Cerebrospinal fluid biomarkers for Alzheimer disease and subcortical axonal damage in 5,542 clinical samples

Tobias Skillbäck,Kaj Blennow,Henrik Zetterberg,Niklas Mattsson

doi:10.1186/alzrt212

Abstract

IntroductionThe neuronal loss in Alzheimer disease (AD) has been described to affect grey matter in the cerebral cortex. However, in the elderly, AD pathology is likely to occur together with subcortical axonal degeneration on the basis of cerebrovascular disease. Therefore, we hypothesized that biomarkers for AD and subcortical axonal degeneration would correlate in patients undergoing testing for dementia biomarkers, particularly in older age groups.MethodsWe performed correlation and cluster analyses of cerebrospinal fluid (CSF) biomarker data from 5,542 CSF samples analyzed in our routine clinical neurochemistry laboratory in 2010 through 2012 for the established CSF AD biomarkers total tau (T-tau), phosphorylated-tau (P-tau), amyloid β1-42 (Aβ42), and for neurofilament light (NFL), which is a protein expressed in large-caliber myelinated axons, the CSF levels of which correlate with subcortical axonal injury.ResultsAβ42, T-tau, and P-tau correlated with NFL. By cluster analysis, we found a bimodal data distribution in which a group with a low Aβ42/P-tau ratio (suggesting AD pathology) had high levels of NFL. High levels of NFL also correlated with the presence of an AD biomarker pattern defined by Aβ42/P-tau and T-tau. Only 29% of those with an AD biomarker signature had normal NFL levels. Age was a possible confounding factor for the associations between NFL and established AD biomarkers, but in a logistic regression analysis, both age and NFL independently predicted the AD biomarker pattern.ConclusionsThe association between an AD-like signature using the established biomarkers Aβ42, T-tau, and P-tau with increased levels of NFL provides in vivo evidence of an association between AD and subcortical axonal degeneration in this uniquely large dataset of CSF samples tested for dementia biomarkers.

Highlights

The neuronal loss in Alzheimer disease (AD) has been described to affect grey matter in the cerebral cortex
Cerebrospinal fluid (CSF) AD biomarkers in relation to neurofilament light (NFL) levels We first analyzed the relation between NFL and the other biomarkers in the overall study population (Figure 1)
Both T-tau and phosphorylated tau (P-tau) had positive correlations with NFL (Figure 1A,B; R = 0.416; P ≤ 0.001 for T-tau and r = 0.231, P ≤ 0.001 for P-tau), whereas amyloid β1-42 (Aβ42) had an inverse correlation with NFL (Figure 1C; r = −0.130; P ≤ 0.001)

Summary

Introduction

The neuronal loss in Alzheimer disease (AD) has been described to affect grey matter in the cerebral cortex. The most well-established CSF AD biomarkers are the 42-amino-acid isoform of Aβ (Aβ42), total-tau (T-tau), and phosphorylated tau (P-tau), which are believed to reflect the presence of amyloid plaque deposition, axonal degeneration, and neurofibrillary tangles, respectively [11]. Another CSF biomarker for neuroaxonal injury is neurofilament light (NFL) protein. NFL is often normal in clinically pure AD [19] but abnormal in the presence of vascular pathology (for example, small-vessel disease [20], which mainly affects subcortical brain regions). Mutations in the NFL gene cause Charcot-Marie-Tooth disease [29]

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Discussion

Conclusion