Association between cerebrospinal fluid neurofilament light chain and markers of neurofibrillary pathophysiology: Findings from the Knight Alzheimer Disease Research Center

Abstract

AbstractBackgroundThe objective of this study was to examine the relationship between cerebrospinal fluid (CSF) neurofilament light (NfL) chain levels and established biomarkers of neurofibrillary tangle (NFT) pathophysiology. Secondarily, we assessed the discordance of beta‐amyloid, NFT, and neurodegeneration markers.Method236 individuals (207 cognitively normal and 29 cognitively impaired) were selected based on completion of CSF collection and AV1451 and AV45 PET imaging within 1 year, and measurement of CSF NfL, beta‐amyloid‐42, total‐tau, and phosphorylated‐tau181 (p‐tau). Using covariate‐adjusted linear regressions we compared log‐transformed CSF NfL to AV1451 summary SUVRs and CSF p‐tau. Using Gaussian mixture models, we determined positivity thresholds in markers of beta‐amyloid (CSF beta‐amyloid‐42 and AV45), NFT (CSF p‐tau and AV1451), and neurodegeneration (CSF total‐tau and CSF NfL), and assessed discordant results between related biomarkers.ResultCSF NfL was highly associated with CSF p‐tau (p=9.83e‐10), whereas CSF NfL was marginally associated with AV1451 (p=0.006). CSF p‐tau and AV1451 were only moderately correlated (r=0.457). The differences in relationship between tau and NfL markers may be due to effects of age on these three biomarkers of interest. Age was minimally correlated with AV1451 (r=0.326) and moderately correlated with CSF p‐tau and NfL (r=0.410 and 0.512, respectively). Secondarily, we found that our sample was 18.2% discordant between beta‐amyloid markers, 18.7% discordant between NFT markers, and 17.8% discordant between neurodegeneration markers.ConclusionThe relationship between CSF NfL and NFT pathophysiology differed depending on the NFT biomarker that was considered and may be related to elevations in certain CSF biomarkers as a function of age. Currently, CSF p‐tau and AV1451 are often considered interchangeable measures of NFT pathophysiology. These results suggest more careful consideration and assessment of biomarkers should be taken when choosing markers of beta‐amyloid, NFT, and neurodegeneration.