Sex and aging signatures in human CSF proteomics and their link to neurologic diseases

Abstract

AbstractBackgroundSex and age are major risk factors for several chronic diseases. Recent human and mouse studies of age‐related molecular changes in blood provided new insights into age‐related disease biology. Cerebrospinal fluid (CSF) is more closely related to brain than blood and can provide additional insights to sex and age‐related brain diseases.MethodWe measured over 7000 proteins in CSF from 998 healthy individuals representing middle and old age (43‐91) across four multiple cohorts. After stringent QC, we performed weighted gene co‐expression network analysis (WGCNA) to group CSF proteins with similar sex and age trajectories. Each cluster was then tested for aging and sex differences. Cell‐type enrichment and disease ontology enrichment was also performed.ResultCo‐expression network analysis identified 24 modules for CSF 4926 proteins. Sex difference was detected for 2949 proteins (1730 were higher in females; 1219 were higher in males). Aging signature was detected for 4480 proteins (2999 increasing; 1481 decreasing with age). The pink module (containing SERPINA3, TREML2, and additional 197 proteins) had proteins higher in males and increasing with ages and were enriched in endothelial cell (P = 0.04). Cardiovascular diseases (FDR = 2.6E‐9), ischemic stroke (FDR = 1.7E‐7) and Alzheimer’s disease (AD) (FDR = 7.3E‐3) were significantly enriched in this module. The blue module (containing APOE, APP and additional 681 proteins) had proteins higher in females and decreasing with ages, were enriched in microglia and macrophage (P = 0.01). AD (FDR = 0.043) and vascular dementia (FDR = 0.025) were enriched. The yellow module (containing SMPD1, GNS, CTSB and additional 331 proteins) had proteins higher in females and non‐linear aging trajectory (increasing until 70 years old and decreasing) were enriched in neurons (P = 4.6E‐9). Lysosomal storage diseases (FDR = 3.4E‐03) showed enrichment for them. Among the 46 plasma proteins showing conserved aging signature in mice and humans (Lehallier et al 2019), 20 proteins including TNFSF15 and PPBP were also conserved in CSF. In addition, nine of them show the sex‐specific signature conserved across all three datasets.ConclusionOur study in CSF proteomic signatures identified clusters of proteins in distinct patterns and their relation to Alzheimer’s disease and other neurodegeneration. More detailed characterization of proteomic signatures for other age‐related chronic diseases is underway.