Association of neurofilament light chain with renal function: mechanisms and clinical implications

Background: Blood-based neurofilament light chain (NfL) is a promising biomarker of neurodegeneration across multiple neurodegenerative diseases. However, blood-based NfL is highly associated with renal function in older adults, which leads to the concern that blood-based NfL levels may be influenced by renal function, rather than neurodegeneration alone. Despite growing interest in using blood-based NfL as a biomarker of neurodegeneration in research and clinical practices, whether renal function should always be accounted for in these settings remains unclear. Moreover, the mechanisms underlying this association between blood-based measures of NfL and renal function remain elusive. In this study, we first evaluated the effect of renal function on the associations of plasma NfL with other measures of neurodegeneration. We then examined the extent of genetic and environmental contributions to the association between plasma NfL and renal function. Methods: In a sample of 393 adults (mean age=75.22 years, range=54-90), we examined the associations of plasma NfL with cerebrospinal fluid (CSF) NfL and brain volumetric measures before and after adjusting for levels of serum creatinine (an index of renal function). In an independent sample of 969 men (mean age=67.57 years, range=61-73) that include monozygotic and dizygotic twin pairs, we replicated the same analyses and leveraged biometrical twin modeling to examine the genetic and environmental influences on the plasma NfL and creatinine association. Results: Plasma NfL's associations with cerebrospinal fluid NfL and brain volumetric measures did not meaningfully change after adjusting for creatinine levels. Both plasma NfL and creatinine were significantly heritable (h(2)=0.54 and 0.60, respectively). Their phenotypic correlation (r=0.38) was moderately explained by shared genetic influences (genetic correlation=0.46) and unique environmental influences (unique environmental correlation=0.27). Conclusions: Adjusting for renal function is unnecessary when assessing associations between plasma NfL and other measures of neurodegeneration but is necessary if plasma NfL is compared to a cutoff for classifying neurodegeneration-positive versus neurodegeneration-negative individuals. Blood-based measures of NfL and renal function are heritable and share common genetic influences.