Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-beta in a Heterogenous Clinical Cohort

Background: Neuroinflammation is an integral part of Alzheimer's disease (AD) pathology. Inflammatory mediators can exacerbate the production of amyloid-beta (A beta), the propagation of tau pathology and neuronal loss. Objective: To evaluate the relationship between inflammation markers and established markers of AD in a mixed memory clinic cohort. Methods: 105 cerebrospinal fluid (CSF) samples from a clinical cohort under investigation for cognitive complaints were analyzed. Levels of A beta(42), total tau, and phosphorylated tau were measured as part of the clinical pathway. Analysis of inflammation markers in CSF samples was performed using multiplex immune assays. Participants were grouped according to their A beta, tau, and neurodegeneration status and the Paris-Lille-Montpellier (PLM) scale was used to assess the likelihood of AD. Results: From 102 inflammatory markers analyzed, 19 and 23 markers were significantly associated with CSF total tau and phosphorylated tau levels respectively (p < 0.001), while none were associated with A beta(42). The CSF concentrations of 4 inflammation markers were markedly elevated with increasing PLM class indicating increased likelihood of AD (p < 0.001). Adenosine deaminase, an enzyme involved in sleep homeostasis, was the single best predictor of high likelihood of AD (AUROC 0.788). Functional pathway analysis demonstrated a widespread role for inflammation in neurodegeneration, with certain pathways explaining over 30% of the variability in tau values. Conclusion: CSF inflammation markers increase significantly with tau and neurodegeneration, but not with A beta in this mixed memory clinic cohort. Thus, such markers could become useful for the clinical diagnosis of neurodegenerative disorders alongside the established A beta and tau measures.