levels and risk of clinically diagnosed mild cognitive impairment (MCI) or AD. Mediation analysis was conducted to examine whether hippocampal atrophy mediates the relationship between NT1 and memory decline. Spearman correlations were used to examine continuous relationships between plasma NT1 and continuous fluid and neuroimaging markers.

A total of 755 participants (mean age: 72.9 [7.0], female: 375 [50%]) were included in the study. Plasma NT1 levels were elevated in MCI/AD individuals (B_MCI/AD [SE] = 0.09 [0.022], p = 1.98 × 10^-4) and were cross-sectionally associated with worse memory performance (B [SE] = -0.25 [0.09], p = 0.005). Aβ moderated the association between elevated NT1 and greater cognitive decline across multiple domains (memory: B [SE] = -0.17 [0.074], p = 0.022; executive function: B [SE] = -0.24 [0.082], p = 0.004; language: B [SE] = -0.21 [0.075], p = 0.006). NT1 levels were negatively associated with hippocampal volume (B [SE] = -264.49 [125.99], p = 0.036) and predicted longitudinal atrophy (B [SE] = -42.00 [16.90], p = 0.013). Accelerated hippocampal atrophy largely mediated the association between higher baseline NT1 level and greater memory decline (B [95% CI]_{indirect effect} = -0.082 [-0.135 to -0.03], p = 0.003, B [95% CI]_{proportion mediated} = 70.1% [32.6%-155.3%], p = 0.004). Higher NT1 levels were associated with higher levels of plasma biomarkers, including NULISA-based brain-derived (BD) plasma pTau (BD-pTau181, BD-pTau217, BD-pTau231: p's < 5.01 × 10^-6) and Simoa-Based pTau181 (p < 4.51 × 10^-15) and neurofilament light chain (p < 5.34 × 10^-7).

Plasma NT1 may be useful in assessing amyloid-dependent cognitive decline and neurodegeneration.