Role of Neurofilament Light Chain as a Potential Biomarker for Alzheimer's Disease: A Correlative Meta-Analysis

Abstract

Neurofilament light (NFL) is a putative biomarker of neurodegeneration. This study evaluates the correlative association of NFL with Alzheimer's disease (AD) indices. Relevant studies were identified after a literature search in electronic databases and study selection was based on pre-determined eligibility criteria. Correlation coefficients between NFL levels and important AD indices reported by individual studies were pooled as z-scores. Meta-regression analyses were performed to evaluate the relationships between important covariates. Data from 38 studies (age 68.3 years [95% confidence interval (CI): 65.7, 70.9]; 54 % [95% CI: 50, 57] females) were used. Meta-analyses of correlation coefficients reported by the included studies showed that NFL levels in blood and cerebrospinal fluid (CSF) correlated well (r = 0.59 [95% CI: 0.45, 0.71]; p < 0.0001). NFL levels correlated with MMSE score (r = −0.345 [95% CI: −0.43, −0.25]; p = 0.0001), and age (r = 0.485 [95% CI: 0.35, 0.61]; p = 0.00001). CSF NFL levels correlated with total tau (t-tau; r = 0.39 [95% CI: 0.27, 0.50]; p = 0.0001), phosphorylated tau (p-tau; r = 0.34 [95% CI: 0.19, 0.47]; p = 0.00001), and neurogranin (r = 0.25 [95% CI: 0.12, 0.37]; p = 0.001) but not with beta amyloid (Aβ) (r = 0.00 [95%CI: −0.13, 0.12]; p = 0.937). In meta-regression, MMSE scores were associated inversely with blood NFL (metaregression coefficient (MC) −0.236 [95% CI:−0.40, −0.072; p = 0.008), and age (MC) −0.235 [−0.36, −0.11]; p = 0.001) and positively with CSF Aβ-42 (MC 0.017 [0.010, 0.023]; p = 0.00001). NFL has good correlations with t-tau, and p-tau in CSF and CSF NFL levels correlates well with blood NFL levels. These results show that NFL can be a useful biomarker for improving diagnosis and predicting prognosis in AD patients especially if age weighted.

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

“…The neurofilament heteropolymers are the primary cytoskeleton proteins predominantly found in axons. Among the four subunits, namely the three isoforms NFL, neurofilament medium and neurofilament heavy, and alpha-internexin, NFL is the most abundant [ 59 , 62 ]. Forming the core of the neurofilament, NFL is a triplet protein essential to the structure of the myelin that surrounds the axons within the central nervous system [ 62 , 63 ].…”

“…Forming the core of the neurofilament, NFL is a triplet protein essential to the structure of the myelin that surrounds the axons within the central nervous system [ 62 , 63 ]. As their presence within the CSF is specific for axonal injury, elevated NFL concentrations have been widely reported in neurodegenerative disorders, especially in AD patients [ 59 , 62 , 63 , 64 ]. While the mechanisms of NFL aggregation are still unelucidated, they are thought to be similar to the hyperphosphorylation process of tau proteins [ 65 ].…”

Clinical Utility of the Pathogenesis-related Proteins in Alzheimer&rsquo;s Disease

“…T-tau had the strongest association with cognition in the presence of amyloidosis; followed by Ng. Variables associations with NfL did not differ by amyloid status [38].…”

“…NFL and YKL-40 were associated with Aβ+ in non-demented individuals only [37]. CSF YKL-40 was positively associated with both CSF NFL and T-Tau [38]. Jin M [39] reported that CSF NFL levels correlated with total tau, phosphorylated tau, and neurogranin but not with beta amyloid (Aβ).…”

Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis

“…Neurofilaments accumulate specifically in the cell bodies and proximal areas of neurons during neurological disorders (Liu et al, 2009). The concentrations of NFL is increased both in the plasma (Lin et al, 2018) and CSF (Jin et al, 2019 in AD. The level of CSF NFL increases as a function of age (Bacioglu et al, 2016) in mice model of Aβ amyloidosis, while NFL deficiency aggravates amyloid pathology in NFL knock out (KO) mice (Fernandez-Martos et al, 2015).…”