Inflammation and Alzheimer’s disease: Possible role
of periodontal diseases
Angela R. Kamera,*, Ronald G. Craiga,b, Ananda P. Dasanayakec, Miroslaw Brysd,
Lidia Glodzik-Sobanskad, Mony J. de Leond,e
aDepartment of Periodontology and Implant Dentistry, College of Dentistry, New York University, New York, NY, USA
bDepartment of Basic Sciences and Craniofacial Biology, College of Dentistry, New York University, New York, NY, USA
cDepartment of Epidemiology and Health Promotion, College of Dentistry, New York University, New York, NY, USA
dDepartment of Psychiatry, School of Medicine, New York University, New York, NY, USA
eNathan Kline Institute, Orangeburg, NY, USA
The molecular and cellular mechanisms responsible for the etiology and pathogenesis of
Alzheimer’s disease (AD) have not been defined; however, inflammation within the brain is thought
to play a pivotal role. Studies suggest that peripheral infection/inflammation might affect the
inflammatory state of the central nervous system. Chronic periodontitis is a prevalent peripheral
infection that is associated with gram-negative anaerobic bacteria and the elevation of serum
inflammatory markers including C-reactive protein. Recently, chronic periodontitis has been asso-
ciated with several systemic diseases including AD. In this article we review the pathogenesis of
chronic periodontitis and the role of inflammation in AD. In addition, we propose several potential
mechanisms through which chronic periodontitis can possibly contribute to the clinical onset and
progression of AD. Because chronic periodontitis is a treatable infection, it might be a readily
modifiable risk factor for AD.
© 2008 The Alzheimer’s Association. All rights reserved.
Alzheimer’s disease; Inflammation; Periodontitis; Pathogenesis model
Alzheimer’s disease (AD) is one of the leading causes of
dementia afflicting the elderly. In the United States, approx-
imately 4.5 million patients are currently diagnosed with
AD. The prevalence of AD increases with age from 4% in
the 65 to 75 years age group to 19% in the 85 to 89 years
age group, and the incidence of AD increases from
7/1000 in the 65 to 69 years age group to 118/1000 in the
85 to 89 years age group. Undoubtedly, as the population
ages and life span increases, the prevalence of AD will
increase even further and in 50 years is predicted to
include approximately 14 million people. Although the
above statistics underscore AD as a major public health
concern, the prevalence of AD will not significantly de-
crease unless new approaches to treatment emerge that
can delay the onset, slow the progression, or reverse the
disease process. Efforts to identify treatable factors in-
volved in the initiation and progression of AD are there-
fore of paramount importance.
Early onset AD is thought to be genetically deter-
mined, whereas late onset or sporadic AD, which in-
cludes the majority of patients, is believed to result from
the interaction of genetic and environmental factors. Age
is a significant risk factor for AD. Other risk factors for
late onset AD identified to date include family history,
education, high fat diet, hypertension, diabetes, history of
head trauma, and susceptibility genes such as APOE.
Among them, age, family history, and APOE ?4 allele are
accepted risk factors. The others are possible and are still
being investigated. Table 1 presents odds ratios for se-
lected risk factors.
*Corresponding author. Tel.: 212-998-9868; fax: 212-995-4603.
E-mail address: email@example.com
Alzheimer’s & Dementia 4 (2008) 242–250
1552-5260/08/$ – see front matter © 2008 The Alzheimer’s Association. All rights reserved.
Some of the above risk factors for AD are immutable, but
the identification of modifiable risk factors might hold the
potential for intervention, thus limiting the prevalence and
morbidity of AD in the future. Although the molecular
mechanisms involved in the etiology and pathogenesis of
AD have not been completely characterized, inflamma-
tion within the central nervous system (CNS) is thought
to play a pivotal role. Central to the role of inflammation
in AD is the hypothesis that peripheral infection/inflam-
mation might alter the inflammatory state in the brain.
Indeed, preliminary studies have shown that peripheral
infections might hasten the onset and progression of AD
, although the specific mechanisms and pathways in-
volved have not been defined. The intent of this article is
to review the role of inflammation in the pathogenesis of
AD and suggest the contribution of periodontal disease to
the clinical onset and progression of AD.
2. The association of inflammation with AD
2.1. Inflammatory mechanisms in AD
A prominent hypothesis forwarded to explain the patho-
genesis of AD is the inflammatory hypothesis , whose
central theme is a self-perpetuating progressive inflamma-
tion in the brain culminating in neurodegeneration. At
present, no local inciting inflammatory factors for AD are
accepted. It has been suggested that inflammation might be
induced by the pathologic features of AD, including A?-
amyloid 1-42 peptide (A?42) found in senile plaques, hy-
perphosphorylated tau protein (P-Tau) comprising the neu-
rofibrillary tangles, or components of degenerated neurons
. These pathologic changes are believed to stimulate glial
cells to produce proinflammatory cytokines including tumor
necrosis factor (TNF)–?, interleukin (IL)-1?, IL-6, and in-
flammation reactive proteins such as C-reactive protein
(CRP). Elevated proinflammatory cytokines and CRP might
then act via paracrine and/or autocrine pathways to stimu-
late glial cells to further produce additional A?42, P-Tau,
and proinflammatory molecules. Thus, a positively reinforc-
ing cycle is established in which inflammatory mediators
play a dual role by both stimulating glial cells and activating
molecular pathways, leading to neurodegeneration . Sev-
eral lines of evidence support this model. Senile plaques are
associated with reactive astrocytes and activated microglial
cells  and immunoreact with antibodies against TNF-?,
IL-1?, IL-6, CRP, and complement proteins . TNF-?,
IL-1?, and IL-6 are capable of stimulating the synthesis of
A?42 and the phosphorylation of tau protein, and A?42 and
P-Tau can stimulate the production of TNF-?, IL-1?, and
IL-6 by glial cells [2–5].
Clinical studies in support of the role of inflammation in
the pathogenesis of AD, although limited, have investigated
the value of CRP (an acute phase protein whose synthesis is
regulated by proinflammatory cytokines in response to in-
fection/inflammation) and other systemic inflammatory
markers in predicting the onset of AD. Elevated CRP in-
creased the risk of both developing AD  and of cognitive
decline in various populations . A nested case-control
study of 1,050 subjects from the Honolulu-Asia Aging
Study reported that higher levels of CRP increased the risk
of developing AD 25 years later . Proinflammatory cy-
tokines as predictors of AD have also been investigated,
however with conflicting results. For example, elevated
IL-6 moderately increased the risk of AD, even after ad-
justing for age, gender, smoking, body mass index, medi-
cations, and diabetes, and correlated with disease severity
. AD subjects with elevated IL-1? were at increased risk
of cognitive decline compared with those with low IL-1?
, whereas the presence of a composite genotype char-
acterized by the presence of IL-1?-889 and IL-1??3953
polymorphisms conferred an almost 11-fold increased risk
of developing AD , presumably as a result of increased
Risk Factors for AD
Risk factorOdds ratio Source
Family history of AD
ApoE 4 at least 1 allele
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Farrer et al,31997
Clarke et al,41998, Quadri
Fleminger et al,62003 (review)
Hofman et al,71997
Tyas et al,82003
Kivipelto et al,92001
Kivipelto et al,92001
Andersen et al,102005, Speck
Brayne et al,21998
NOTE. Odd ratios for AD risk factors are presented. Family history and
APOE with an e4 allele are accepted risk factors. The other risk factors are
possible and are being investigated. References are also given. These
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