Alteration of Peripheral Cytokines in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with the clinical symptoms of gradual cognitive decline and memory loss. Biologically, abnormal accumulation of Aβ (Aβ) plaque and tau tangles in the brain are the core pathological hallmarks in AD. Although inflammatory response is not specific to AD, emerging evidence suggests that the disrupted innate immune system within the central nervous system, particularly microglial activation, might act as the bridge linking Aβ aggregation to pathological phosphorylation and aggregation of tau. The inflammatory response was suggested to initially have a neuroprotective role of attempting to clear Aβ plaques, and then become neurotoxic in a chronic inflammatory state upon failure to clear Aβ. Cytokines, as a family of small proteins acting as the chemical messengers in the immune system, are the potential biomarker candidates reflecting the changes in the immune system. Many studies have evaluated the concentration difference of cytokines between patients in the AD continuum and controls to examine neuroinflammation in AD, however, substantial discrepancies were observed between studies. Considering the dual role of inflammation in AD and the competing and synergistic effects of numerous cytokines in the body, we analyzed the cytokine data from human participants and APP mice with the hypothesis that 1) cytokine concentrations change in a nonlinear fashion with disease progression and 2) the interaction between cytokines is disrupted in AD. We found that multiple cytokines had discrepant association with brain amyloid burden before and after brain amyloid reaching pathological level, and most of them were closely relevant to hematopoietic function. In addition, the correlations between cytokines were substantially different between amyloid positive participants (A+) and cognitively unimpaired amyloid negative participants (CU-). Pairwise correlation analysis between cytokines showed that the cytokine pairs having strong correlations in CU- were more likely to have weaker correlations in A+ group, such a change was consistently observed in the comparison between APP mice and wild-type mice. A discordance score was defined to characterize the less concordant cytokine levels in the disease population at the individual level. Compared to cytokine concentration, the discordance score had better discriminative power in separating A+ participants from CU- participants. Our findings suggest that the immunotherapy targeting at hematopoietic function might be beneficial for delaying AD progression, although the effect might depend on the disease stage and the signaling pathway at the molecular level remains to be identified. Furthermore, compared to the concentration of each cytokine, the interaction between peripheral cytokines might be a more promising metric to characterize altered immune responses in AD.