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

Introduction: The 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. Methods: We 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 beta 1-42 (A beta 42), 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. Results: A beta 42, T-tau, and P-tau correlated with NFL. By cluster analysis, we found a bimodal data distribution in which a group with a low A beta 42/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 A beta 42/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. Conclusions: The association between an AD-like signature using the established biomarkers A beta 42, 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.