Amyloid-beta modulates the association between neurofilament light chain and brain atrophy in Alzheimer’s disease

Abstract

Neurofilament light chain (NFL) measurement has been gaining strong support as a clinically useful neuronal injury biomarker for various neurodegenerative conditions. However, in Alzheimer's disease (AD), its reflection on regional neuronal injury in the context of amyloid pathology remains unclear. This study included 83 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 73 AD subjects who were further classified based on amyloid-beta (Aβ) status as positive or negative (Aβ+ vs Aβ−). In addition, 13 rats (5 wild type and 8 McGill-R-Thy1-APP transgenic (Tg)) were examined. In the clinical study, reduced precuneus/posterior cingulate cortex and hippocampal grey matter density were significantly associated with increased NFL concentrations in cerebrospinal fluid (CSF) or plasma in MCI Aβ+ and AD Aβ+. Moreover, AD Aβ+ showed a significant association between the reduced grey matter density in the ADvulnerable regions and increased NFL concentrations in CSF or plasma. Congruently, Tg rats recapitulated and validated the association between CSF NFL and grey matter density in the parietotemporal cortex, entorhinal cortex, and hippocampus in the presence of amyloid pathology. In conclusion, reduced grey matter density and elevated NFL concentrations in CSF and plasma are associated in AD-vulnerable regions in the presence of amyloid positivity in the AD clinical spectrum and amyloid Tg rat model. These findings further support the NFL as a neuronal injury biomarker in the research framework of AD biomarker classification and for the evaluation of therapeutic efficacy in clinical trials.

Cerebral amyloid‐β load is associated with neurodegeneration and gliosis: Mediation by p‐tau and interactions with risk factors early in the Alzheimer'scontinuum

“…Interestingly, we found a tau‐dependent but also a relevant tau‐independent effect of Aβ PET on CSF NfL (40.5% of the total effect, Figure 3). This is in line with a recent publication that shows a direct effect of Aβ accumulation on CSF NfL levels and neurodegeneration in AD‐regions in a rat model with minimal tau pathology 36 . In the same study, these results were replicated in humans even when accounting for tau pathology.…”

Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer’s disease therapeutic

“…This platform capitalizes on the properties of the McGill-R-Thy1-APP rat model, which has been previously characterized based on the in vivo biomarker platform. 17,33 The McGill-R-Thy1-APP rat model progressively develops Ab pathology, indicated by the significant increase in the [ 18 F]AZD4694 PET and decline in the CSF Ab 42/40 ratio, at a similar rate as AD patients and recapitulates AD biomarker abnormalities. 17,33 For example, the McGill-R-Thy1-APP rat model has an increased CSF NFL concentration, reduction in hippocampal volume, cingulate connectivity, and CSF Ab 42/40 ratio, which have been shown to be sensitive biomarkers for AD pathological progression and disease severity, ultimately leading to memory impairment.…”

Diagnostic Fluid Biomarkers in Alzheimer’s Disease: Blood and Cerebrospinal Fluid

“…Previously studies have mainly focused on the use of NFL as a neurodegeneration biomarker [10,11,14,16]. However, the present study is the first study to observe changes in NFL and Aβ1-currently approved AD-CSF biomarkers (Aβ1-42, t-Tau, and p-Tau181) and neuroimaging biomarkers (Aβ-PET and MRI).…”

“…The protein Aβ1-42 (amyloid, Aβ), t-Ta u , and p-Ta u 181 have been employed as CSF biomarkers for AD [8]. In addition, neurofilament light chain (NFL) has recently attracted attention as a biomarker for neuroaxonal damage [9][10][11][12]. The ATN system (ATN: amyloid, tau, neurodegeneration) has been established as a multimodal classification scheme [13].…”