Chronic gingivitis increases the risk of early-onset Alzheimer's disease

Background Periodontal disease has two types of inflammatory states: gingivitis and periodontitis. While studies suggest a link between periodontal disease and Alzheimer's disease (AD), current evidence is insufficient to establish causality. This study employed Mendelian randomization (MR) and bioinformatics to investigate causal relationships between gingivitis, periodontitis, and AD types, while identifying diagnostic biomarkers through transcriptome-based bioinformatics approaches. Objective This study aims to explore the causal relationship between periodontal disease and AD using MR combined with bioinformatics analysis, investigate potential pathogenesis, and construct/validate diagnostic biomarkers. Methods Exposures and outcomes were selected from the Open whole-genome association study. Causal relationships were assessed using inverse variance-weighted (IVW), MR-Egger, and other supplementary methods. Transcriptome sequencing datasets were downloaded from Gene Expression Omnibus datasets. Key pathways and functions were identified through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Protein-protein interaction and LASSO regression were used to construct and evaluate the diagnostic signature for early-onset AD (EOAD). Gene Set Enrichment Analysis was applied to analyze gene set enrichment between high and low-risk groups. Results IVW showed a positive correlation (OR = 1.161, 95% CI = 1.011–1.332, p = 0.035), and MR-Egger validated this result (OR = 1.296, 95% CI = 1.020–1.645, p = 0.049). These findings suggest that chronic gingivitis may increase EOAD risk. Reverse analysis results were negative. Immune activation, angiogenesis, and blood-brain barrier damage link the two diseases. The Inter-alpha-trypsin inhibitor heavy chain H5 ( ITIH5 ) gene and TGFB pathway emerged in MR and bioinformatics analyses. A gene signature composed of ITIH5 , MFAP4 , and PRELP shows potential for diagnosing EOAD. Conclusions Chronic gingivitis may be associated with an increased risk of EOAD.