Refinement of Neurofilament light Dynamics in CSF and Blood for familial Alzheimer’s Disease
Authors: Hofmann Anna , Haesler Lisa M. , Preische Oliver , Gräber‐Sultan Susanne , Obermüller Ulrike , Vöglein Jonathan , Levin Johannes , Laske Christoph , Fitzpatrick Colleen D , Levin Raina , Joseph‐Mathurin Nelly , Chen Charles D. , Cruchaga Carlos , Goate Alison , Allegri Ricardo Francisco , Benzinger Tammie L.S. , Berman Sarah , Chui Helena C , Fagan Anne M. , Farlow Martin R. , Fox Nick C , Day Gregory S. , Hassenstab Jason J. , Jack Clifford R. , Lee Jae‐Hong , Levey Allan I. , Martins Ralph N , Mori Hiroshi , Noble James M , Perrin Richard J. , Sperling Reisa A. , Rosa‐Neto Pedro , Salloway Stephen , Sanchez‐Valle Raquel , Schofield Peter R , Xiong Chengjie , Karch Celeste M. , Graff‐Radford Neill R , Gordon Brian A. , Morris John C , McDade Eric , Bateman Randall J. , Chhatwal Jasmeer P. , Jucker Mathias , Schultz Stephanie A. 
Published: December 2023

Background

Disease‐modifying therapies for Alzheimer’s Disease (AD) are likely most beneficial when initiated in the pre‐symptomatic phase. To track success of such interventions fluid biomarkers became instrumental, with neurofilament light chain (NfL) showing particular promise. We previously reported that serum NfL increases in pre‐symptomatic phases of familial (autosomal‐dominantly inherited) AD (fAD) and that within‐person rate‐of‐change in NfL is an earlier predictor of fAD symptom onset compared to cross‐sectional levels. The aim of the study at hand was to extend these initial findings in a larger cohort.

Method

Participants enrolled in the Dominantly Inherited Alzheimer Network (DIAN) with matched cross‐sectional and longitudinal cerebrospinal fluid (CSF; n = 962) as well as plasma (n = 1294) samples were used. NfL measurements have been performed on the SIMOA platform using commercially available assay‐kits. To investigate the influence of physiological factors independent from AD, we first analyzed whether age and body mass index (BMI) could account for observed variation in inter‐individual CSF and plasma NfL levels considering non‐carrier family‐members (NC) as a healthy control group. Next, utilizing estimated years to symptom onset (EYO) and previously published methods (Preische et al., 2019), we determined the point in disease course when baseline and longitudinal CSF and plasma NfL concentrations started to increase in mutation carriers (MC) relative to NC, after adjusting for age and BMI.

Result

Our results reveal a tight correlation of CSF and blood NfL values within MC as well as NC (figure 1A‐B). However, within NC, after correction for age and BMI, some unexplained variability remained (figure 1C). Further, a decrease of the NfL plasma/CSF ratio over age was found after correcting for BMI (figure 1D). The discrimination of MC from NC was equally good for plasma compared to CSF, being possible on the group level as early as around ‐15 to almost ‐20 EYO depending on the modelling (figure 2).

Conclusion

Our results support plasma equivalently to CSF NfL as a clinically useful biomarker to longitudinally track neurodegeneration in fAD. The systemic factors influencing physiological NfL values in blood should be investigated in future studies to further improve interpretation of this biomarker.