Introduction Porphyromonas gingivalis and Treponema species have been found to invade the central nervous system through virulence factors, causing inflammation and influencing the host immune response. P. gingivalis interacts with astrocytes, microglia, and neurons, leading to neuroinflammation. Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum may also play a role in the development of Alzheimer's disease. Interactomic hub genes, central to protein-protein interaction networks, are vulnerable to perturbations, leading to diseases such as cancer, neurodegenerative disorders, and cardiovascular diseases. Machine learning can identify differentially expressed hub genes in specific conditions or diseases, providing insights into disease mechanisms and developing new therapeutic approaches. This study compares the performance of light gradient boosting and logistic regression in identifying interactomic hub genes in P. gingivalis and F. nucleatum -induced periodontitis with those in Alzheimer's disease. Methods Using the GSE222136 dataset, we analyzed differential gene expression in periodontitis and Alzheimer's disease. The GEO2R tool was used to identify differentially expressed genes under different conditions, providing insights into molecular mechanisms. Bioinformatics tools such as Cytoscape and CytoHubba were employed to create gene expression networks to identify hub genes. Logistic regression and light gradient boosting were used to predict interactomic hub genes, with outliers removed and machine learning algorithms applied. Results The data were cross-validated and divided into training and testing segments. The top hub genes identified were TNFRSF9, LZIC, TNFRSF8, SLC45A1, GPR157, and SLC25A33, which are induced by P. gingivalis and F. nucleatum and are responsible for endothelial dysfunction in brain cells. The accuracy of logistic regression and light gradient boosting was 67% and 60%, respectively. Discussion The logistic regression model demonstrated superior accuracy and balance compared to the light gradient boosting model, indicating its potential for future improvements in predicting hub genes in periodontal and Alzheimer's diseases.