Whereas, periodontitis is a common oral infection associated with the gram negative anaerobic bacteria. Periodontitis can be marked as a “low-grade systemic disease” by release of proinflammatory cytokines into systemic circulation and elevation of C-reactive protein (CRP) Inflammation is known to play a pivotal role in both the disease process serving as a connecting link between periodontitis and AD.

2. Periodontitis and Alzheimer’s disease
Assistant lecture of Oral Medicine, Periodontology, Diagnosis and Dental
Radiology (Al-Azhar University)

3. Content:
Introduction
Pathogenesis of AD
Mechanisms involved in spread of
inflammation to brain
Microbiota in AD
Periodontal Disease: As a low-grade
systemic disease
AD and periodontitis — A correlation

4. Alzheimer’s disease (AD) is a neurodegenerative disease
which significantly increases with age. Its onset can be either
early or late.
AD is characterized by the salient
inflammatory features, microglial
activation, and increased levels of
proinflammatory cytokines which contribute
to the inflammatory status of the central
nervous system (CNS).

5. It appears more frequently in people over 65 years of age,
though there is an affected group of younger age and
is more prevalent in women than in men
According to the Worlds Alzheimer’s Report of 2018,
there are 50 million people in the world living with
dementia, of which two-thirds are affected by AD .
As life expectancy increases, it is estimated that the
incidence of AD increases to 152 million people
by 2050, becoming a major health problem

7. Early onset AD is believed to be extremely
determined by genetic factors, while late or sporadic
onset, which includes 95% of patients, resulting from the
interaction of risk and environmental factors

8. Age is a major risk factor for AD.
Other risk factors for late onset AD include family history,
education, high fat diet, hypertension, diabetes, history of
head trauma, and susceptibility genes such as
apolipoprotein E (APOE).

9. Among all these risk factors; age, family history, and
APOE 4 allele are considered to be accepted risk factors.
Periodontitis is also considered to be one of the
probable risk factors for AD

10. Periodontitis is a chronic inflammation of the tissue
surrounding the teeth which is due to complex bacterial
interaction, resulting in breakdown and loss of
supporting structures around the teeth.

12. Whereas, periodontitis is a common oral infection
associated with the gram negative anaerobic bacteria.
Periodontitis can be marked as a “low-grade systemic
disease” by release of proinflammatory cytokines into
systemic circulation and elevation of C-reactive protein (CRP)
Inflammation is known to play a pivotal role in both
the disease process serving as a connecting link
between periodontitis and AD.

15. : Common pathophysiological pathways between AD and periodontitis.
The increase in inflammatory activity is the point of confluence between AD and
periodontitis. As a result of the activity of periodontopathogens on the one hand and
microglial activation on the other, an increase in the levels of the main proinflammatory
molecules and their metabolites is produced, when this state is maintained in the long
term it generates tissue destruction

16. Neuroinflammatory hypotesis in the establishment of AD. When the
inflammatory state is persistent, microglia and astrocytes modify their
phenotype to reactive cells, increasing the secretion of pro-inflammatory
cytokines and generating a metabolic, energetic and oxidative imbalance in
the neuron that will respond by increasing the production of Aβ and the
hyperphosphorylation of the microtubule-associated protein, Tau, events
that generate neuro and synaptotoxicity

18. Pathogenesis of AD

19. These pathologic changes in turn are
likely to stimulate microglial cells.
These microglial cells are protective in
nature at low levels (concentration).
AD is characterized by the formation of extracellular amyloid
β-peptide (AβP) plaques and intraneuronal neurofi brillary
tangles (NFTs) of hyperphosphorylated tau protein, leading to
gradual loss of neuronal synapses and ultimately neuronal
degeneration with diminution of essential neurotransmitters

20. The APP C-terminal fragment is then processed by γ-secretase to
release an intracellular domain (AICD) and the P3 fragment.
Amyloidogenic pathway: β-secretase processes APP to generate the
soluble fragment, sAPP-β, then cleaved γ-secretase Aβ peptides
(AβPs), and the AICD.
| Diagram of the non-
amyloidogenic and the
amyloidogenic
proteolytic pathway for
the amyloid precursor
protein (APP). Non-
amyloidogenic
pathway: α-secretase
cleaves the
transmembrane protein
APP to release the
soluble APP fragment,
sAPPα.

21. The induced microglial cells now referred to as “activated
microglial cells” alters its morphology and secrete cell
antigens, which in turn results in uncontrolled expression of
proinfl ammatory factors.
This uncontrolled expression of factor levels as in AD can
induce neurodegeneration, suggesting that the
expression of inflammatory molecules will
contribute to the progression of the AD

22. The function of microglial cell is like a
“double-edged sword” being either
damaging or protective depending on
the situation.
Stimulated/activated microglial cells
produce proinflammatory cytokines
such as tumor necrosis factor (TNF)-α,
interleukin (IL)-1β, IL-6, and C-reactive
protein (CRP).
These elevated
proinflammatory cytokines
and CRP might then act via
paracrine and/or autocrine
pathways to stimulate glial
cells to further produce
additional Aβ42, P-Tau, and
proinflammatory molecules

23. Senile plaques are associated with reactive astrocytes
and activated microglial cells which react with antibodies against TNF-
α, IL-1β, IL-6, CRP, and complement proteins.
TNF-α, IL-1β, and IL-6 are capable of
stimulating the synthesis of Aβ42 and
the phosphorylation of tau protein, and
Aβ42 and P-Tau can in turn stimulate
the production of TNF-α, IL-1α, and IL-6
by glial cells.

26. Other mechanism include the presence of
receptors for CD14 present in the brain which can get
activated by LPS derived from invasive bacteria or AD AβP,
which in turn will activate CD14 cells.
These CD14 cells are exposed to
systemic circulation such as
leptomeninges, circumventricular areas,
and choroid plexus; thus increasing further brain
cytokines and hypothetically contributing to the
infl ammatory burden of AD

32. Periodontitis which is primarily a result of plaque
exists in the form of biofilm and consists of
numerous microorganisms.
Characteristic features of periodontitis
include, bleeding and purulent discharge from
the gums, progressive deepening of gingival sulcus
(referred as pocket formation), oral halitosis, spacing
between the teeth, and mobility of teeth in advanced
stages.

33. The predominant periodontal pathogens involved in periodontitis
are Aggregatibacter actinomycetemcomitans (Aa),
Porphyromonas gingivalis (Pg), Prevotella intermedia
(Pi), Fusobacterium nucleatum (Fn), Tannerella
forsythensis (Tf), Eikenella corrodens (Ec), and Treponema
denticola (Td).[

35. The host response also plays a vital role in inducing systemic
effects by producing a multitude of inflammatory mediators
including cytokines (against the periodontal microbiota) that gain access to the
systemic circulation.

38. Inflammation is known to play a pivotal role in this
process. It is proposed that periodontitis can lead to progression
of AD by two probable mechanisms

40. Cytokines which are released (especially TNF-α)
during inflammation play a major role in
neurodegenerative disease.
TNF-α exaggerates the inflammatory process
resulting in gliosis, demyelination, BBB deterioration,
and cell death. Thus, TNF-α plays a very important role
in the neurodegenerative process.

41. Studies conducted on mice models have revealed
salutary effects of anti-inflammatory agents in the
amelioration of neuroinfl ammation and amyloid
plaque deposition.

43. FIGURE 2 | Scheme of the proposed mechanism linking periodontitis to
Alzheimer’s disease: (1) Oral dysbiosis of the dental plaque leads to proliferation,
tissue invasion, and then dissemination into the bloodstream of oral pathogens. (2)
Next, the oral pathogens and their toxic molecules, such as lipopolysaccharide (LPS),
bind to microglia via Toll-like receptors 2/4 (TLR2/4), inducing the release of
cytokines (3) and inflammatory mediators that, in turn, lead to APP processing from
neuronal cells. (3–4) Subsequently, the activation of β- and γ-secretase leads to an
increased secretion of Aβ peptides (AβPs), in particular Aβ42 monomers and sAPPβ,
outside of the cells and AICD intracellularly. (
4) AβPs form oligomers, protofibrils, or fibrils and then amyloid
plaques that are recognized by TREM2 receptors on the microglia
plasma membrane, thus triggering an inflammatory response, which
again stimulates AβP production. Dysfunctional neurons present
also increased tau phosphorylation (p-tau) with the formation of
neurofibrillary tangles (p-tau tangles). All these processes induce
neuronal degeneration.

44. Fig 1. Mendelian randomization (MR)
estimates for the risk of Alzheimer’s disease
associated with periodontitis.
(A) Using instrumental SNPs from Munz et
al. for periodontitis. (B) Using instrumental
SNPs from Shungin et al. for periodontitis.
MR estimates were calculated using the
inverse-variance weighted (IVW) method to
summarize the effect from each individual
single-nucleotide polymorphism (SNP) in a
random effects model. Odds ratio (OR)
represents the risk of Alzheimer’s disease
per genetically determined 1-unit increase
in ln (OR) of periodontitis. 95% CI: 95%
confidence interval of the odds ratio. AD:
Alzheimer’s disease; IV: instrumental
variable.