Plasma neurofilament light as a biomarker for vascular contributions to cognitive impairment and dementia
Authors: Kautz Tiffany F. , Mathews Julia J , Bernal Rebecca , Wang Chen‐Pin , Liu Qianqian , Gonzales Mitzi M. , Tracy Russell P. , Parent Danielle , Wilcock Donna M. , Sudduth Tiffany L. , Wang Danny JJ , Sagare Abhay P , Rosenberg Gary A. , Lu Hanzhang , Kramer Joel H. , Decarli Charles , Jin Lee‐Way , Maillard Pauline , Singh Herpreet , Schwab Kristin , HELMER Karl , Greenberg Steven M. , Kivisäkk Pia , Aparicio Hugo J. , Beiser Alexa S , Ghosh Saptaparni , Fornage Myriam , Mosley Thomas H. , Mbangdadji Djass , Launer Lenore J. , Gudnason Vilmundur , Bis Josh , Psaty Bruce M. , Seshadri Sudha , Satizabal Claudia L 
Published: January 2025

Background

The MarkVCID consortium was established to address the paucity of biomarkers for vascular contributions to cognitive impairment and dementia (VCID), a leading cause of dementia. Plasma neurofilament light (NfL), a neuroaxonal injury marker elevated in several neurological and neurodegenerative diseases, was selected as one of the first biomarkers to be examined. We performed comprehensive instrumental and clinical validation of the Quanterix Simoa NfL assay using the first MarkVCID cohort.

Method

Plasma NfL was measured using HD‐X and HD‐1 Simoa instruments. Samples from the MarkVCID consortium were used to evaluate intra‐ and inter‐plate reliability, test‐retest repeatability, and inter‐site reproducibility. We used linear regression models to assess the association of NfL in MarkVCID with general cognitive function (GCF) as the primary outcome (n=331). In secondary analyses we assessed NfL associations with white matter hyperintensities (WMH). Models were adjusted for potential confounders, including eGFR as renal function influences NfL clearance. We replicated our findings using cohorts from the CHARGE consortium (CARDIA, ARIC, FHS, AGES; n=4,772), the UKY ADRC (n=350), and the UCD ADRC (n=196).

Result

We found the Quanterix Simoa platform to be reliable with low coefficients of variation (average CV<12%), high inter‐site reproducibility (overall ICC = 0.93) and high repeatability in test‐retest samples drawn within 30 days (ICC=0.968). There was strong consistency across Quanterix instruments (HD‐X and HD‐1; R2≥0.98) and kits (N4PA and single molecule NfL; ICC≥0.81). We observed consistent significant associations between higher NfL concentrations and worse GCF in MarkVCID (β=‐0.23; [95% CI ‐0.41; ‐0.01), CHARGE cohorts (meta‐analysis β=‐0.11; [95% CI ‐0.17; ‐0.06]), the UKY ADRC (β=‐0.16; [95% CI ‐0.27; ‐0.05]) and the UCD ADRC (UCD: β=‐0.28; [95% CI ‐0.48; ‐0.08). Secondary analyses revealed significant associations between elevated NfL concentrations and higher WMH burden in MarkVCID (when controlled for eGFR), CHARGE, and the UCD ADRC.

Conclusion

We have found that NfL can be reliably measured using the Quanterix platform, making this marker ideal for multi‐site clinical trials. We observed consistent associations for plasma NfL concentrations with cognition and WMH in MarkVCID and across independent samples, providing evidence that it can be a useful biomarker for stratification in VCID trials.