ApoE ε4-dependent alteration of CXCR3+CD127+ CD4+ T cells is associated with elevated plasma neurofilament light chain in Alzheimer's disease

Recent findings indicate a correlation between the peripheral adaptive immune system and neuroinflammation in Alzheimers disease (AD). To characterize the composition of adaptive immune cells in the peripheral blood of AD patients, we utilized single-cell mass cytometry (CyTOF) to profile peripheral blood mononuclear cells (PBMCs). Concurrently, we assessed the concentration of proteins associated with AD and neuroinflammation in the plasma of the same subjects. We found that the abundance of proinflammatory CXCR3+CD127+ Type 1 T helper (Th1) cells in AD patients was negatively correlated with the abundance of neurofilament light chain (NfL) protein. This correlation is apolipoprotein E (ApoE) {varepsilon}4-dependent. Analyzing public single-cell RNA-sequencing (scRNA-seq) data, we found that, contrary to the scenario in the peripheral blood, the cell frequency of CXCR3+CD127+ Th1 cells in the cerebrospinal fluid (CSF) of AD patients was increased compared to healthy controls (HCs). Moreover, the proinflammatory capacity of CXCR3+CD127+ Th1 cells in the CSF of AD patients was further increased compared to HCs. These results reveal an association of a peripheral T-cell change with neuroinflammation in AD and suggest that dysregulation of peripheral adaptive immune responses, particularly involving CXCR3+CD127+ Th1 cells, may potentially be mediated by factors such as ApoE {varepsilon}4 genotype. One sentence summaryAn apolipoprotein E (ApoE) {varepsilon}4-dependent alteration of CD4 T cell subpopulation in peripheral blood is associated with neuroinflammation in patients with Alzheimers disease.