CSF IL-6, GDF-15, GFAP and NfL levels in early Alzheimer disease: a pilot study

Abstract

Background: Despite their potential usefulness as biomarkers, no study has investigated the interactions between cerebrospinal fluid (CSF) changes of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), growth differentiation factor 15 (GDF-15), transactive response DNA binding protein (TDP-43) and interleukin-6 (IL-6) and the core AD CSF biomarkers in the same cohort of AD patients.

Objectives: The aim of this pilot study is to evaluate the CSF levels of these analytes in patients with AD and assess their clinical relevance in this neurological condition.

Design: Cross-sectional study.

Methods: We assessed the levels of NfL, GFAP, GDF-15, TDP-43 and IL-6 in the CSF samples of 52 early AD patients and evaluated their partial reciprocal correlations and those with Abeta42, p-Tau, t-Tau and Mini-Mental State Examination (MMSE), always adding age, sex and educational level as covariates.

Results: MMSE score showed a positive correlation with the Aβ 1-42 concentrations (r = 0.485; p < 0.001), and a negative correlation with GDF-15 concentrations (r = -0.418; p = 0.002). IL-6 concentrations showed a positive correlation with NfL concentrations (r = 0.312; p = 0.026) and a negative correlation with TDP-43 concentrations (r = -0.322; p = 0.021). TDP-43 concentrations showed a positive correlation with GFAP (r = 0.33, p = 0.018). The mediation analysis suggests that the association between GDF-15 and MMSE is primarily mediated by Aβ 1-42. CSF GDF-15 concentrations were higher in AD patients with low Aβ 1-42 concentrations than those with high Aβ 1-42 concentrations (p < 0.001).

Conclusion: Our findings highlight that CSF IL-6 levels correlate positively with markers of neuronal damage. CSF TDP-43 levels significantly correlated with GFAP, suggesting a potential link with reactive gliosis and astrocyte activation. In addition, while CSF GDF-15 levels negatively correlate with MMSE scores, mediation analysis revealed that this association is primarily indirect and mediated through Aβ 1-42 levels.

Keywords: Alzheimer’s disease; aging; amyloid beta-peptides; inflammageing; mitochondrial dysfunction.

Figure 1.

CSF levels of GDF-15 values in the ‘low Aβ’ and the ‘high Aβ’ groups of patients with Alzheimer’s disease. Box plots express the first (Q1) and third (Q3) quartiles by the upper and lower horizontal lines in a rectangular box, in which there is a horizontal line showing the median. The whiskers extend upwards and downwards to the highest or lowest observation within the upper (Q3 + 1.5 × IQR) and lower (Q1 − 1.5 × IQR) limits. p Values indicate statistical significance between the different groups. CSF, cerebrospinal fluid; GDF-15, growth differentiation factor-15; Aβ, beta-amyloid.

Figure 2.

Simple mediation models representing Aβ 1-42 and GDF-15 as the mediator variable or as independent variable, MMSE score as the dependent variable. β coefficients are reported and p values are indicated. Aβ 1-42, beta-amyloid 1-42; GDF-15, growth differentiation factor-15; MMSE, mini-mental state examination.