Distinct cerebrospinal fluid immune perturbations in healthy brain aging and cognitive impairment

Abstract Background Cerebrospinal fluid (CSF) contains a tightly regulated, specialized immune system. Yet, little is known about how aging influences CSF immunity in cognitively typical versus cognitively impaired individuals. Method Here, we performed single cell RNA sequencing (scRNAseq) on CSF collected from 45 cognitively typical subjects ranging from 54‐82 years old. We then assessed age‐related transcriptomic changes using bioinformatic approaches, including linear and local polynomial regression. We reveal pronounced changes to several CSF immune cell types, underscored by increased expression of lipid processing genes in activated monocytes with age. We then compared CSF immune systems from cognitively typical subjects to 14 subjects with mild cognitive impairment or Alzheimer’s disease. Result Our results indicate disparate age‐related CSF immune system perturbations, including the upregulation of C‐X‐C Motif Chemokine Receptor 6 in clonally expanded T cells of cognitively impaired subjects. Conclusion These results highlight the utility of CSF immune system changes to identify therapeutic targets of neurodegenerative disease‐associated neuroinflammation.