Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment

Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. [Display omitted] •Monocytes upregulate lipid processing genes with age in cognitively normal CSF•Monocyte lipid processing genes are dysregulated in cognitively impaired CSF•Monocytes signal to clonal CD8+ T cells via CXCL16-CXCR6 in cognitively impaired CSF•CXCL16 is increased in cognitively impaired CSF and relates to neurodegeneration A single-cell transcriptomic resource exploring the cerebrospinal fluid immune system in healthy brain aging and cognitive impairment uncovers the CXCL16-CXCR6 pathway as a mediator of CD8+ T cell trafficking to the CSF.