Immune-related molecular links between asthma and Alzheimer's disease identified by multi-omics, machine learning and...

Epidemiological evidence suggests that asthma increases the risk of Alzheimer's disease (AD), yet their shared immune-related molecular mechanisms remain unclear. This study aimed to identify immune-associated molecular links between the two diseases.

Gene expression datasets from GEO were analyzed to identify differentially expressed genes (DEGs) and enriched pathways. WGCNA was used to detect immune-related modules, and machine learning algorithms were applied to refine candidate biomarkers. Mendelian randomization (MR) and experimental validation were conducted to investigate genetic associations and expression correlations. A logistic regression model and nomogram were constructed. Immune characteristics were further explored using GSEA, immune-cell signature analysis, and single-cell RNA sequencing (scRNA-seq).

CD163 and CHST6 were identified as cross-disease candidate genes. MR analyses showed nominal genetic associations of CD163 expression and plasma protein levels with asthma- and AD-related phenotypes, although these associations did not remain significant after FDR correction. CD163 and CHST6 also showed increased expression in independent asthma and AD mouse models. The combined diagnostic model showed good discrimination (AUC >0.87). Immune-cell signature analysis revealed tissue-dependent associations between the candidate genes and immune-related signatures. scRNA-seq revealed cell-type-specific expression patterns, with CD163 predominantly localized to myeloid-lineage populations, including microglia in AD and monocytes in severe asthma, whereas CHST6 showed context-dependent localization across glial and airway epithelial populations.

CD163 and CHST6 represent potential cross-disease molecular candidates associated with asthma and AD. CD163 may reflect a systemic immune-associated signal, whereas CHST6 may reflect tissue- and context-dependent cellular changes. These findings provide a preliminary framework for further investigation of asthma-AD comorbidity and require validation in prospective and functional studies.