ArticleJournal of pain research2026
Toothache and Alzheimer's Disease: A Mendelian Randomization Study of the NAAG-CD33 Neuroimmune Axis.
Article in Journal of pain research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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10 authors.
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Abstract
Background: 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. Methods: 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. Results: 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. Conclusion: 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.
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