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 (n = 33,697; defined as self-reported toothache or painful gums via touchscreen questionnaire) and an oral pain-free group (n = 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, P < 0.001). Individuals with OP also demonstrated poorer cognitive functions and reduced gray matter volumes in the left parahippocampal gyrus (Padj = 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, P = 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.
AmievaHMeillonCProust-LimaCDartiguesJF. 2019. Is low psychomotor speed a marker of brain vulnerability in late life? Digit symbol substitution test in the prediction of Alzheimer, Parkinson, stroke, disability, and depression. Dement Geriatr Cogn Disord. 47(4–6):297–305. https://doi.org/10.1159/000500597
2.
AvellanNL, et al. 2005. Painful tooth stimulation elevates matrix metalloproteinase-8 levels locally in human gingival crevicular fluid. J Dent Res. 84(4):335–339. https://doi.org/10.1177/154405910508400408
3.
CasanovaR, et al. 2024. Associations of plasma proteomics and age-related outcomes with brain age in a diverse cohort. Geroscience. 46(4):3861–3873. https://doi.org/10.1007/s11357-024-01112-4
4.
CetinsoyO, et al. 2024. Gene association study of the urokinase plasminogen activator and its receptor gene in Alzheimer’s disease. J Alzheimers Dis. 99(1):241–250. https://doi.org/10.3233/jad-231383
5.
ChungJW, et al. 2004. Chronic orofacial pain among korean elders: prevalence, and impact using the graded chronic pain scale. Pain. 112(1–2):164–170. https://doi.org/10.1016/j.pain.2004.08.014
6.
ColluRGiuntiEDaleySChenMXiaW.2023. Angiotensin-converting enzyme inhibitors and statins therapies-induced changes in omics profiles in humans and transgenic tau mice. Biomed Pharmacother. 168:115756. https://doi.org/10.1016/j.biopha.2023.115756
7.
ConteM, et al. 2021. Disease-specific plasma levels of mitokines FGF21, GDF15, and humanin in type II diabetes and Alzheimer’s disease in comparison with healthy aging. Geroscience. 43(2):985–1001. https://doi.org/10.1007/s11357-020-00287-w
8.
CuiS-SJiangQ-WChenS-D.2023. Sex difference in biological change and mechanism of Alzheimer’s disease: from macro- to micro-landscape. Ageing Res Rev. 87:101918. https://doi.org/10.1016/j.arr.2023.101918
9.
DalyB, et al. 2017. Evidence summary: the relationship between oral health and dementia. Br Dent J. 223(11):846–853. https://doi.org/10.1038/sj.bdj.2017.992
10.
DelwelS, et al. 2019. Orofacial pain and its potential oral causes in older people with mild cognitive impairment or dementia. J Oral Rehabil. 46(1):23–32. https://doi.org/10.1111/joor.12724
DibelloV, et al. 2023. Oral frailty indicators to target major adverse health-related outcomes in older age: a systematic review. Geroscience. 45(2):663–706. https://doi.org/10.1007/s11357-022-00663-8
ElovainioM, et al. 2023. Association of social isolation and loneliness with risk of incident hospital-treated infections: an analysis of data from the UK Biobank and Finnish Health and Social Support studies. Lancet Public Health. 8(2):e109–e118. https://doi.org/10.1016/s2468-2667(22)00253-5
15.
GregsonJ, et al. 2019. Nonproportional hazards for time-to-event outcomes in clinical trials: JACC review topic of the week. J Am Coll Cardiol. 74(16):2102–2112. https://doi.org/10.1016/j.jacc.2019.08.1034
16.
GuerreiroSR, et al. 2022. Chronic pain causes tau-mediated hippocampal pathology and memory deficits. Mol Psychiatry. 27(11):4385–4393. https://doi.org/10.1038/s41380-022-01707-3
HajishengallisG.2022. Interconnection of periodontal disease and comorbidities: evidence, mechanisms, and implications. Periodontol2000. 89(1):9–18. https://doi.org/10.1111/prd.12430
19.
HajishengallisGChavakisT.2021. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol. 21(7):426–440. https://doi.org/10.1038/s41577-020-00488-6
20.
HeL, et al. 2022. Prospective associations of plasma growth differentiation factor 15 with physical performance and cognitive functions in older adults. J Gerontol A Biol Sci Med Sci. 77(12):2420–2428. https://doi.org/10.1093/gerona/glac020
21.
HigginsDMMartinAMBakerDGVasterlingJJRisbroughV.2018. The relationship between chronic pain and neurocognitive function: a systematic review. Clin J Pain. 34(3):262–275. https://doi.org/10.1097/ajp.0000000000000536
LarvinH, et al. 2023. The impact of study factors in the association of periodontal disease and cognitive disorders: systematic review and meta-analysis. Age Ageing. 52(2):afad015. https://doi.org/10.1093/ageing/afad015
25.
LinC-S, et al. 2024. An umbrella review on the association between factors of oral health and cognitive dysfunction. Ageing Res Rev. 93:102128. https://doi.org/10.1016/j.arr.2023.102128
26.
LobbezooFParisiusKGHVerhoeffMC. 2024. Orofacial pain and dysfunction in patients with special needs, with a focus on interdisciplinarity. Pain. 165(11S):S15–S22. https://doi.org/10.1097/j.pain.0000000000003302
MacedoAC, et al. 2024. Prevalence of orofacial pain in individuals with mild cognitive impairment or dementia: a systematic review and meta-analysis. Gerodontology. 41(3):335–345. https://doi.org/10.1111/ger.12740
29.
MilletALedoJHTavazoieSF.2024. An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains. Immunity. 57(1):153–170.e6. https://doi.org/10.1016/j.immuni.2023.12.001
30.
SadlonA, et al. 2024. Association of chronic pain with biomarkers of neurodegeneration, microglial activation, and inflammation in cerebrospinal fluid and impaired cognitive function. Ann Neurol. 95(1):195–206. https://doi.org/10.1002/ana.26804
31.
ShunginD, et al. 2019. Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data. Nat Commun. 10(1):2773. https://doi.org/10.1038/s41467-019-10630-1
SuthanaNA, et al. 2015. High-resolution 7T fMRI of human hippocampal subfields during associative learning. J Cogn Neurosci. 27(6):1194–1206. https://doi.org/10.1162/jocn_a_00772
van de RijtLJFeastARVickerstaffVLobbezooFSampsonEL. 2020. Prevalence and associations of orofacial pain and oral health factors in nursing home residents with and without dementia. Age Ageing. 49(3):418–424. https://doi.org/10.1093/ageing/afz169
36.
WalkerRM, et al. 2024. The circulating proteome and brain health: Mendelian randomisation and cross-sectional analyses. Transl Psychiatry. 14(1):204. https://doi.org/10.1038/s41398-024-02915-x
37.
WangD, et al. 2024. Association between periodontal diseases and chronic obstructive pulmonary disease: evidence from sequential cross-sectional and prospective cohort studies based on uk biobank. J Clin Periodontol. 51(1):97–107. https://doi.org/10.1111/jcpe.13890
38.
WuB, et al. 2023. Diabetes, edentulism, and cognitive decline: a 12-year prospective analysis. J Dent Res. 102(8):879–886. https://doi.org/10.1177/00220345231155825
39.
YassaMA, et al. 2010. High-resolution structural and functional MRI of hippocampal CA3 and dentate gyrus in patients with amnestic mild cognitive impairment. Neuroimage. 51(3):1242–1252. https://doi.org/10.1016/j.neuroimage.2010.03.040
40.
YoshijiS, et al. 2023. Proteome-wide Mendelian randomization implicates nephronectin as an actionable mediator of the effect of obesity on COVID-19 severity. Nat Metabol. 5(2):248–264. https://doi.org/10.1038/s42255-023-00742-w
41.
ZhangY, et al. 2023. Identifying modifiable factors and their joint effect on dementia risk in the UK Biobank. Nat Hum Behav. 7(7):1185–1195. https://doi.org/10.1038/s41562-023-01585-x
42.
ZhangY-B, et al. 2021. Associations of healthy lifestyle and socioeconomic status with mortality and incident cardiovascular disease: two prospective cohort studies. BMJ. 373:n604. https://doi.org/10.1136/bmj.n604
43.
ZhaoWZhaoLChangXLuXTuY.2023. Elevated dementia risk, cognitive decline, and hippocampal atrophy in multisite chronic pain. Proc Natl Acad Sci U S A. 120(9):e2215192120. https://doi.org/10.1073/pnas.2215192120
