Plasma neurofilament light chain and amyloid-β are associated with the kynurenine pathway metabolites in preclinical Alzheimer's disease

Background: Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-beta; A beta), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and A beta correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation. Methods: Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and A beta concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65-90 years, with normal global cognition (Mini-Mental State Examination Score >= 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort. Results: A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2, 3-dioxygenase activity was observed (r=.451, p <.0001). Positive correlations were also observed between NFL and kynurenine (r=.364, p <.0005), kynurenic acid (r=.384, p <.0001), 3-hydroxykynurenine (r=.246, p=.014), anthranilic acid (r=.311, p=.002), and quinolinic acid (r=.296, p=.003). Further, significant associations were observed between plasma A beta 40 and the K/T (r=.375, p <.0005), kynurenine (r=.374, p <.0005), kynurenic acid (r=.352, p <.0005), anthranilic acid (r=.381, p <.0005), and quinolinic acid (r=.352, p <.0005). Significant associations were also observed between plasma A beta 42 and the K/T ratio (r=.215, p=.034), kynurenic acid (r=.214, p=.035), anthranilic acid (r=.278, p=.006), and quinolinic acid (r=.224, p=.027) in the cohort. On stratifying participants based on their neocortical A beta load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma A beta and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent. Conclusions: The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma A beta seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential.