Transcriptome profiling of cerebrospinal fluid in Alzheimer’s Disease reveals molecular dysregulations associated with disease

ABSTRACT Despite the increasing prevalence of neurodegenerative diseases, the molecular characterization of the brain remains challenging due to limited access to the tissue. Cerebrospinal fluid (CSF) contains a significant proportion of molecular contents originating from the brain, and characterizing these molecules has served as a surrogate to evaluate molecular dysregulation in the brain. Here we performed cell-free messenger RNA (cf-mRNA) RNA-sequencing on 52 human CSF samples, and further compared their transcriptomic profiles to matched plasma samples. In addition, we evaluated the molecular dysregulation of cf-mRNA in CSF between individuals with Alzheimer’s disease (AD) and non-cognitively impaired (NCI) controls. The molecular content of CSF cf-mRNA was distinct from plasma cf-mRNA, with a substantially higher number of brain-associated genes identified in CSF. We identified a large set of dysregulated gene transcripts in the CSF cf-mRNA population of individuals with AD, and these gene transcripts were used to establish a diagnostic classifier to discriminate AD from NCI subjects. Notably, the gene transcripts were enriched in biological processes closely associated with AD, such as brain development and synaptic signaling. We also discovered a subset of gene transcripts within AD subjects that exhibit a strong correlation between CSF and plasma cf-mRNA. This study not only reveals the novel cf-mRNA content of CSF but also highlights the potential of CSF cf-mRNA profiling as a tool to garner pathophysiological insights into AD.