Comparison of CSF neurofilament light chain and total tau as neurodegeneration markers: Associations with synaptic markers and cognitive outcomes

This is the authors' abstract. We don't add key points for this paper.

Clinically, Alzheimer's disease (AD) is characterized by progressive cognitive decline due to neuronal and synaptic degeneration. Neurofilament light chain (NfL) and total tau (T-tau) reflect neurodegeneration, NfL putatively more related to white and T-tau to grey matter. This study examines how cerebrospinal fluid (CSF) neurodegeneration markers (T-tau, NfL or both) are correlated with synaptic markers and clinical progression. We included 331 individuals with (n = 212) and without (n = 119) pathological CSF Aβ42/40 ratios. Associations between CSF NfL, T-tau, and the synaptic biomarkers neurogranin and BACE1 were assessed using Pearson’s correlation. Group differences in synaptic marker levels were evaluated using linear regression comparing individuals with isolated pathological T-tau, NfL, or both, versus biomarker-negative individuals. Clinical progression to MCI or dementia was assessed using a Cox proportional hazards model (n = 257; mean follow-up = 3.75 years). Linear regression and Cox proportional hazards models included age, sex, and dichotomized APOE -ε4 carriership as covariates. T-tau had a stronger correlation with neurogranin(r = 0.84) and BACE1(r = 0.73) than NfL(r = 0.51 and 0.48; p < 0.001). Group-wise comparisons confirmed this, showing that only individuals with pathological T-tau—alone or with NfL—had significantly higher synaptic marker levels (p < 0.001). Only the combination of pathological T-tau and NfL was associated with a significantly increased risk of clinical progression(HR=6.79; p < 0.001). These findings suggest that T-tau is more closely related to early synaptic dysfunction in AD than NfL. The combined elevation of both biomarkers, linked to greater clinical decline, supports a dual contribution of grey- and white matter degeneration to disease progression. Graphical illustrating the spatial distribution of the neurodegenerations markers . Total tau (T-tau) and the synaptic biomarkers neurogranin (Ng) and beta-site amyloid precursor protein cleaving enzyme (BACE1) are all located in the grey matter and neurofilament light chain (NfL) located in the neuronal axons in the white matter. In the synapse, BACE1 is located in the presynaptic terminal, and Ng in the postsynaptic dendritic spine. The healthy brain is illustrated in the left part of the figure, while neurodegeneration is illustrated to the right. Created with BioRender Nordengen, K. (2025) https://BioRender.com/ efhtnxn • T-tau showed stronger correlations with synaptic biomarkers than NfL at baseline. • Combined elevated NfL and T-tau increased risk of clinical progression. • There are cognitive test results at baseline among those with elevated NfL and/or T-tau.