Oral Pain and Alzheimer’s Disease: Prospective Cohort and Cross-Sectional Analyses

Given the limited effectiveness of Alzheimer's disease (AD) treatments, modifiable risk factors warrant attention. Oral pain (OP), a common inflammatory symptom, may be linked to neurodegeneration. This study aimed to investigate associations between OP and AD risk, cognitive performance, and brain structure. Data from 490,035 UK Biobank participants free of AD at baseline and with complete OP records were analyzed, while other dementias were excluded. Participants were categorized into an OP group (<i>n</i> = 33,697; defined as self-reported toothache or painful gums via touchscreen questionnaire) and an oral pain-free group (<i>n</i> = 456,338). AD diagnoses were ascertained using ICD-10 codes from linked electronic health records and analyzed in a cohort design using multivariable Cox proportional hazards models. A cross-sectional analysis method of cognitive and brain outcomes was performed using multivariable generalized linear models. Over an average follow-up period of 14.1 ± 1.7 y, OP was associated with a 30.7% increased risk of AD (hazard ratio [HR] = 1.307, 95% confidence interval [CI]: 1.165 to 1.466, <i>P</i> < 0.001). Individuals with OP also demonstrated poorer cognitive functions and reduced gray matter volumes in the left parahippocampal gyrus (<i>P</i>_adj = 0.014, β = -27.383, SE = 7.728). Among those whose oral pain resolved, the occurrence of AD was lower (HR = 0.360, 95% CI: 0.197 to 0.660, <i>P</i> = 0.011), along with improved cognitive functions and brain structures as compared with those with persistent OP. Proteomic analyses identified potential mediators, including GDF15, BCAN, and PLAUR, which are involved in pathways related to wound healing and immune regulation. Emerging evidence suggested a possible association between OP and AD through neuroimmune pathways, including potential Tau-related changes in the hippocampus. These findings suggested a potential association between maintaining oral health and reduced risk of AD and cognitive impairment. This study addresses a critical gap in understanding how OP may associate with the development of AD.