Human brain and organoid transcriptomes reveal key receptor tyrosine kinase pathways and genetic signatures in Alzheimer's disease.

Alzheimer disease (AD) is a progressive neurodegenerative disorder marked by transcriptomic alterations affecting multiple genes. Many researchers have tried to predict major hallmarks of AD pathogenesis for diagnosis but the association between receptor tyrosine kinase (RTK) pathways and AD diagnosis is still unclear. This study aims to identify RTK-associated gene signatures crucial to AD pathogenesis and assess their potential as diagnostic biomarkers for AD. The study investigated changes in RTK pathway gene expression related to AD by analyzing brain transcriptome data from two independent public data sets (GSE84422 and GSE109887). Differentially expressed genes (DEGs) were analyzed from the GSE84422 and GSE109887 data sets and overlapping genes (oDEGs) were identified. RTK-related genes (ooDEGs) were subsequently selected through functional enrichment analysis. These were further refined into AD-related genes (disease-associated genes (DAGs)) through protein-protein interaction network analysis. Logistic regression and receiver operating characteristic analyses were conducted on the selected DAGs to evaluate their diagnostic potential, with additional gene expression validation performed in brain organoids and primary neurons. A total of 145 genes were identified as oDEGs in the above two data sets, and 18 genes were selected as ooDEGs. Six DAGs (ITGB1, AXL, GFAP, NRG1, CAV1, and RHOA) were selected. The diagnostic powers of the six DAGs for AD were 0.825 (GSE84422) and 0.884 (GSE109887). Human brain organoids and primary neuronal models were used to validate the biological relevance of these findings. AXL and ITGB1 were finally selected as key genes for RTK pathway in AD and were significantly increased in AD.