Saliva Neurofilament Light Chain Is Not a Diagnostic Biomarker for Neurodegeneration in a Mixed Memory Clinic Population

Abstract

Neurodegeneration and axonal injury result in an increasing release of neurofilament light chain (NfL) into bodily fluids, including cerebrospinal fluid (CSF) and blood. Numerous studies have shown that NfL levels in CSF and blood are increased in neurodegenerative disorders and monitor neurodegeneration. Saliva is an easily accessible biofluid that could be utilized as a biofluid measurement of Alzheimer's disease (AD) biomarkers. In this study, for the first time, salivary NfL was measured and compared to plasma NfL in a consecutive cohort of patients referred to cognitive assessments. In two mixed memory clinic cohorts, saliva samples were taken from 152 patients, AD (n = 49), mild cognitive impairment (MCI) (n = 47), non-AD (n = 56), and also 17 healthy controls. In addition, 135 also had a matching plasma sample. All saliva and plasma samples were analyzed for NfL, and the association between saliva and plasma NfL and CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and beta amyloid 1-42 (Aβ42) were investigated. In total, 162/169 had quantifiable levels of salivary NfL by single molecule array (Simoa). No statistically significant differences were found in salivary NfL concentration across the diagnostic groups, but as expected, significant increases were found for plasma NfL in dementia cases (P < 0.0001). There was no association between saliva and plasma NfL levels. Furthermore, saliva NfL did not correlate with CSF Aβ42, p-tau, or tau concentrations. In conclusion, NfL is detectable in saliva but does not reflect neurodegeneration in the brain.

Keywords: Alzheimer’s disease; biomarker; dementia; neurodegeneration; neurofilament light chain; plasma; saliva.

FIGURE 1

Box plots of neurofilament light chain levels in saliva and plasma and the normalized levels of saliva NfL. (A) The boxplots show the median, interquartile range, and the extreme values of salivary NfL for HC, MCI, AD, and non-AD. The 2.5–97.5 percentile of all data had been included in the boxplots. (B) The boxplots show the median, interquartile range, and the extreme values of the normalized levels of salivary NfL for HC, MCI, AD, and non-AD. The 2.5–97.5 percentile of all data had been included in the boxplots. (C) The boxplots show the median, interquartile range, and the extreme values of plasma NfL for HC, MCI, AD, and non-AD. The 2.5–97.5 percentile of all data had been included in the boxplots. NfL, neurofilament light chain; HC, healthy controls; MCI, mild cognitive impairment; AD, Alzheimer’s disease.

FIGURE 2

The association between neurofilament light chain in plasma and normalized salivary neurofilament light chain. The figure shows the relationship between NfL in plasma and normalized NfL in saliva for HC, MCI, AD, and non-AD. NIL, neurofilament light chain; HC, healthy controls; MCI, mild cognitive impairment; AD, Alzheimer’s disease.