Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer’s disease pathology and clinical disease progression

Abstract

Background To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer’s disease (AD) pathology and predict clinical progression in a memory clinic setting. Methods Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression. Results Plasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ1–42 > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ1–42, and Aβ1–42/Aβ1–40 in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants. Conclusion Plasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment.

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

“…This finding was subsequently verified by others ( Lewczuk et al, 2004 ; Fagan et al, 2011 ; Tang et al, 2014 ) and later also was confirmed with the measurement of serum ptau181 ( Shekhar et al, 2016 ). Recent studies demonstrated that blood ptau181 can predict cortical brain atrophy ( Llibre-Guerra et al, 2019 ; Tissot et al, 2021 ), tau and amyloid-beta pathology ( Lantero Rodriguez et al, 2020 ; Clark et al, 2021 ; Moscoso et al, 2021b ), differentiate AD from other neurodegenerative diseases ( Mielke et al, 2018 ; Thijssen et al, 2020 ; Grothe et al, 2021 ) and identify AD across the clinical continuum ( Janelidze et al, 2020a ; Karikari et al, 2020b , 2021 ). In familial AD, plasma ptau181 levels may rise as early as 16 years before clinical onset ( O’connor et al, 2020 ).…”

A Peek into Pandora’s Box: COVID-19 and Neurodegeneration

“…Results from a very recent study seem to be in agreement with these findings as blood biomarkers of neuronal and glial degeneration were found to be elevated in hospitalized COVID-19 patients with new onset cognitive dysfunction (specifically, toxic-metabolic encephalopathy, TME) [ 269 ]. Specifically, they showed increased levels of total tau, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) in the blood of neuro-COVID patients, which together indicated a profound neurological insult comparable to non-COVID patients with AD [ 269 , 270 ]. It is of great significance to note that these neurodegenerative biomarkers are also elevated after BBB disruption and were found to be associated with a higher risk of in-hospital death and reduced rates of discharge from hospital [ 269 ].…”

Blood-Based Biomarkers of Neuroinflammation in Alzheimer’s Disease: A Central Role for Periphery?

“…According to this vision, peripheral biomarkers of neuroinflammation should be considered as true core markers of AD, accessible for implementing the diagnosis and the clinical follow-up of patients. Further studies with novel sensitive techniques (e.g., Simoa) comparing the central and peripheral compartments are therefore advisable, analogously to what has been recently made, for example, for phosphorylated tau [ 194 ].…”