Identification of novel biomarkers for cognitive function via an integrative analysis

Cognitive dysfunction associated with various diseases and its biomarkers have been extensively studied. However, research focusing on biomarkers related to cognitive function remains limited. This study aims to identify potential biomarkers associated with cognitive function and validate them through in vitro and in vivo experiments to address the current research gaps. We employed GWAS, PWAS, and TWAS analyses, combined with Mendelian randomization and colocalization analysis, to identify potential cognitive function-related biomarkers from European cohorts. An Alzheimer's disease (AD) cell model was established in SH-SY5Y and BV2 cells using Aβ_25-35 oligomers, and an APP/PS1 (AD mouse model) was purchased. The mRNA and protein expression levels of potential biomarkers were assessed in AD cells and mouse models using RT-qPCR and western blotting. Immunofluorescence was used to evaluate the fluorescence expression of these biomarkers in the AD cells, while immunohistochemistry was employed to assess staining intensity in the dorsolateral prefrontal cortex of AD model mice. Three potential biomarkers associated with cognitive function were identified: GPX1, CSE1L, and SULT1A1. KEGG enrichment analysis indicated that GPX1, CSE1L, and SULT1A1 are involved in various metabolic pathways, including those related to amyotrophic lateral sclerosis and Huntington's disease signaling. RT-qPCR and western blotting revealed low expression of GPX1 and CSE1L, and high expression of SULT1A1 in both AD cells and mouse models. These findings were further confirmed by immunofluorescence and immunohistochemistry, which demonstrated similar expression patterns in the AD cell and mouse models. GPX1, CSE1L, and SULT1A1 serve as biomarkers of cognitive function.