LAX1 as a core biomarker in Alzheimer's disease and periodontitis via the STAT signaling pathway.

BACKGROUND: The relationship between Alzheimer's disease (AD) and chronic periodontitis (PD) rarely share the medical spotlight, yet epidemiological mirroring hints at a common inflammatory root. METHODS: Mining four GEO (Gene Expression Omnibus) cohorts (211 AD + 27 controls; 24 PD + 23 controls), batch-corrected and validated by principal component analysis (PCA)/t-distributed stochastic neighbour embedding (t-SNE)/uniform manifold approximation and projection (UMAP), we identified 61 shared differentially expressed genes (DEGs) with lymphocyte transmembrane adaptor 1 (LAX1) ranked first in weighted gene co-expression network analysis (WGCNA), maximum clique centrality (MCC), Degree, edge percolated component (EPC) and Stress algorithms, tightly co-expressed with colony-stimulating factor 3 receptor (CSF3R) and signal transducer and activator of transcription 1/3 (STAT1/3). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) uniquely highlighted the "LAX1/CSF3R/STAT" triad in apoptosis and JAK-STAT cascades. CIBERSORT de-convolution showed LAX1 covaried with plasma-cell, mast-cell and M0-macrophage infiltration. RESULTS: Plasma from 42 AD and 38 stage-III/IV PD patients showed elevated soluble LAX1 (sLAX1) correlating with Mini-Mental State Examination (MMSE) decline (r =-0.67) and clinical attachment loss (r = 0.71), outperforming Aβ42 and receptor activator of nuclear factor-κB ligand (RANKL) in receiver operating characteristic (ROC) analyses (area under the curve [AUC] = 0.91). We hypothesised that LAX1 orchestrates the dialogue via the STAT axis. In human periodontal-ligament fibroblasts and 5 × FAD glia exposed to Porphyromonas gingivalis LPS or amyloid-β42 (Aβ42), LAX1 overexpression (pCMV6-LAX1) amplified STAT1/3 phosphorylation, elevated interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by 2.3-3.1-fold and escalated p53, cleaved caspase-3 and FAS, whereas LAX1 small interfering RNA (siRNA) abolished these effects. In other words, targeting of the LAX1 validated that the inflammatory/apoptotic signature scales with LAX1 abundance. CONCLUSION: LAX1 gates STAT-dependent neuroinflammation and periodontal destruction, offering a druggable checkpoint and blood-based biomarker for these convergent chronic diseases.