Table 2.
Characteristics of the included studies
| Study | Study design | Aim | Population | Gender, M (%) | Age, mean (SD)-yrs | Outcomes | MINORS score | Follow-up (years) |
|---|---|---|---|---|---|---|---|---|
| Role of oral pathogens | ||||||||
| Panzarella et al. 2020(39) | Cross-sectional | To evaluate the oral health status and its relationship with cognitive impairment of participants, enrolled in the Zabut Aging Project, a community-based cohort study performed in rural community in Sicily, Italy. | 60 (20 AD, 20 MCI and 20 controls) | AD 12 (60) | AD 83.5 (7.7) | The decayed, missing, and filled teeth (DMFT) total score of AD subjects was significantly higher than for a MCI and controls. Furthermore, the «M» component of DMFT (i.e., the number of missing teeth) was significantly higher in AD than in a MCI and controls. A Poisson regression model revealed that age, male gender, and AD were positively correlated with DMFT. Concerning oral microbial load, the presence of Fusobacterium nucleatum was significantly higher in AD than in controls, and a higher load of Treponema denticola was found in aMCI than with AD. OHR-QoL scores did not differ among the groups. | 20 | 10 |
| Leblhuber et al. 2019(34) | Cross-sectional | To find a link exist between oral pathogens and Alzheimer’s disease. | 20 AD | 11 (55) | 78.1(2.2) | The presence of Porphyromonas gingivalis was found to be associated with lower mini mental state examination scores and with a tendency to lower scores in the clock drawing test. Furthermore, association between lower serum concentrations of the immune biomarker neopterin and the presence of Treponema denticola as well as of kynurenine were found in Alzheimer patients positive vs. negative for Tannerella forsytia. Six of the patients positive for periodontal pathogens were ApoE4 (apolipoprotein E4) allele carriers, two of them homozygous. | 5 | NA |
| Stein et al. 2012(41) | Prospective | To examine serum antibody levels to bacteria of periodontal disease in participants who eventually converted to AD compared with the antibody levels in control subjects. | 158 (35 AD, 46 MCI and 77 controls) | 9 (26%) | 74.1 (7.5) | Antibody levels to F nucleatum and P. intermedia were significantly increased (a<0.05) serum draw in the patients with AD compared with controls. These results remained significant when controlling for baseline age, Mini-Mental State Examination score, and apolipoprotein epsilon 4 status. | 20 | 11,7 |
| Riviere et al. 2002(33) | Prospective | The purpose of this investigation was to use molecular and immunological techniques to determine whether oral Treponema infected the human brain. | 34 (16 AD and 18 controls) | NA | NA | CR detected Treponema in 14/16 Alzheimer’s disease (AD) and 4/18 non-AD donors, and AD specimens had more Treponema species than controls. PCR also detected Treponema in trigeminal ganglia from three AD and two control donors. Cortex from 15/16 AD subjects and 6/18 controls contained Treponema pectinovorum and /or Treponema socranskii species-specific antigens. T. pectinovorum and /or T. socranskii antigens were also found in trigeminal ganglia and pons from four embalmed cadavers, and 2/4 cadavers also had Treponema in the hippocampus. | 14 | NA |
| Wu et al. 2021(38) | Prospective | To evaluate sequence to determine the relative abundance and diversity of bacterial taxa in the dental plaque of elderly patients with AD and controls. | 35 (17 AD and 18 controls) | 6(35) | 77.9 (10.5) | Significantly increased numbers of Lactobacillales, Streptococcaceae, and Firmicutes/ Bacteroidetes and a significantly decreased number of Fusobacterium were observed in patients with AD. | 16 | NA |
| Holmer et al. 2021(40) | Cross-sectional | To compare the subgingival microbiota of people with AD, MCI, subjective cognitive decline (SCD) and cognitively healthy individuals. | 132 (46 AD, 40 MCI, 46 subjective cognitive decline (SCD), and 63 controls) | 23 (50) | 71 (11) | Two Operational Taxonomic Units were particularly abundant in AD compared to controls: Slackia exigua, which was also associated with deep periodontal pockets, and a Lachnospiraceae [G-7] bacterium. | 18 | NA |
| Laugisch et al. 2018(37) | Cross-sectional | Verification of the presence of periodontal pathogens and the intrathecal generation of pathogen-specific antibodies in 20 patients with AD and 20 with other forms of dementia (DEM-noAD). | 40 (20 AD and 20 other forms of dementia(DEM-noAD)) | 9 (45) | 58.3 (5.3) | In line with diagnoses, CSF-levels of A1-42 were significantly lower in AD than DEM-noAD patients. Periodontal destruction and inflammation were omnipresent with no difference between groups. P. gingivalis, T. forsythia, and Treponema species were detected in more than 50% of subgingival biofilm samples, but neither in serum nor in the CSF. Elevated levels of anti-pathogen antibodies in CSF of 16 patients (7 AD; 9 DEM-noAD) compared to serum highlight a possibility of the intrathecal immune response to pathogens. There was no significant difference in antibodies levels against selected bacteria in CSF and serum between groups. Multivariate regression analysis and general linear models revealed an association of the T-tau level in AD group with both serum levels of anti-P. gingivalis antibodies and MCP-1/CCL-2. | 18 | NA |
| Noble et al. 2014(35) | Prospective | To study serum IgG to periodontal microbiota as possible predictors of incident AD. | 219 (110 AD and 109 controls) | 35 (31.8) | 78.9 (7.2) | In a model adjusting for age, sex, education, diabetes mellitus, hypertension, smoking, prior history of stroke, and apolipoprotein E genotype, high anti-A.- naeslundii titer (0.640 ng/ml, present in 10% of subjects) was associated with increased risk of AD (HR52.0, 95%CI: 1.1–3.8). This association was stronger after adjusting for other significant titers (HR53.1, 95%CI: 1.5–6.4). In this model, high anti-E. nodatum IgG (.1755 ng/ ml; 19% of subjects) was associated with lower risk of AD (HR50.5, 95%CI: 0.2–0.9). | 22 | 5 |
| Role of inflammatory mediators | ||||||||
| Cestari et al. 2016(49) | Prospective | To investigate the prevalence of oral infections and serum levels of IL-6 and TNF-a in patients with AD, MCI, and non-demented elderly. | 65 (25 AD, 19 MCI and 21 controls) | 10 (40%) | 63–92 years | Patients with AD had high serum IL-6 levels, and patients with periodontitis had high serum TNF-a levels. There was an association between IL-6 and TNF-a in patients with AD/MCI and periodontitis. | 16 | NA |
| Farhad et al. 2014(46) | Prospective | To evaluate the effect of chronic periodontitis on serum levels of tumor necrosis factor-α in Alzheimer disease. | 80 AD (40 chronic periodontitis and 40 controls) | NA | 40 and 70 years | It showed that the mean of tumor necrosis factor-α in patients with Alzheimer and periodontitis was approximately three folds higher than the patients only with Alzheimer, and this difference was statistically significant. | 20 | NA |
| Ide et al. 2016(42) | Prospective | To determine if periodontitis in Alzheimer’s disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. | 59 (22 AD with periodontitis and 37 AD without periodontitis) | 13 (59%) | 74.9 (2.0) | The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. | 20 | 0,5 |
| Gil-Montoya et al. 2020(48) | Prospective | To examine the impact of inflammation on the relationship between periodontitis and cognitive impairment. | 309 (156 AD, 22 MCI and 131 controls) | 59 (33) | 77.1 (7.8) | At the time of sampling, 11 of the 29 inflammatory biomarkers were associated with cognitive impairment in patients with more severe periodontitis. However, the inflammatory response to severe periodontitis was more reduced (lower biomarker concentrations) in cases (with cognitive impairment or dementia) than in (cognitively healthy) controls, an unexpected finding. | 18 | NA |
| Kamer et al. 2009(47) | Prospective | To hypothesize that AD patients would have both an elevated cytokine expression and positive antibodies to P. gingivalis, T. forsythia and A. actinomycetem-comitans, and that these measures would contribute to clinical separation of AD from cognitively normal subjects. | 34 (18 AD and 16 controls) | 4 (22) | 40-80+ years | Plasma TNF-a and antibodies against periodontal bacteria werl?e elevated in AD patients compared with controls and independently associated with AD. The number(47) of positive IgG to periodontal bacteria incremented the TNF-a classification of clinical AD and controls. | 18 | NA |
| Role of APOE-4 allels | ||||||||
| Popovac et al. 2020(52) | Prospective | To examine the impact of dental status and different APOE gene variants on AD occurrence. Secondly, socio demo graphic variables were investigated as factors potentially associated with AD. | 179 (116 AD and 27 controls) | 39 (33.6) | 65–85+ years | Number of total FTU and presence of APOE4 allele remained significant as independent risk factors for AD even when adjusted for age, sex, and level of education. | 16 | NA |
| Popovac et al. 2016(53) | Cross-sectional | To determine the frequency of APOE alleles and their association with the dental status in elderly demented patients. | 67 AD | 19 (28.4) | 65 or older | DNA was isolated from buccal swabs and genotyping was done by PCR-RFLP. The majority of participants had E3/E4 genotype (55.2%) and these heterozygotes were significantly more frequent than any other genotype (p<0.001). | 8 | NA |
| Role of Amyloid B peptide | ||||||||
| Kubota et al. 2014(54) | Prospective | To analyse the expression levels of ABP, IL-lb, and C1QA and determined the localisation of ABP in gingival tissues. | 28 (14 periodontitis patients and 14 controls) | 7 (50%) | 58.0 (16.0) | ABP, IL-lb, and C1QA mRNA levels were significantly up regulated in periodontitis affected gingival tissues. ABP was mainly localized in macrophages in gingival connective tissues underneath the epithelial layers. | 15 | NA |
| Gil-Montoya et al. 2017(55) | Prospective | To determine whether periodontitis is related to the amyloid b (Ab) load in blood and the role of any such relationship in the association between ABP and cognitive impairment. | 288 (166 cognitive impairment with or without AD and 122 controls) | 57 (34.3) | 77.3 (7.8) | Higher blood Ab1–42 levels (P = 0.01) and higher Ab42:40 ratio (P = 0.06) were observed in participants with severe attachment loss than in other participants. Periodontitis was a significant interaction variable, given that the association between Ab1–42 and Ab1–40 and cognitive impairment was only observed in patients with severe periodontitis. According to these data, periodontitis may be a modulating variable of the association between ABP and cognitive impairment. | 16 | NA |