Toothache and Alzheimer's Disease: A Mendelian Randomization Study of the NAAG-CD33 Neuroimmune Axis

Toothache, as an oral pain condition, may disrupt neuroimmune signaling and potentially influence neurodegenerative processes. This study investigated the relationship between toothache and Alzheimer's disease (AD) through a neuroimmune axis involving N-acetylaspartylglutamate (NAAG) and CD33+ myeloid monocytes.

We conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics from the UK Biobank for toothache, a large-scale plasma metabolomics study for NAAG, and immune cell trait cohorts for CD33+ myeloid monocyte-related traits, including CD33 on HLA DR+/CD11b+ cells and monocytic myeloid-derived suppressor cells. The AD dataset, derived from a large-scale meta-analysis, primarily focused on late-onset sporadic cases. Pairwise associations among toothache, NAAG, CD33-related traits, and AD were explored. Heterogeneity and horizontal pleiotropy were assessed using Cochran's Q test and MR Egger regression.

Reduced NAAG in toothache individuals (p = 0.024) exhibited a robust association with increased CD33 expression in myeloid monocytes (p = 0.005), which were associated with increased AD risk (p = 0.003). Sensitivity analyses confirmed the robustness of the results.

This study provides preliminary evidence for a potential causal axis linking toothache, reduced NAAG, increased CD33+ myeloid monocytes, and AD. This study bridges the gap between clinical observations of oral pain-related cognitive decline and the neuroimmune mechanisms underlying this process.