Restricted accessResearch articleFirst published online 2026-4
Periodontitis associated with multi-region brain functional alterations and cognitive impairment: A cross-sectional study in normal cognition,amnestic mild cognitive impairment,and Alzheimer's disease
Growing evidence links periodontitis to Alzheimer's disease (AD), yet the specific links between periodontitis severity gradients and brain functional alterations remain poorly understood.
Objective
To investigate brain functional alterations quantified by functional connectivity density (FCD) and regional homogeneity (ReHo) across periodontitis severity gradients, include microbiota measures as explanatory variables, and assess correlations between these functional alterations and cognitive impairment.
Methods
Clinical periodontal data, subgingival plaque, cognitive tests, and brain MRI data were collected from all 89 participants, including community-recruited normal cognition (NC) and patients with amnestic mild cognitive impairment (aMCI) and AD from a hospital neurology department. According to periodontal examination, participants were categorized into mild, moderate, and severe groups. FCD and ReHo were compared among different periodontal condition groups and subgroups. Correlation analyses were conducted to explore the relationship among FCD, ReHo, periodontal indices, and cognition.
Results
With increasing severity of periodontitis, the FCD of bilateral middle frontal gyrus (MFG.R, MFG.L), right inferior frontal gyrus, triangular part (IFGtriang.R), and the ReHo of IFGtriang.R all decreased. These regions are commonly associated with executive control, working memory, and attention. These changes were more strongly correlated with overall periodontal inflammatory burden and cognitive performance than to the abundance of specific taxa in the subgingival plaque microbiota.
Conclusions
Periodontitis severity is associated with reduced prefrontal FCD/ReHo and cognitive decline, and these associations appear to be more strongly driven by overall periodontal inflammatory burden than by specific subgingival taxa.
KassebaumNJBernabéEDahiyaM, et al.Global burden of severe tooth loss. J Dent Res2014; 93: 20S–28S.
3.
CekiciAKantarciAHasturkH, et al.Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontol 20002014; 64: 57–80.
4.
DengDMten CateJM. Demineralization of dentin by Streptococcus mutans biofilms grown in the constant depth film fermentor. Caries Res2004; 38: 54–61.
5.
XuHQianYJiaS, et al.Comparative analysis of subgingival microbiota in patients with mild, moderate, and severe chronic periodontitis. Oral Dis2023; 29: 2865–2877.
6.
GencoRJSanzM. Clinical and public health implications of periodontal and systemic diseases: an overview. Periodontol 20002020; 83: 7–13.
7.
SteinPDesrosiers MarkFDoneganS, et al.Tooth loss, dementia and neuropathology in the Nun Study. J Am Dent Assoc2007; 138: 1314–1382.
8.
HajishengallisGChavakisT. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol2021; 21: 426–440.
9.
PotempaJMydelPKozielJ. The case for periodontitis in the pathogenesis of rheumatoid arthritis. Nat Rev Rheumatol2017; 13: 606–620.
10.
SanzMDel CastilloAMJepsenS, et al.Periodontitis and cardiovascular diseases: consensus report. J Clin Periodontal2020; 47: 268–288.
11.
Albuquerque-SouzaESahingurSE. Periodontitis, chronic liver diseases, and the emerging oral-gut-liver axis. Periodontol 20002022; 89: 125–141.
12.
SanzMCerielloABuysschaertM, et al.Scientific evidence on the links between periodontal diseases and diabetes: consensus report and guidelines of the joint workshop on periodontal diseases and diabetes by the International Diabetes Federation and the European Federation of Periodontology. J Clin Periodontol2018; 45: 138–149.
13.
PlassmanBLLangaKMFisherGG, et al.Prevalence of dementia in the United States: the Aging, Demographics, and Memory Study. Neuroepidemiology2007; 29: 125–132.
14.
NicholsEVosT. The estimation of the global prevalence of dementia from 1990-2019 and forecasted prevalence through 2050: an analysis for the Global Burden of Disease (GBD) study 2019. Alzheimers Dement2021; 17: e051496.
15.
PetersenRCSmithGEWaringSC, et al.Mild cognitive impairment. Arch Neurol1999; 36: 303–308.
16.
AsherSStephenRMäntyläP, et al.Periodontal health, cognitive decline, and dementia: a systematic review and meta-analysis of longitudinal studies. J Am Geriatr Soc2022; 70: 2695–2709.
17.
ChenC-KWuY-TChangY-C. Association between chronic periodontitis and the risk of Alzheimer’s disease: a retrospective, population-based, matched-cohort study. Alzheimers Res Ther2017; 9: 56.
18.
DominySSLynchCErminiF, et al.Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv2019; 5: eaau3333.
19.
BeydounMABeydounHAHossainS, et al.Clinical and bacterial markers of periodontitis and their association with incident all-cause and Alzheimer’s disease dementia in a large national survey. J Alzheimers Dis2020; 75: 157–172.
20.
BelskyDWCaspiAHoutsR, et al.Quantification of biological aging in young adults. Proc Natl Acad Sci U S A2015; 112: E4104–E4110.
21.
WangWTaoYZhuW, et al.Periodontitis and subgingival plaque microbiota associated with brain grey matter volume and cognitive impairment. J Clin Periodontol2025; 52: 1327–1337.
22.
AbbayyaKChidambarYNaduwinmaniS, et al.Association between periodontitis and Alzheimer’s disease. N Am J Med Sci2015; 7: 241.
23.
ZhengDKangXWangY, et al.Periodontal disease and emotional disorders: a meta-analysis. J Clin Periodontol2021; 48: 180–204.
24.
Sansores-EspañaLDMelgar-RodríguezSOlivares-SagredoK, et al.Oral-gut-brain axis in experimental models of periodontitis: associating gut dysbiosis with neurodegenerative diseases. Front Aging2021; 2: 781582.
25.
ZangYJiangTLuY, et al.Regional homogeneity approach to fMRI data analysis. NeuroImage2004; 22: 394–400.
26.
TomasiDVolkowND. Functional connectivity density mapping. Proc Natl Acad Sci U S A2010; 107: 9885–9890.
27.
von ElmEAltmanDGEggerM, et al.The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med2007; 4: e296.
28.
McKhannGDrachmanDFolsteinM, et al.Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology1984; 34: 939–944.
29.
McKhannGMKnopmanDSChertkowH, et al.The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement2011; 7: 263–269.
30.
AlbertMSDeKoskySTDicksonD, et al.The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement2011; 7: 270–279.
LiXTaoYLiH, et al.Periodontitis is associated with altered brain structure and function in normal cognition middle-aged and elderly individuals. J Periodontal Res2024; 59: 299–310.
33.
TonettiMSGreenwellHKornmanKS. Staging and grading of periodontitis: framework and proposal of a new classification and case definition. J Periodontol2018; 89: S159–S172.
34.
ChappleILCMealeyBLVan DykeTE, et al.Periodontal health and gingival diseases and conditions on an intact and a reduced periodontium: consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Periodontol2018; 89: S74–S84.
35.
EklundANicholsTEKnutssonH. Cluster failure: why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci U S A2016; 113: 7900–7905.
36.
SmithSNicholsT. Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage2009; 44: 83–98.
37.
ShiJHuangHJiangR, et al.The right inferior frontal gyrus plays an important role in unconscious information processing: activation likelihood estimation analysis based on functional magnetic resonance imaging. Front Neurosci2022; 16: 781099.
38.
BoenRRaudLHusterRJ. Inhibitory control and the structural parcelation of the right inferior frontal gyrus. Front Hum Neurosci2022; 16: 787079.
39.
HartwigsenGNeefNECamilleriJA, et al.Functional segregation of the right inferior frontal gyrus: evidence from coactivation-based parcellation. Cereb Cortex2019; 29: 1532–1546.
40.
ChenYDuCDangM, et al.Divergent brain regional atrophy and associated fiber disruption in amnestic and non-amnestic MCI. Alzheimers Res Ther2023; 15: 199.
41.
XueJGuoHGaoY, et al.Altered directed functional connectivity of the hippocampus in mild cognitive impairment and Alzheimer’s disease: a resting-state fMRI study. Front Aging Neurosci2019; 11: 326.
42.
BarbeyAKKoenigsMGrafmanJ. Dorsolateral prefrontal contributions to human working memory. Cortex2013; 49: 1195–1205.
43.
SmucnyJDienelSJLewisDA, et al.Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia. Neuropsychopharmacology2022; 47: 292–308.
44.
LiuLWangTDuX, et al.Concurrent structural and functional patterns in patients with amnestic mild cognitive impairment. Front Aging Neurosci2022; 14: 838161.
45.
ShiCDengHDengX, et al.The structural changes of frontal subregions and their correlations with cognitive impairment in patients with Alzheimer’s disease. J Integr Neurosci2023; 22: 99.
46.
Penalba-SánchezLOliveira-SilvaPSumichAL, et al.Increased functional connectivity patterns in mild Alzheimer’s disease: a rsfMRI study. Front Aging Neurosci2023; 14: 1037347.
47.
ZhangQWangQHeC, et al.Altered regional cerebral blood flow and brain function across the Alzheimer’s disease spectrum: a potential biomarker. Front Aging Neurosci2021; 13: 630382.
48.
WeiCGongSZouQ, et al.A comparative study of structural and metabolic brain networks in patients with mild cognitive impairment. Front Aging Neurosci2021; 13: 774607.
49.
GogollaN. The insular cortex. Curr Biol2017; 27: R580–R586.
50.
HsiehJBelfrageMStone-ElanderS, et al.Central representation of chronic ongoing neuropathic pain studied by positron emission tomography. Pain1995; 63: 225–236.
51.
LabrakakisC. The role of the insular cortex in pain. Int J Mol Sci2023; 24: 5736.
52.
WuZNiJLiuY, et al.Cathepsin B plays a critical role in inducing Alzheimer’s disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice. Brain Behav Immun2017; 65: 350–361.
53.
PooleSSinghraoSKKesavaluL, et al.Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis2013; 36: 665–677.
54.
ubinsteinTBrickmanAMChengB, et al.Periodontitis and brain magnetic resonance imaging markers of Alzheimer’s disease and cognitive aging. Alzheimers Dement2024; 20: 2191–2208.
