Uncorrected Author Proof

Journal of Alzheimers Disease xx (20xx) xxx 1
DOI 10.3233/JAD-140387
IOS Press
1 Review
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2 Oral Inflammation, Tooth Loss, Risk Factors,
3 and Association with Progression of
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4 Alzheimers Disease
5
6 and StJohn Creanb,1,

or
Sim K. Singhraoa, , Alice Hardingb , Tal Simmonsc , Sarita Robinsond , Lakshmyya Kesavalue,1,
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a Oral & Dental Sciences Research Group, School of Medicine and Dentistry, University of Central Lancashire,
8 Preston, UK
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b Specialist in Special Care Dentistry, University of Central Lancashire, Preston, UK
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c School of Forensic and Investigative Sciences, University of Central Lancashire, Preston, UK
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d School of Psychology, University of Central Lancashire, Preston, UK
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e Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL, USA
Accepted 14 April 2014

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13 Abstract. Periodontitis is a polymicrobial chronic inflammatory disease of tooth-supporting tissues with bacterial etiology
14 affecting all age groups, becoming chronic in a subgroup of older individuals. Periodontal pathogens Porphyromonas gingivalis,
15 Tannerella forsythia, and Treponema denticola are implicated in the development of a number of inflammatory pathologies
16 at remote organ sites, including Alzheimers disease (AD). The initial inflammatory hypothesis proposed that AD hallmark
proteins were the main contributors of central nervous system (CNS) inflammation. This hypothesis is expanding to include
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17
18 the role of infections, lifestyle, and genetic and environmental factors in the pathogenesis of AD. Periodontal disease (PD)
19 typifies a condition that encompasses all of the above factors including pathogenic bacteria. These bacteria not only are the
20 source of low-grade, chronic infection and inflammation that follow daily episodes of bacteremia arising from everyday tasks
21 such as brushing, flossing teeth, chewing food, and during dental procedures, but they also disseminate into the brain from
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22 closely related anatomical pathways. The long-term effect of inflammatory mediators, pathogens, and/or their virulence factors,
23 reaching the brain systemically or otherwise would, over time, prime the brains own microglia in individuals who have inherent
24 susceptibility traits. Such susceptibilities contribute to inadequate neutralization of invading agents, upon reaching the brain.
25 This has the capacity to create a vicious cycle of sustained local inflammatory milieu resulting in the loss of cytoarchitectural
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26 integrity and vital neurons with subsequent loss of function (deterioration in memory). The possible pathways between PD and
27 AD development are considered here, as well as environmental factors that may modulate/exacerbate AD symptoms.
28 Keywords: Alzheimers disease, inflammation, oral health, periodontal disease
INTRODUCTION 29
Alzheimers disease (AD), a form of dementia, is the 30
Correspondence
most common neurodegenerative disease worldwide 31
to: Dr. Sim K. Singhrao, Oral & Dental Sci-
ences Research Group, School of Medicine and Dentistry, University
[1]. The prevalence of AD increases exponentially 32
of Central Lancashire, Preston, UK. Tel.: +44 1772 895137; Fax: +44 with age, rising from 3% among the 65 to 74 year 33
1772 892965; E-mail: SKSinghrao@uclan.ac.uk. age group and to almost 50% among those around 85 34
1 These authors contributed equally to this work. years and older [2, 3]. Mental deterioration is slow 35
ISSN 1387-2877/14/$27.50 2014 IOS Press and the authors. All rights reserved
2 S.K. Singhrao et al. / Pathways and Factors Affecting AD
36 but progressive, contributing to poor memory, disorien- with other cytoskeletal elements eventually leading to 85
37 tation, confusion, and eventually profound dementia. further synaptic loss and the demise of the NFT-bearing 86
38 Susceptible individuals can take decades before clini- neurons [17, 18, 20, 21]. 87
39 cally presenting with the disease. This implies that the Amyloid plaques are largely made up of fibrillary 88
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40 etiology of AD is heterogeneous and that the impor- A peptides A40/42 amino-acid residues and are 89
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41 tance of finding new risk factors for development in the result of -, -, and -secretase enzymes cleav- 90
42 the case of late-onset AD remains a priority. ing the transmembrane amyloid- protein precursor 91
43 Although partial efficacy of non-steroidal anti- expressed by all CNS cells. The proteolytic fragment 92
44 inflammatory drugs in some AD patients [4, 5] gave consisting of the last 28 residues of the amyloid- pro- 93
45 rise to the inflammatory hypothesis that accounts tein precursor ectodomain prior to the membrane and 94
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46 for the intrinsic elements of CNS inflammation [6], including the first 12 to 14 residues of the transmem- 95
47 support also exists for the extrinsic inflammatory brane region generate A40/42 amino-acid residues 96
48 mediators. The elderly, for example, having suffered that lead to deposition of extracellular, insoluble fibril- 97
49
50
51
multiple episodes of recurrent infections, can present
with dementia like clinical symptoms in likely late-
onset AD cases [7] as well as those subjects with
or
lar A. Clearing insoluble A peptides from the brain
involves phagocytosis by microglial cells [22, 23], an
activity that invariably fails with the consequences of
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99
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52 confirmed clinical diagnoses of AD [8, 9]. further accumulation of fibrillary A. 101
53 The innate immune responses suggest extrinsic A peptides and insulin are known substrates of 102
54 inflammatory cytokines are involved in exacerbat- an insulin-degrading enzyme [24, 25]. Both of these 103
55 ing neurocognition [9] and cytokine-related genes are proteins are important in the pathogenesis of AD 104
56 being implicated in the susceptibility to inflamma- and type II diabetes mellitus, respectively. Literature 105
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57 tion in late-onset AD [1012]. Furthermore, human supports the risk-factor relationship between type II 106
58 brain tissue specimens from postmortem AD patients diabetes with increased risk of cognitive impairment 107
59 demonstrate evidence for neuroinflammation via the and dementia via its potential pro-inflammatory toxic- 108
60 activated complement system as C1q, C3b, and reac- ity from perturbed glucose metabolism [26]. However, 109
61 tive oxygen species are all involved in the amyloid it is not clear if A itself promotes insulin resistance in 110
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62 fibril formation [11, 13, 14]. These observations are AD with the generation of subsequent oxidative stress, 111
63 strengthened by genome-wide studies supporting the reactive oxygen species, and related pro-inflammatory 112
64 role of innate immune components such as comple- cascades [27]. Streptozotocin used for generating 113
65 ment receptor 1 (CR1) and a fluid-phase regulatory experimental diabetic rats as a model for investigating 114
66 protein clusterin [15, 16]. late-onset AD in relation to insulin resistance is a toxin 115
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derived from Streptomyces species of bacteria [28]. It 116
is, therefore, plausible to suggest that an initial micro- 117
67 PATHOLOGICAL HALLMARKS OF bial trigger may be responsible for insulin resistance 118
68 ALZHEIMERS DISEASE and the subsequent deposition of A in late-onset AD. 119

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A plaques can be observed in the brains of cogni- 120
69 In AD, marked neuronal loss is observed in the tively intact individuals, but they are fewer and are 121
70 hippocampus where high densities of the classi- generally of the diffuse (A40 ) type, which so far 122
71 cal hallmark lesions are initially observed [17]. An appear to have little pathological significance. Of the 123
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72 accumulation of intraneuronal neurofibrillary tangles two forms of amyloid, fibrillary A is regarded as 124
73 (NFTs) and extracellular amyloid- (A) plaques are being neurotoxic [29] and in vitro studies have shown 125
74 the two easily demonstrated histological features of it to lyse all types of cells by apoptosis [30]. Evidence 126
75 AD brains [18]. Synaptic dysfunction is considered from neuroradiological and neuropathological inves- 127
76 as one of the earliest structural defects [19]. Specif- tigations link this hallmark (A40/42 ) to the initiation 128
77 ically, NFTs indicate the severity of disease with of intracerebral inflammatory response in the inherited 129
78 A plaques depicting disease progression [17]. NFTs forms of AD as well as late-onset AD [14, 31, 32]. 130
79 in neurons constitute hyperphosphorylated tau pro- The inflammatory element of the disease may be a 131
80 tein that alters the polymerization and stability of significant risk factor for late-onset AD, specifically 132
81 microtubules [20]. The loss of synapses between neu- as innate immune components such as C1q and C3b 133
82 rons correlates well with cognitive decline [19]. The are involved with plaque maturation [11, 13]. The rel- 134
83 cumulative knock-on effect of these cytoarchitectural evance of detecting C1q and C3b within A40/42 also 135
84 changes is compromised protein-protein interactions draws attention to the cellular mechanisms involved 136
S.K. Singhrao et al. / Pathways and Factors Affecting AD 3
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Fig. 1. Nerve pathways from the oral and nasal cavity to the brain, showing the 2nd and 3rd branches of the Trigeminal (CN V) and the Olfactory
nerve (CN I). The middle meningeal artery enters the brain at the foramen spinosum in the lateral portion of the greater wing of the sphenoid,
and then follows the cranial base and lateral potions of the vault, supplying the dura and bones of the calvarium.
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137 with regulating inflammation in neurodegeneration prevent inappropriate glial cell activation] cannot cross 160
138 and in clearing A40/42 . The inflammatory compo- the blood-brain barrier (BBB). However, it is now 161
139 nents corroborate data from genetic studies proposing understood that the circumventricular organs are not 162
140 a relationship between AD and cytokine polymor- subject to the BBB [35], a region of the brain where 163
141 phisms [12, 33], as well as the complement proteins infections (both systemic and direct via the trigem- 164
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142 such as clusterin and CR1 in its pathogenesis [15, 16]. inal and olfactory nerve pathways (see Fig. 1) and 165
143 With respect to the complement activation cascade, inflammatory mediators can access the brain [3638]. 166
144 CR1 is a membrane-associated complement inhibitory The brain deals with inappropriate toxins derived 167
145 protein that binds C4b and C3b acting at the C3/C5 locally (A deposits) or from extracerebral sources 168
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146 convertase stage of the alternative and classical com- (infectious agents) using its own innate immune system 169
147 plement pathway, and clusterin is a fluid-phase protein consisting of ependymal cells, microglia, astrocytes, 170
148 that interferes with the assembly of the lytic mem- and oligodendrocytes [39]. Normally these cells reg- 171
149 brane attack complex. Decrease in clearance of the ulate the production and uptake of endotoxins and 172
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150 lesion by the innate immune system contributes to secrete trophic factors that nurture the CNS cells 173
151 bystander damage that promotes a vicious cycle of and protect their functions [40]. However, following 174
152 chronic intra-cerebral inflammatory (high endogenous physical damage and/or invasion by foreign agents 175
153 levels of inflammatory mediators) response [14, 34]. (lipopolysaccharide, LPS), glial cells (specifically 176
microglia) bearing the LPS receptor (CD14) and the 177
highly conserved toll-like receptors 2 and 4 (TLR 2 178
154 WHAT IS INTRA-CEREBRAL and 4) undergo a number of phenotypic (resting to 179
155 INFLAMMATION? activated state) and functional changes. Key morpho- 180
logical changes include thickening and shortening of 181
156 In the past the brain was considered as an immuno- branching processes attached to a hypertrophic glial 182
157 privileged organ, as elements of the immune system cell body [41]. Once activated, microglia upregulate 183
158 [such as neutrophils, naive T cells (adaptive immune the expression of MHC class II molecules along with 184
159 system), plasma proteins, and extra-cerebral-toxins to the secretion of pro-inflammatory cytokines (TNF- 185
186 and IL-), complement proteins, quinolinic acid, of AD [51]. Currently, the greater accumulation of A 238
187 arachidonic acid and its metabolites, nitric oxide, deposits in late-onset AD is considered to be the result 239
188 platelet activating factor, and chemokines exci- of defects in the clearance system [52]. Therefore, the 240
189 tatory amino acids, and free radicals [14]. When these pertinent question would be, what initially triggers 241
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190 innate factors are secreted by microglia, a local CNS A40/42 release in patients with late-onset AD? 242
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191 inflammatory response is mounted. Infections are common in elderly individuals and 243
192 In AD brains, A is recognized as a nidus for are the main cause of death in a majority of neu- 244
193 intracerebral inflammation placing chronic neuroin- rodegenerative conditions. One hypothesis is that the 245
194 flammation downstream of this primary hallmark [13, elderly, per se, are immunocompromised and this 246
195 14]. However, this view is changing, especially with correlates with their susceptibility to an increased inci- 247
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196 late-onset AD cases as the importance of the innate dence of infection [53, 54]. Recurrent bacteremia from 248
197 immune molecules is being uncovered by genome- common infections in the elderly, due to, for exam- 249
198 wide studies [11]. If nerve cell death and chronic CNS ple, chronic periodontitis [55, 56], intra-abdominal 250
199
200
201
inflammation are common precursors of the develop-
ment of dementia, explaining equivalent numbers of
A deposits and NFTs in clinical and subclinical AD
or
[57], and urinary tract infections [58], will con-
tribute to systemic circulation infections. In addition,
chronic periodontitis demonstrates a promising link
251
252
253
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202 in the very elderly who bypass dementia is important that encompasses environmental influences, suscepti- 254
203 [4245] and adds further complications to the etiolog- bility profiles, infectious agents, and a multitude of 255
204 ical nature of AD. hosts factors that affect its episodic re-occurrence 256
205 Even A in subclinical AD subjects, which initi- [59]. Numerous studies show that tooth loss due to 257
206 ates intracerebral inflammation [11, 46, 47], appears PD to correlate with cognitive impairment in AD 258
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207 not to lead to clinical decline in cognition. One possi- [6063]. Further studies have demonstrated systemi- 259
208 ble explanation for the lack of cognitive decline could cally derived immune components such as antibodies 260
209 lay in the inflammatory genetic traits of these and to the periodontal pathogens circulating in the blood 261
210 the non-impaired individuals with vital neuronal cells plasma of AD subjects [64]. In addition, AD patients 262
211 being rescued from death and so providing a cognitive with antibodies to the periodontal pathogens in 263
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212 reserve. The inflammatory signals that initiate phago- their blood have displayed inflammatory mediators 264
213 cytosis by microglia are driven by A that involve the (cytokines) in the systemic circulation [64]. As Holmes 265
214 CD14 and TLR 2 and 4 signaling [22, 23, 48, 49], et al. [9] suggest, these cytokines and those from alter- 266
215 a pathway also used by microglia for bacterial LPS native sources in the peripheral circulation have the 267
216 recognition [50]. Spontaneous loss-of-function muta- potential to reach the brain parenchyma, and subse- 268
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217 tion in the TLR 4 gene has been demonstrated to have quently prime microglia to mount a local immune 269
218 an inhibitory effect on microglial cell activation. For response with appropriate stimuli, and impair memory. 270
219 example, presence of A in the microglia with mutated An alternative hypothesis for the role of A in 271
220 gene expression [49] demonstrated reduced secretion subclinical and/or clinical AD individuals is that A 272
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221 of inflammatory mediators such as interleukin-6 (IL-6) is acting as an antimicrobial peptide [65] to coun- 273
222 and tumor necrosis factor- (TNF-) and nitric oxide. teract infections by functioning as part of the early 274
223 These findings further strengthen the cognitive reserve innate immune defense mechanisms that mediate 275
224 hypothesis in very old subjects in the presence of clas- innate and adaptive immune responses [66]. Tradi- 276
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225 sical AD hallmark lesions. tionally, antimicrobial peptides act as look-outs for 277
226 Using an ex-vivo experimental model to examine invading micro-organisms to maintain the balance 278
227 the expression of pro-inflammatory cytokine profiles in between commensals. The main target for antimicro- 279
228 whole blood from the healthy middle-aged offspring of bial peptides is the pathogen cell membrane, as most 280
229 patients affected by late-onset AD, van Exel et al. [10] antimicrobial peptides are cationic [67]. Antimicrobial 281
230 reported higher levels of specific cytokines than were peptides undergo electrostatic interactions with neg- 282
231 found in the siblings from non-AD parents. This find- atively charged molecules to penetrate bacterial cell 283
232 ing also demonstrates that inflammation-related risk walls, including anionic lipids and LPS [67]. They 284
233 factors are present in currently healthy subjects who then invade the lipid bilayer, creating trans-membrane 285
234 may have a genetic susceptibility profile a phrase, pores through which leakage of ions and metabo- 286
235 coined by McGeer and McGeer [33] to late-onset AD. lites, cytoplasmic components, dissipation of electrical 287
236 Despite the inheritance factors, the brains response to potentials, and cell death of microbes takes place 288
237 inflammation is slow as supported by animal models [68]. This hypothesis suggests the involvement of a 289
290 pathogenic precursor in the initiation of A release of care within the establishment for the level of oral 339
291 before inflammation becomes detectable in the pres- hygiene and dental health they receive. These factors 340
292 ence of this hallmark. We support this hypothesis and were supported in a large-scale survey carried out in 341
293 propose a suite of susceptibility traits and immuno- the US by Griffin et al. [79], which found that older 342
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294 suppressive (stressed or rundown) episodes during life age groups were more likely to be edentulous or have 343
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295 that give way to chronic bacterial infections. These untreated dental disease and root caries. Those who 344
296 bacterial elements in the individuals with susceptibil- were either residents in institutions or homebound had 345
297 ity profiles may trigger release of A to neutralize higher levels of untreated cavities, gingivitis (a marker 346
298 their effect. Over time A will accumulate in the of poor oral hygiene), and poorer overall oral health 347
299 brains of healthy but susceptible individuals and ini- than the elderly living independently. The study shows 348
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300 tiate neuroinflammation that may cross the threshold that cost, lack of transportation, and limited mobility 349
301 from subclinical to late-onset AD. were key barriers to accessing dental care for nursing 350
302 The etiological hypothesis suggests that viruses and home residents [79]. Other groups of elderly that show 351
303
304
305
bacteria and/or their virulence factors access the brain
and thereby contribute to AD pathogenesis. A review
by Holmes and Cotterell [69] provides a range of infec-
or
higher untreated dental disease and lower levels of oral
health are those from ethnic minorities and low-income
families [79].
352
353
354
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306 tive agents consistently being linked to AD. These
307 include viruses such as Herpes simplex virus type
308 I [70], Chlamydophila pneumoniae [71], Treponema PERIODONTAL DISEASE 355
309 spp., [72] Borrelia burgdorferi [73], and more recently

310 LPS from P. gingivalis [74], one of the key bacteria PD is a polymicrobial inflammatory disease that 356
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311 causing PD in humans. has been estimated to affect 1015% of the developed 357
world population and is a major cause of tooth loss. 358
The prevalence of PD increases with age, affecting 359
312 AGE-RELATED PERSONAL HYGIENE around 50% of people over the age of 55 years [82]. The 360
313 CHANGES AS RISK FOR INFECTIONS disease affects tooth supporting tissues wherein the 361
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interaction of specific bacteria and the hosts immune 362
314 Advancing age is the greatest risk factor for all forms responses play a pivotal role [59]. The hosts response 363
315 of AD. Some consequences of advancing age are a to bacteria and their products is an important factor in 364
316 compromised immune system [53, 54] and a neglect of determining the extent and severity of PD [83]. The 365
317 general and oral personal hygiene [61, 75, 76], and such acute bacterial challenges stimulate junctional trans- 366
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318 conditions are associated with recurrent, chronic infec- formed pocket epithelium to produce a broad range of 367
319 tions. Recurrent, chronic infections enhance systemic inflammatory mediators to guard against gingival tis- 368
320 hyperinflammatory profile that may lead to confusion sue damage. The inefficient clearance of subgingival 369
321 and other dementia-like clinical features [79] in which pathogens by the innate immune system compromises 370
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322 the exact structural/cellular changes taking place at the the integrity of periodontal tissues and eventually 371
323 time remain unknown. results in the formation of periodontal pockets. 372
324 Several studies support deterioration in oral health Periodontitis, involving specific bacteria coupled 373
325 with increasing age [7780]. The exact reasons are with the hosts response, initiates an acute phase 374
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326 poorly understood, but advancing age is likely to com- receptor-mediated cytokine production by epithelial 375
327 promise the manual dexterity of senior citizens and cells and simultaneous neuropeptide release, resulting 376
328 this may make cleaning their teeth more difficult, in vasodilation of local vessels. Chemokines mobi- 377
329 or perhaps it is because as general health concerns lize neutrophils from blood vessels for migration 378
330 and conditions increase with age, maintenance of to the area of bacterial invasion. Gingival bleeding, 379
331 oral health becomes a lower priority. The elderly are swelling, and redness together with the presence of 380
332 more likely to be on multiple medications, many of neutrophils/macrophages within the inflamed gingivae 381
333 which, as a side effect, cause xerostomia and this indicate clinical signs of inflammation. The infection 382
334 will inevitably be a factor in deteriorating oral health is both confined to, and subsequently cleared by, neu- 383
335 [81]. Furthermore, if the elderly suffer from physi- trophils and macrophages, or expands to include other 384
336 cal impairments, accessing the dentist may become cells and structures [84]. In the high susceptibility pro- 385
337 more difficult. Elderly people resident in care insti- file group of individuals, the acute phase responses fail 386
338 tutions are, to a certain extent, dependent on the level to clear the infection, and chronic inflammatory lesions 387
388 develop within a matter of weeks. The pathogenic Cranial nerve V (CN V) or the trigeminal nerve, 437
389 consortium consisting of Porphyromonas gingivalis arising from the mid-lateral surface for the pons, 438
390 (P. gingivalis), Tannerella forsythia (T. forsythia), and is primarily a general sensory nerve with smaller 439
391 Treponema denticola (T. denticola) appear to be the motor component. There are three divisions of the 440
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392 main organisms involved in the development of chronic CN V which are ophthalmic (V I), maxillary (V2 ) and 441
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393 PD [85, 86]. The subgingival sulcus serves as a mandibular (V3 ) where, the motor root of CN V travels 442
394 niche enabling a cyclic chronic inflammatory process with the mandibular branch. The ophthalmic division 443
395 which in turn facilitates recurrent bacteremia follow- (V I) exits the neurocranium through the supraor- 444
396 ing routine oral health regimes [55, 56, 87]. A number bital fissure, the maxillary division (V2 ) through the 445
397 of inflammatory pathologies are said to develop in foramen rotundum in the sphenoid bone and the 446
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398 this way, including cardiovascular diseases [88, 89], mandibular (V3 ) branch through the sphenoids fora- 447
399 rheumatoid arthritis [9092], diabetes mellitus [93], men ovale. CN V is a general sensory nerve to the scalp, 448
400 and others as well as AD [60, 61, 64, 72, 74]. face, nasal and oral cavities (including the teeth and 449
401 ANATOMICAL RELATIONSHIP OF FACIAL

or
tongue), and brachial motor nerve to the muscles of
mastication (temporalis, masseter, medial pterygoid,
and lateral pterygoid), tensor tympani, tensor (veli)
450
451
452
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402 NERVES AND THE BLOOD SUPPLY TO palitini, mylohyoid, and the anterior belly of the digas- 453
403 THE BRAIN tric. When dental or periodontal therapy is performed 454
using local anesthesia (e.g., novocaine, xylocaine), the 455
404 The position of the oral cavity, serving the need drug is injected into the oral mucosa covering the bony 456
405 for speech and food consumption, connects with the foramina where the sensory branches of the CN V exit 457
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406 brain via series of nerves. Cranial nerve 1 (CN1) is into the oral cavity. For the maxillary dental arcade, 458
407 the special sensory nerve for olfaction and contributes the injection is aimed toward the pterygopalatine gan- 459
408 not only to our sense of smell but also to that of glion; for the mandibular teeth, this is directed toward 460
409 taste. CN1 has complex pathways that trigger vis- the mandibular foramen. In the case of the pterygopala- 461
410 ceral responses (salivation and nausea or accelerated tine ganglion, this supplies sensation via branches of 462
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411 peristalsis in the intestinal tract and increased gastric V2 from the nasal cavity, plate, nasopharynx, and max- 463
412 secretion) to various odors. Although CN1 is recog- illary teeth. The lingual and inferior alveolar nerve 464
413 nized and named as the olfactory nerve, the majority branches carry sensation from the entirety of the lower 465
414 of the olfactory tract comprises of secondary, rather jaw, mandibular teeth, gums, and anterior two thirds 466
415 than primary sensory axons; thus it is really not a of the tongue as shown in Fig. 1. As with most nerves, 467
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416 nerve but rather a bulb and tract. There is a physical the branches of the trigeminal nerve are accompanied 468
417 connection between the oral and nasal cavity, extend- by veins and arteries along the peripheries of their 469
418 ing onto the superior nasal conchae and nasal septum pathways [94]. 470
419 and contains neurosensory cells and olfactory glands, The olfactory and the trigeminal nerve(s) pathways 471
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420 which keep the mucosa moist and in which the disso- are also exploited by periodontal pathogens as a means 472
421 lution of inhaled scents (aromatic molecules) occurs. of bypassing the BBB for direct entry into the CNS 473
422 The peripheral processes of the primary sensory neu- [72, 95, 96], an observation supported by studies in 474
423 rons in the epithelium perform as sensory receptors immunosuppressed animal models using T. denticola 475
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424 and transmit sensation centrally, which congregate into [97]. The animal model study allows some insight into 476
425 around 20 bundles, which, in turn, pass through foram- the virulence of the organism and the hosts immune 477
426 ina of the cribiform plate of the ethmoid bone. The defenses as being important for this occurrence. 478
427 cribiform plate of the ethmoid bone is the porous bar- The systemic route as an alternative mode of 479
428 rier between the nasal passages and the brain itself. bacterial entry into the brain is favored due to 480
429 Once they have passed through the cribiform plate, bacteremia as mentioned earlier, association of peri- 481
430 the central processes synapse on the secondary sen- odontal pathogens with atherosclerotic lesions and in 482
431 sory neurons in the olfactory bulb itself, which houses particular P. gingivalis having the ability to adhere to 483
432 the nerve cell bodies. Behind this area is the olfactory erythrocytes for innate immune evasion [87, 98, 99] as 484
433 tract and trigone; the nerve cell bodies travel to the well as gaining advantage for transportation to remote 485
434 three olfactory areas, located in the anterior part of the body organs [99]. 486
435 entorhinal cortex area, encompassing the hippocampal The brain is supplied by three paired blood vessels: 487
436 gyrus and all ultimately lead to the hippocampus [94]. the right and left internal carotid arteries, arising from 488
489 the common carotid artery at the base of the neck. causes some individuals to harbor periodontal bacte- 538
490 It has three divisions that enter the cranium, anteri- ria rather than other species? Could there be as yet 539
491 orly through the carotid canal of the temporal bone unknown genetic factors/inflammatory traits, lifestyle 540
492 and through foramen lacerum in the middle cranial driven environmental stressors? 541
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493 fossa. The vertebral arteries arise from the subclavian However, it should be noted that patients suf- 542
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494 arteries, bilaterally and both enter the cranium via the fering from AD cognitive impairment are poor at 543
495 foramen magnum. The vertebral and internal carotid managing their personal oral health. In addition, a 544
496 arteries unite on the base of the brain at the Circle of caregiver or dentist may face a marked decrease in co- 545
497 Willis, via a series of interconnecting smaller arter- operation from the AD patient, making management 546
498 ies. The basilar artery is created when the vertebral of oral health more challenging. With patients hav- 547
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499 arteries join. The Circle of Willis itself is composed ing increased cognitive impairment, such as reduced 548
500 of the posterior cerebral, posterior communicating, adaptation to change, dentists often choose not to carry 549
501 internal carotid, anterior cerebral and anterior commu- out the dental treatment that would give optimal oral 550
502
503
504
nicating arteries; all these arteries branch to supply the
brain itself [94] including the circumventricular organ
regions where bacteria and bacterial products access
or
health. For example, patients with AD may well be
unable to cope with extensive, potentially unpleas-
ant dental procedures, leaving them with fewer teeth,
551
552
553
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505 the brain. which could have a detrimental impact on their eating 554
ability. 555
Nutritional deficiencies are documented in the 556
506 THE ASSOCIATION BETWEEN elderly as well as in the dementia subjects, especially 557
507 PERIODONTAL DISEASE AND with regard to lessened intake of B-vitamins and folic 558
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508 ALZHEIMERS DISEASE acid in the diet. The marker that indicates these defi- 559
ciencies also correlates with cognitive decline, but as 560
509 Longitudinal studies have shown that people with consequence of disease rather than a cause [103]. The 561
510 PD who progressed to the development of AD had mechanism of cognitive decline is suggested via synap- 562
511 poorer oral health [61, 76, 79, 100102]. Does poor oral tic dysfunction, which is one of the earliest structural 563
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512 health always mean that the pathogens will disseminate defects associated with decline in memory [19]. Diet 564
513 to the brain even in AD patients? Both our unpublished provides the essential B-vitamins, phospholipids, and 565
514 data from controlled experiments using animal models, other micronutrients, which are required for the for- 566
515 and that of Foschi et al. [97], indicate that the presence mation of new synapses [104]. 567
516 and motility of the low virulence strains of periodontal

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517 pathogens may not be sufficient for them to access the

518 brain. However, animal models of oral diseases (peri- EPIDEMIOLOGICAL EVIDENCE FOR THE 568
519 odontitis and endodontic) may require an adjustment ASSOCIATION BETWEEN CHRONIC 569
520 for the optimization of dosage and/or duration of infec- PERIODONTITIS AND ALZHEIMERS 570
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521 tion to allow for bacteria to translocate to the brain. DISEASE 571
522 Our unpublished data demonstrates that P. gingivalis

523 (FDC381) accessed the brain of ApoEnull mice follow- Clinical/epidemiological studies so far, all agree 572
524 ing an oral infection while P. gingivalis (ATCC 33277) on loss of teeth leading to poor memory [6063]. 573
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525 failed, even in SCID mice mono and poly infections Further studies have examined possible inflamma- 574
526 [97]. It therefore appears that the greater virulence of tory biomarkers in an attempt to link and/or to find 575
527 P. gingivalis (FDC 381) due to having acquired fim- new diagnostic makers of AD. Others have, however, 576
528 briae, likely allowed its adherence to erythrocytes for used more specific measures including IgG levels to 577
529 innate immune evasion, a process that has gained the P. gingivalis and other specific periodontal pathogens 578
530 bacterium an advantage for dissemination [99], to the [64, 105]. A study by Sparks Stein et al. [105] used 579
531 brain (Poole et al. unpublished results). When the dura- cohort methodology analyzing levels of serum anti- 580
532 tion of active infection supersedes the virulence of the bodies to periodontal disease. At the start of the 581
533 bacteria, there remains a high possibility that the host study period, all participants were cognitively intact, 582
534 harboring the periodontal pathogens will demonstrate but higher levels of serum antibodies to periodontal 583
535 these bacteria disseminating to the brain. Immunocom- pathogens at baseline led to some individuals develop- 584
536 promised status seen in AD patients will also enhance ing AD [105]. As baseline measures were taken years 585
537 the infection process. This begs the question as to what before diagnosis of AD, the elevation in serum antibod- 586
587 ies cannot be attributed to secondary effects of AD (for to a compromising immune system and therefore, the 636
588 example, poor oral hygiene). Although clinical mea- ability of the host to defend against periodontal bacte- 637
589 surements of oral health were not taken in the Sparks rial infections. 638
590 Stein et al. [105] investigation, periodontal bacterial It is generally accepted that smoking is the major 639
f
591 species are generally accepted as being specific enough risk factor in periodontal disease. Smokers are 27 640
roo
592 to PD and assessing serum antibody levels to these times more likely to present with PD than non-smokers 641
593 pathogens may prove to be a true indicator of PD in and this is unrelated to oral hygiene. Disease progres- 642
594 AD patients. sion is more rapid and response to treatment is poorer 643
[109]. Smoking is thought to affect neutrophil func- 644
tion, reducing the hosts ability to eliminate periodontal 645
P
595 POSSIBLE CONFOUNDERS pathogens. Smokers with PD have distinct patterns of 646
pathogenic microbial profile than non-smokers with 647
596 Several environmental, epidemiological, and risk PD [110112]. Smoking is also thought to lead to 648
597
598
599
factors show similar trends and patterns in both
PD and AD. Whether or not this is coincidental or
arises through shared developmental pathways remains
or
release of reactive oxidative species and oxidative
stress mediated tissue damage. Inflammatory cytokine
and chemokine expression in smokers compared to
649
650
651
uth
600 unclear. The impact of these associations is the poten- non-smokers show many differences reflecting the 652
601 tial for these factors to act as confounders, influencing immunosuppressant effect of smoking, which may 653
602 the true relationship between PD and AD. contribute to an enhanced susceptibility to periodonti- 654
603 The incidence of both PD and AD increases with tis [113]. 655
604 age; this has already been mentioned in previous sec- The relationship between smoking and AD is less 656
dA
605 tions. Gender related trends exist between AD and clear; with some studies suggesting smoking has a 657
606 periodontal disease. The incidence of AD has been beneficial effect due to nicotine treatment improv- 658
607 shown to be higher in women after 85 years of age. ing cognitive performance in age associated memory 659
608 This is thought to be due to the protective effect of impairment [114], while others suggesting that smok- 660
609 pre-menopause estrogen [106]. Men, however, have ing increase the risk of AD. In the proposed theory, 661
cte
610 been shown to have a greater incidence of PD (up an increased risk of AD is similarly related to the 662
611 to 50%) than women overall [107]. Interestingly, this factors causing periodontal disease, whereby smoking 663
612 study also showed that men with PD also had increased increases free radical generation leading to high oxida- 664
613 incidence of coronary artery disease, suggesting fewer tive stress, or affects the inflammatory immune system 665
614 men than women survive to old age. Physical activity leading to phagocyte activation and further oxidative 666
rre
615 has been shown to have a positive effect on cognitive damage. 667
616 function and those aged 7079 years with high levels PD would appear to have an increased prevalence in 668
617 of activity show lower levels of inflammatory markers both ethnic minority groups and lower socioeconomic 669
618 such as IL-6 and C-reactive protein [106]. Likewise status. This has been attributed to a complex combi- 670
co
619 obesity has shown similar trends, in that those who nation of social, psychological, and structural factors 671
620 are obese suffer a greater incidence of AD. Although including nutrition, oral hygiene, healthcare utiliza- 672
621 physical activity and the incidence of PD have not tion, and access to care. It is thought that having lack of 673
622 been investigated directly, many studies have shown resources to pay for care, not having a regular source 674
Un
623 an indirect relationship, highlighting a greater inci- of care, or availability of transportation to healthcare 675
624 dence of PD with obesity and diabetes [107, 108]. It centers contribute to these trends [115117]. 676
625 has been suggested that obesity may be the second The relationship between race and socioeconomic 677
626 highest risk factor for PD after smoking [109]. The status and AD appears more complex. Meta-analysis 678
627 underlying mechanism for this association is thought assessing the relationship between education level and 679
628 to be related to proinflammatory cytokines, includ- AD showed that overall those with low or no educa- 680
629 ing IL-6 and C-reactive protein that are released by tion were more likely to develop AD, but this was not 681
630 adipose tissue, along with hormones adipokines or shown in all studies. This relationship was stronger 682
631 adipocytokines. With the increasing levels of evidence in developed, compared to developing countries possi- 683
632 supporting inflammatory processes in AD develop- bly due to life-expectancy being shorter in developing 684
633 ment, it is possible that the relationship between AD countries. Individuals with less education appear to 685
634 and obesity may follow similar mechanisms [109]. have lower cognitive function compared to those with 686
635 Poorer general health may be associated with PD due higher education levels. Education-dementia relation- 687
688 ship appears to vary according to age, gender, and by increasing certain hormones, such as adrenaline 734
689 race/ethnicity and the suggestion is that the relationship and cortisol. These, in turn, act on the biological 735
690 ties in with a persons life events beginning prior to and functioning of the individual, such as increased heart 736
691 carrying on beyond years of formal education [118]. rate, inhibition of the digestive system, or increased 737
f
692 These epidemiological trends associated with both PD glucose supply to the muscles. Although the phys- 738
roo
693 and AD demonstrates the importance for excluding iological changes enhance our ability to mount a 739
694 the impact of confounders when investigating a true physical response to threat, the associated neurochem- 740
695 relationship between PD and AD. ical changes can lead to cognitive failures, which may 741
present as dementia-like even within a cognitively nor- 742
GENETIC RISK FACTORS FOR mal population. For example, elevations in cortisol 743
P
696
697 LATE-ONSET ALZHEIMERS DISEASE as a result of activation of the HPA axis can lead 744
698 AND PERIODONTITIS to impairments in attention [125], working memory 745
and inhibitory control [126], and declarative memory 746
699
700
701
The apolipoprotein E (ApoE) gene is a known
genetic risk factor associated with late-onset AD,
and more recent investigations suggest some further
or
[127]. Cognitive impairments due to acute stressors
are reversible. Further acute stress responses may actu-
ally have some benefits for health with enhancements
747
748
749
uth
702 genetic risk factor associations with innate immune in immune function being reported [128]. How- 750
703 molecules and inflammatory traits in late-onset AD ever, when short-term beneficial adaptations designed 751
704 [10, 15, 16]. In particular, cytokine-related genes to maintain homeostasis during acutely stressful 752
705 appear to be involved in the susceptibility to inflam- events become excessive or prolonged, problems can 753
706 mation in late-onset AD [10, 12, 33] as well as in PD occur [129]. 754
dA
707 [119121].
708 As the immune system plays an important role in PD Stress: Periodontal disease 755
709 pathogenesis [59], it is thought that PD itself may have

710 genetic associations. Polymorphisms in IL-, IL-1, Psychological stress may affect periodontal disease. 756
711 IL-6, and TNF- genotype are reported for periodonti- Such stressors can lead to a change in health behaviors, 757
cte
712 tis [119121] and similarly IL-1, IL-1, IL-6, TNF-, which in turn may lead to associated increased risk of 758
713 2-macroglobulin, and 1-antichymotrypsin are all PD. For example, poorer oral hygiene coupled with 759
714 upregulated in AD [12, 33] suggesting commonali- increased smoking [130] and alcohol intake [131]; vis- 760
715 ties between susceptibility profiles in these two disease iting the dentist less regularly, and eating less healthily 761
conditions. As mentioned earlier, offspring of parents with higher fat and sugar diets [132] encourage bacte- 762
rre
716
717 with AD have higher inflammatory cytokines in their rial growth and worsen periodontal status. 763
718 blood than those who are descendants of non-AD par- Stress impairs the balance between pro- and anti- 764
719 ents [10]. Similarly, parents with poor oral health tend inflammatory responses. Alterations in inflammatory 765
720 to have children with poor oral health; however, it is polymorphic gene function, in particular of IL-1 766
co
721 difficult to conclude that the poor oral health trait is a and IL-6 (119121), will affect polymorphonuclear 767
722 result of the genetic makeup of the individual and not leukocyte chemotaxis. The net effect will be reduced 768
723 simply an environmental influence [122]. lymphocyte proliferation and this may increase the 769
vulnerability of periodontal tissue to microorganisms 770

Un
leading to further tissue destruction [133]. Inhibition of 771
724 STRESS ENVIRONMENTAL AND GENETIC T cell responses by glucocorticoids appears to explain, 772
725 FACTORS in part, susceptibility to PD and pro-inflammatory 773
cytokines are potent activators of the HPA axis [134, 774
726 Stress: In health 135]. Patients with PD who are stressed show increased 775
IL-6 and IL-1 levels in gingival crevicular fluid [133]. 776
727 Acute stressors in the environment, such as facing Results of several studies were reviewed and demon- 777
728 a dangerous situation, activate physiological sys- strated a correlation between psychological stress and 778
729 tems designed to enhance self-preservation [123]. salivary and blood stress markers relating to inflamma- 779
730 These include the sympathetic-adrenal-medullary and tory response and progression of PD [134]. However, a 780
731 the more slowly responding hypothalamus pituitary cause and effect relationship has not, so far been found, 781
732 adrenal (HPA) axis. This response prepares the body to therefore stress is considered a risk factor for PD rather 782
733 cope with threat [124]. The two response systems work than a cause. 783
784 Stress: Alzheimers disease et al. [74] studies lacked information concerning the 832
periodontal status of the cases analyzed. 833
785 High levels of environmental stressors could lead to

786 impairments in cognitive processes, which are impor-
f
787 tant for maintaining oral hygiene. For example, acute FUTURE RESEARCH 834
roo
788 and chronic activation of the HPA axis can lead to
789 elevated basal cortisol levels. High levels of circulat- How PD contributes to impaired memory remains 835
790 ing cortisol causes hippocampal damage and so impair intriguing and future studies should be directed 836
791 hippocampus-dependent memory processes [125]. In towards addressing these mechanisms. There is paucity 837
792 a cognitively intact elderly population, higher cortisol of information relating to the exact risk factor(s) for the 838
P
793 levels were indicative of impairments of declarative development of deteriorating memory from missing 839
794 memory and executive functioning [135], both of teeth in the prodromal phase of AD. Are these factors 840
795 which are needed to maintain good oral hygiene. downstream of co-morbidities such as diabetes affect- 841
ing periodontal status of the individual? Or common

796
797
798
The hippocampus is the area of pathology in AD
and is vulnerable to effects of stress and trauma [136].
Chronic stress can impair immune responses and so
or
susceptibility profiles play a key role in loss or gain
of function in future generations of AD parents. Fur-
ther evidence to support an association between PD
842
843
844
uth
845
799 compromise the bodys ability to resist disease [137].
800 The brain attempts to compensate cellular stress, by and AD, research would need to demonstrate that the 846
801 regulatory mechanisms, involving upregulation of heat inflammatory and immunological responses that the 847
802 shock proteins [138]. Loss of heat shock proteins, bacteria and their virulence factors induce may subse- 848
803 in vitro, was shown to contribute to accumulation quently lead to the onset of AD. Perhaps associations 849
between parents with AD and their children at a much

dA
850
804 of hyperphosphorylated tau, a component of NFTs,
805 and a hallmark of AD pathology [139]. In addition, younger age should be monitored for oral health as 851
806 stress activated protein kinases, for example, mitogen- that should eliminate any overlapping confounders that 852
807 activated protein kinase 38 and the c-jun N-terminal may be masking the true links in these two conditions. 853
808 kinases are activated in AD [140, 141]. These two stress This review clearly indicates significant gaps in 854
our current understanding of the causal association 855

cte
809 pathways can also be activated by oxidative stress [142,

810 143], a common denominator of environmental, patho- of pathogens (spirochetes, bacteria, viruses) in a 856
811 logical, and habitual factors. slowly progressive and debilitating disease such as 857
AD. Although various types of neurotropic spirochetes 858
including oral (Treponema spp) and non-oral spiro- 859

rre
chetes (B. burgdorferi) have been detected directly in 860

812 CRITICAL REMARKS ABOUT THE
association with the pathological hallmarks of AD [73] 861
813 PRESENT STATE OF THE RESEARCH TO
but, a causal relationship has not been tested in ani- 862
814 RELATIONSHIP BETWEEN ALZHEIMERS
mal models. To the best of our knowledge, there is 863
815 DISEASE AND CHRONIC PERIODONTITIS
no single in vivo animal model study that has exam-
co
864
ined the role of periodontal bacteria during chronic 865

816 Clinical observational studies thus far all correlate
infection (912 months of exposure times) to study 866
817 with loss of teeth leading to poor memory. However,
the sequence of neuropathological events associated 867
818 direct evidence is lacking to support a causal asso-
Un
with the development of AD pathology. Even though 868

819 ciation between periodontal bacteria and progression
infectious agents have been implicated in relation to 869
820 of AD. The clinical studies have been performed on
AD hallmark pathology for over a century ago, several 870
821 elderly cohorts where overlapping features of the aging
clinical and molecular studies strongly support an asso- 871
822 process, such as deposition of A in the brain is likely
ciation between PD and AD. However, to date, there 872
823 to have already begun. When assessing periodontal
is a paucity of reports supporting a causative relation- 873
824 status clinically, levels of caries may not have been
ship between periodontal pathogens and AD cases and 874
825 accounted for. Oral hygiene studies were based on ret-
in vivo transgenic mice. 875
826 rospective questionnaire surveys, which may introduce
827 selection bias depending on the response rate. People
828 who are motivated to complete questionnaires may be ACKNOWLEDGMENTS 876
829 more likely to visit the dentist than those who do not.
830 Genetic factors have not given importance in some of The authors thank the project support to LK 877
831 the studies. Both the Riviere et al. [72] and the Poole by 1R01 DE020820-01A1, NIH/NIDCR, USA. The 878
879 work described in this manuscript was fully funded mice are closely associated with a local inflammatory pro- 938
880 by the University of Central Lancashire. SKS is a cess. Virchows Arch B (Cell Pathol) 60, 329-336. 939
[14] Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole 940

881 privileged recipient of the 2011, Don Claugher Bur- GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich 941
882 sary prize which was awarded by the Committee BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull
f
942
883 of the Society of Electron Microscope Technology M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer 943
roo
884 (http://www.semt.org.uk). PL, OBanion MK, Pachter J, Pasinetti G, Plata-Salaman 944
C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, 945
885 Authors disclosures available online (http://www.j- Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, 946
886 alz.com/disclosures/view.php?id=2275). Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) 947
Inflammation and Alzheimers disease. Neurobiol Aging 21, 948
383-421. 949
P
[15] Lambert JC, Heath S, Even G, Campion D, Sleegers K, 950
887 REFERENCES Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tav- 951
ernier B, Letenneur L, Bettens K, Berr C, Pasquier F, 952
888 [1] Winblad B (2002) Socio-economic perspectives of demen- Fievet N, Barberger-Gateau P, Engelborghs S, De Deyn 953
889
890
891
892 [2]
tia and cost effectiveness of treatment. 7th International
Geneva/Springeld Symposium on Advances in Alzheimer
Therapy, April 3-6, Geneva, Switzerland.
Evans DA (1990) Estimated prevalence of Alzheimers dis-
or
P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon
O; European Alzheimers Disease Initiative Investigators,
de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Lev-
eillard T, Alvarez V, Bosco P, Mancuso M, Panza F,
954
955
956
957
uth
893 ease in the United States. Milbank Q 68, 267-289. Nacmias B, Bossu P, Piccardi P, Annoni G, Seripa D, Gal- 958
894 [3] Small GW, Donohue JA, Brooks RL (1998) An economic imberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, 959
895 evaluation of donepezil in the treatment of Alzheimers dis- Blanche H, Dartigues JF, Tzourio C, Gut I, Van Broeck- 960
896 ease. Clin Ther 20, 839-850. hoven C, Alperovitch A, Lathrop M, Amouyel P (2009) 961
897 [4] Stewart WF, Kawas C, Corrada M, Metter EJ (1997) Risk Genome-wide association study identifies variants at CLU 962
898 of Alzheimers disease and duration of NSAID use. Neurol and CR1 associated with Alzheimers disease. Nat Genet 41, 963
dA
899 48, 626-632. 1094-1099. 964
900 [5] Anthony JC, Breitner JC, Zandi PP, Meyer MR, Jurasova I, [16] Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, 965
901 Norton MC, Stone SV (2000) Reduced prevalence of AD in Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams 966
902 users of NSAIDs and H2 receptor antagonists: The Cache A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone 967
903 County study. Neurol 54, 2066-2071. S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein 968
904 [6] Broe GA, Grayson DA, Creasey HM, Waite LM, Casey DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, 969
BJ, Bennett HP, Brooks WS, Halliday GM (2000) Anti- Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, 970
cte
905
906 inflammatory drugs protect against Alzheimer disease at low Mann D, Smith AD, Love S, Kehoe PG, Hardy J, Mead S, 971
907 doses. Arch Neurol 57, 1586-1591. Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schurmann 972
908 [7] Dunn N, Mullee M, Perry VH, Holmes C (2005) Association B, Heun R, van den Bussche H, Heuser I, Kornhuber J, 973
909 between dementia and infectious disease: Evidence from a Wiltfang J, Dichgans M, Frolich L, Hampel H, Hull M, 974
910 case-control study. Alzheimer Dis Assoc Disord 19(2), 91- Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny 975
P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs
rre
976
911 94.
912 [8] Holmes C, El-Okl M, Williams AL, Cunningham C, S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass 977
913 Wilcockson D, Perry VH (2003) Systemic infection, inter- NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al- 978
914 leukin 1 and cognitive decline in Alzheimers disease. J Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, 979
915 Neurol Neurosurg Psychiatry 74, 788-789. Muhleisen TW, Nothen MM, Moebus S, Jockel KH, Klopp 980
916 [9] Holmes C, Cunningham C, Zotova E, Woolford J, Dean N, Wichmann HE, Carrasquillo MM, Pankratz VS, Younkin 981
co
917 C, Kerr S, Culliford D, Perry VH (2009) Systemic inflam- SG, Holmans PA, ODonovan M, Owen MJ, Williams J 982
918 mation and disease progression in Alzheimers disease. (2009) Genome-wide association study identifies variants 983
919 Neurology 73, 768-774. at CLU and PICALM associated with Alzheimers disease. 984
920 [10] van Exel E, Eikelenboom P, Comijis H, Frolich M, Amit JH, Nat Genet 41, 1088-1093. 985
[17] Braak H, Braak E (1995) Staging of Alzheimers disease-

Un
921 Stek ML, Scheltens P, Eefsting JE, Westendorp RG (2009) 986
922 Vascular factors and markers of inflammation in offspring related neurofibrillary changes. Neurobiol Aging 16, 271- 987
923 with a parental history of late onset Alzheimer disease. Arch 278. 988
924 Gen Psychiatry 66, 1263-1270. [18] Alzheimer A (1907) Ueber eine eigenartige Erkankung der 989
925 [11] Eikelenboom P, Veerhuis R, van Exel E, Hoozemans JJM, Hirnrinde. Allgemein Zeitschrift Psychiatrie 64, 146-148. 990
926 Rozemuller AJM, van Gool WA (2011) The early involve- [19] Terry RD (1991) Physical basis of cognitive alterations in 991
927 ment of the innate immunity in the pathogenesis of late-onset Alzheimers disease: Synapse loss is the major correlate of 992
928 Alzheimers disease: Neuropathological, epidemiological cognitive impairment. Ann Neurol 30, 572-580. 993
929 and genetic evidence. Curr Alzheimer Res 8, 142-150. [20] Iqbal K, Grundke-Iqbal I (1991) Ubiquitination and 994
930 [12] Nicoll JA, Mrak RE, Graham DI, Stewart J, Wilcock G, abnormal phosphorylation of paired helical filaments in 995
931 MacGowan S, Esiri MM, Murray LS, Dewar D, Love S, Alzheimers disease. Mol Neurobiol 5, 399-410. 996
932 Moss T, Griffin WS (2000) Association of interleukin-1 gene [21] Brion JP, Hanger DP, Bruce MT, Couck AM, Flament- 997
933 polymorphisms with Alzheimers disease. Ann Neurol 47, Durand J, Anderton BH (1991) Tau in Alzheimer 998
934 365-368. neurofibrillary tangles. N- and C-terminal regions are dif- 999
935 [13] Eikelenboom P, Rozemuller JM, Kraal G, Stam FC, ferentially associated with paired helical filaments and 1000
936 McBride PA, Bruce ME, Fraser H (1991) Cerebral amyloid the location of a putative abnormal phosphorylation site. 1001
937 plaques in Alzheimers disease but not in scrapie-affected Biochem J 273, 127-133. 1002
1003 [22] Kopec KK, Carroll RT (1998) Alzheimers beta-amyloid [39] Morgan BP, Gasque P (1996) Expression of complement in 1067
1004 peptide 1-42 induces a phagocytic response in murine the brain: Role in health and disease. Immunol Today 17, 1068
1005 microglia. J Neurochem 71, 2123-2131. 461-466. 1069
1006 [23] Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE [40] Freeman MR (2006) Sculpting the nervous system: Glial 1070
(2009) CD14 and toll-like receptors 2 and 4 are required for control of neuronal development. Curr Opin Neurobiol 16,
f
1007 1071
1008 fibrillar Abeta-stimulated microglial activation. J Neurosci 119-125. 1072
roo
1009 29, 11982-11992. [41] Perry VH, Nicoll JA, Holmes C (2010) Microglia in neu- 1073
1010 [24] Duckworth WC, Bennett RG, Hamel FG (1998) Insulin rodegenerative disease. Nat Rev Neurol 6, 193-201. 1074
1011 degradation: Progress and potential. Endocr Rev 19, 608- [42] Hitt R, Young-Xu Y, Silver M, Perls T (1999) Centenarians: 1075
1012 624. The older you get the healthier youve been. Lance 354, 1076
1013 [25] Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, 652. 1077
1014 Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette [43] Kliegel M, Moor C, Rott C (2004) Cognitive status and 1078
P
1015 S (2003) Insulin-degrading enzyme regulates the levels of development in the oldest old: A longitudinal analysis from 1079
1016 insulin, amyloid beta-protein, and the beta-amyloid precur- the Heidelberg Centenarian study. Arch Gerontol Geriatr 1080
1017 sor protein intracellular domain in vivo. Proc Natl Acad Sci 39, 143-156. 1081
1018 U S A 100, 4162-4167. [44] Perls T (2004) Centenarians who avoid dementia. Trends 1082
1019
1020
1021
1022
[26] Biessels GJ, Kappelle LJ (2005) Increased risk of
Alzheimers disease in type II diabetes: Insulin resistance
of the brain or insulin-induced amyloid pathology? Biochem
Soc Trans 33, 1041-1044.
[45]
or
Neurosci 27, 633-636.
Imhof A, Kovari E, von Gunten A, Gold G, Rivara CB, Her-
rmann FR, Hof PR, Bouras C, Giannakopoulos P (2007)
Morphological substrates of cognitive decline in nonage-
1083
1084
1085
1086
uth
1023 [27] Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de narians and centenarians: A new paradigm? J Neurol Sci 1087
1024 la Monte SM (2006) Intracerebral streptozotocin model of 257, 72-79. 1088

[46] Cagin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, 1089
1025 type 3 diabetes: Relevance to sporadic Alzheimers disease.
Turkheimer FE, Jones T, Banati RB (2001) In-vivo mea- 1090
1026 J Alzheimers Dis 9, 13-33.
surement of microglia in dementia. Lancet 358, 461-467. 1091
1027 [28] Labak M, Foniok T, Kirk D, Rushforth D, Tomanek B,
[47] Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, 1092
1028 Jasinski A, Grieb P (2010) Metabolic changes in the rat
Bullock R, Walker Z, Kennedy A, Fox N, Rossor M, Brooks
dA
1093
1029 brain following intracerebriventricular injections of strep-
DJ (2009) Microglial activation and amyloid deposition in 1094
1030 tozotocin: A model of sporadic Alzheimers disease. Acta
mild cognitive impairment: A PET study. Neurology 72, 56- 1095
1031 Neurochir Suppl 106, 177-181.
62. 1096
1032 [29] Yanker BA, Duffy LK, Kirschner DA (1990) Neurotrophic [48] Fassbender K, Walter S, Kuhl S, Landmann R, Ishii K, 1097
1033 and neurotoxic effects of amyloid beta protein: Reversal by Bertsch T, Stalder AK, Muehlhauser F, Liu Y, Ulmer AJ, 1098
1034 tachykinin neuropeptides. Science 250, 279-282. Rivest S, Lentschat A, Gulbins E, Jucker M, Staufenbiel 1099
[30] Deshpande A, Mina E, Glabe C, Busciglio J (2006) Differ-
cte
1035
M, Brechtel K, Walter J, Multhaup G, Penke B, Adachi Y, 1100
1036 ent conformations of amyloid beta induces neurotoxicity by Hartmann T, Beyreuther K (2004) The LPS receptor (CD14) 1101
1037 distinct mechanisms in human cortical neurons. J Neurosci links innate immunity with Alzheimers disease. FASEB J 1102
1038 26, 6011-6018. 18, 203-205. 1103
1039 [31] Banati RB, Myers R, Kreutzberg (1997) GW PK (periph- [49] Walter S1, Letiembre M, Liu Y, Heine H, Penke B, Hao 1104
1040 eral benzodiazepine)-binding sites in the CNS indicate W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, 1105
rre
1041 early and discrete brain lesions: Microautoradiographic Fassbender K (2007) Role of Toll-like receptor 4 in neuroin- 1106
1042 detection of [3H]pk11195 binding to activated microglia. flammation in Alzheimers disease. Cell Physiol Biochem 1107
1043 J Neurocytol 26, 77-82. 20, 947-956. 1108
1044 [32] Banati RB (2002) Visualising microglial activation in vivo. [50] Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison 1109
1045 Glia 40, 206-217. JC (1990) CD14, a receptor for complexes of lipopolysac- 1110
[33] McGeer PL, McGeer EG (2001) Polymorphisms in inflam-
co
1046 charide (LPS) and LPS binding protein. Science 12, 56-63. 1111
1047 matory genes and the risk of Alzheimer disease. Arch Neurol [51] Spires TL, Hayman BT (2005) Transgenic models of 1112
1048 58, 1790-1792. Alzheimers disease: Learning from Animals. NeuroRx 2, 1113
1049 [34] Schwab C, McGeer PL (2008) Inflammatory aspects of 423-437. 1114
1050 Alzheimer disease and other neurodegenerative disorders. [52] Zlokovic BV, Frangione B (2003) Transport clearance 1115
Un
1051 J Alzheimers Dis 13, 359-369. hypothesis for A metabolism and Alzheimers disease. 1116
1052 [35] Oldfield BJ, Mckinley MJ (1995) Circumventricular organs, In A Metabolism and Alzheimers Disease. Saido TC, ed. 1117
1053 In The Rat Nervous System, Paxinos G, ed. Academic Press, Landes Bioscience, Georgetown, Texas, 117-125. 1118
1054 San Diego, pp. 391-403. [53] Pawelec G (1999) Immunosenescence: Impact in the young 1119
1055 [36] Lacroix S, Feinstein D, Rivest S (1998) The bacterial endo- as well as the old? Mech Ageing Dev 108, 1-7. 1120
1056 toxin lipopolysaccharide has the ability to target the brain [54] Targonski PV, Jacobson RM, Poland GA (2007) Immunose- 1121
1057 in upregulating its membrane CD14 receptor within specific nescence: Role and measurement in influenza vaccine 1122
1058 cellular populations. Brain Pathol 8, 625-640. response among the elderly. Vaccine 25, 3066-3069. 1123
1059 [37] Ross TM, Martinez PM, Renner JC, Thorne RG, Hanson LR, [55] Forner L, Larsen T, Kilian M, Holmstrup P (2006) Incidence 1124
1060 Frey WH 2nd (2004) Intranasal administration of interferon of bacteremia after chewing, tooth brushing, and scaling in 1125
1061 beta bypasses the blood-brain barrier to target the central individuals with periodontal inflammation. J Clin Periodon- 1126
1062 nervous system and cervical lymph nodes: A non-invasive tol 33, 401-407. 1127
1063 treatment strategy for multiple sclerosis. J Neuroimmunol [56] Lockhart PB, Brennan MT, Sasser HC, Fox PC, Paster BJ, 1128
1064 151, 66-77. Bahrani-Mougeot FK (2008) bacteremia associated with 1129
1065 [38] Rivest S (2009) Regulation of innate immune responses in tooth brushing and dental extraction. Circulation 117, 3118- 1130
1066 the brain. Nat Rev Immunol 9, 429-439. 3125. 1131
1132 [57] Norman DC, Yoshikawa TT (1983) Intraabdominal infec- lence factors in short-term postmortem Alzheimers disease 1197
1133 tions in the elderly. J Am Geriatr Soc 31, 677-684. brain tissue. J Alzheimers Dis 36, 665-677. 1198
1134 [58] De Vecchi E, Sitia S, Romano CL, Ricci C, Mattina R, Drago [75] de Oliveira C, Watt R, Hamer M (2010) Tooth brushing, 1199
1135 L (2013) Aetiology and antibiotic resistance patterns of uri- inflammation, and risk of cardiovascular disease: Results 1200
nary tract infections in the elderly: A six months study. J from Scottish Health Survey. BMJ 340, c2451.
f
1136 1201
1137 Med Microbiol 62, 859-863. [76] Paganini-Hill A, White SC, Atchison KA (2012) Denti- 1202
roo
1138 [59] Haffajee AD, Socransky SS, Dzink JL, Taubman MA, Eber- tion, dental health habits, and dementia: The Leisure World 1203
1139 sole JL, Smith DJ (1988) Clinical, microbiological and Cohort study. J Am Geriatr Soc 60, 1556-1563. 1204
1140 immunological features of subjects with destructive peri- [77] Aida J, Kondo K, Kondo N, Watt RG, Sheiham A, Tsakos 1205
1141 odontal diseases. J Clin Periodontol 15, 240-246. G (2011) Income inequality, social capital and self-rated 1206
1142 [60] Gatz M, Mortimer JA, Fratiglioni L, Johansson B, Berg health and dental status in older Japanese. Soc Sci Med 73, 1207
1143 S, Reynolds CA, Pedersen NL (2006) Potentially modifi- 1561-1568. 1208
P
1144 able risk factors for dementia in identical twins. Alzheimers [78] Arai K, Sumi Y, Uematsu H, Miura H (2003) Association 1209
1145 Dement 2, 110-117. between dental health behaviours, mental/physical function 1210
1146 [61] Stein PS, Desrosiers M, Donegan SJ, Yepes JF, Kryscio and self-feeding ability among the elderly: A cross-sectional 1211
1147 RJ (2007) Tooth loss, dementia and neuropathy in the Nun survey. Gerodontology 20, 78-83. 1212
1148
1149
1150
1151
[62]
study. J Am Dent Assoc 138, 1314-1322.
Stewart R, Sabbah W, Tsakos G, DAiuto F, Watt RG (2008)
Oral health and cognitive function in the Third National
Health and Nutrition Examination Survey (NHANES III).
[79]
or
Griffin SO, Jones JA, Brunson D, Griffin P, Bailey WB
(2012) Burden of oral diseases among older adults and impli-
cations for public health priorities. Am J Public Health 102,
411-418.
1213
1214
1215
1216
uth
1152 Psychosom Med 70, 936-941. [80] Philip P, Rogers C, Kruger E, Tennant M (2012) Oral 1217
1153 [63] Noble JM, Borrell LN, Papapnou PN, Elkind MSV, hygiene care status of elderly with dementia and in res- 1218
1154 Scarmeas N, Wright CB (2009) Periodontitis is associated idential aged care facilities. Gerodontology 29, e306- 1219
1155 with cognitive impairment among older adults: Analysis e311. 1220
1156 of NHANES-III. J Neurol Neurosurg Psychiat 80, 1206- [81] Friedlander AH, Norman DC, Mahler ME, Norman KM, 1221
1157 1211. Yagiela JA (2006) Alzheimers disease: Psychopathology, 1222
dA
1158 [64] Kamer AR, Craig RG, Pirraglia E, Dasanayake AF, Norman medical management and dental implications. J Am Dent 1223
1159 RG, Boylan RJ, Nehorayoff A, Glodzik L, Brys M, de Leon Assoc 137, 1240-1251. 1224
1160 MJ (2009) TNF and antibodies to periodontal bacteria dis- [82] Chapple I, Milward MR, Dietrich T (2007) The prevalence 1225
1161 criminate between Alzheimers disease patients and normal of inflammatory periodontitis is negatively associated with 1226
1162 subjects. J Neuroimmunol 216, 92-97. serum antioxidant concentrations. J Nutr 137, 657-664. 1227
1163 [65] Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson [83] Kinane DF, Marshall GJ (2001) Periodontal manifestations 1228
1164 M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi of systemic disease. Aust Dent Jl 46, 2-12. 1229
cte
1165 RE, Moir RD (2010) The Alzheimers disease-associated [84] Hasturk H, Kantarci A, Van Dyke TE (2012) Oral inflam- 1230
1166 amyloid beta-protein is an antimicrobial peptide. PLoS One matory diseases and systemic inflammation: Role of the 1231
1167 5, e9505. macrophage. Front Immunol 3, 1-11. 1232
1168 [66] Zaiou M (2007) Multifunctional antimicrobial peptides: [85] Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL 1233
1169 Therapeutic targets in several human diseases. J Mol Med (1998) Microbial complexes in subgingival plaque. J Clin 1234
1170 (Berl) 85, 317-329. Periodontol 25, 134-144. 1235
rre
1171 [67] Dennison SR, Morton LH, Harris F, Phoenix DA (2008) [86] Holt SC, Ebersole JL (2005) Porphyromonas gingivalis, 1236
1172 The impact of membrane lipid composition on antimicrobial Treponema denticola, and Tannerella forsythia: The red 1237
1173 function of an alpha-helical peptide. Chem Phys Lipids 151, complex, a prototype polybacterial pathogenic consortium 1238
1174 92-102. in periodontitis. Periodontology 38, 72-122. 1239
1175 [68] Kawahara M, Ohtsuka I, Yokoyama S, Kato-Negishi [87] Bahrani-Mougeot FK, Paster BJ, Coleman S, Ashar J, Bar- 1240
co
1176 M, Sadakane Y (2011) Membrane incorporation, Chan- buto S, Lockhart PB (2008) Diverse and novel oral bacterial 1241
1177 nel formation, and disruption of calcium homeostasis by species in blood following dental procedures. J Clin Micro- 1242
1178 Alzheimers -Amyloid protein. Int J Alzheimers Di 2011, biol 46, 2129-2132. 1243
1179 304583. [88] DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell 1244
1180 [69] Holmes C, Cotterell D (2009) Role of infection in the patho- CM (1993) Dental disease and risk of coronary artery disease 1245
Un
1181 genesis of Alzheimers disease. CNS Drugs 23, 993-1002. and mortality. BMJ 306, 688-691. 1246
1182 [70] Itzhaki RF, Wozniak MA (2008) Herpes simplex virus type [89] Scannapieco FA, Bush RB, Paju S (2003) Associations 1247
1183 I in Alzheimers disease: The enemy with. J Alzheimers Dis between periodontal disease and risk for atherosclerosis, 1248
1184 13, 393-405. cardiovascular disease, and stroke. A systematic review. Ann 1249
1185 [71] Balin BJ, Little CS, Hammond CJ, Appelt DM, Whittum- Periodontal 8, 38-53. 1250
1186 Hudson JA, Gerard HC, Hudson AP (2008) Chlamydophila [90] Gleissner C, Willershausen B, Kaesser U, Bolten WW 1251
1187 pneumoniae and the etiology of late-onset Alzheimers dis- (1998) The role of risk factors for periodontal disease in 1252
1188 ease. J Alzheimers Dis 13, 371-380. patients with rheumatoid arthritis. Eur J Med Res 3, 387-392. 1253
1189 [72] Riviere GR, Riviere KH, Smith KS (2002) Molecular and [91] Bartold PM, Marshall RI, Haynes DR (2005) Periodontitis 1254
1190 immunological evidence of oral Treponema in the human and rheumatoid arthritis: A review. J Periodontol 76, 2066- 1255
1191 brain and their association with Alzheimers disease. Oral 2074. 1256
1192 Microbiol Immunol 17, 113-118. [92] Pischon N, Pischon T, Kroger J, Gulmez E, Kleber BM, 1257
1193 [73] Miklossy J (2011) Emerging roles of pathogens in Bernimoulin JP, Landau H, Brinkmann PG, Schlattmann P, 1258
1194 Alzheimers disease. Expert Rev Mol Med 13, e30. Zernicke J, Buttgereit F, Detert J (2008) Association among 1259
1195 [74] Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean StJ rheumatoid arthritis, oral hygiene, and periodontitis. J Peri- 1260
1196 (2013) Determining the presence of periodontopathic viru- odontol 79, 979-986. 1261
1262 [93] Grossi SG, Genco RJ (1998) Periodontal disease and dia- [109] Neto JBC, Rosa EF, Pannuti CM, Romito GA (2012) Smok- 1327
1263 betes mellitus: A two-way relationship. Ann Periodontol 3, ing and periodontal disease: A review. Braz Oral Res 26, 1328
1264 51-61. 25-31. 1329
1265 [94] Wilson-Pauwels L, Akesson E, Stewart P, Spacey S (1988) [110] Shchipkova AY, Nagaraja HN, Kumar PS (2010) Subgingi- 1330
Cranial Nerves in Health and Disease. Decker BC Inc., val microbial profiles of smokers with periodontitis. J Dent
f
1266 1331
1267 Toronto. Res 89, 1247-1253. 1332
roo
1268 [95] Danielyan L, Schafer R, von Ameln-Mayerhofer A, Buadze [111] Kumar PS, Matthews CR, Joshi V, de Jager M, Aspiras M 1333
1269 M, Geisler J, Klopfer T, Burkhardt U, Proksch B, Verleys- (2011) Tobacco smoking affects bacterial acquisition and 1334
1270 donk S, Ayturan M, Buniatian GH, Gleiter CH, Frey WH colonization in oral biofilms. Infect Immun 79, 4730-4738. 1335
1271 2nd (2009) intranasal delivery of cells to the brain. Eur J [112] Kumar PS (2012) Smoking and the subgingival ecosystem: 1336
1272 Cell Biol 88, 315-324. A pathogen-enriched community. Future Microbiol 7, 917- 1337
1273 [96] Johnson NJ, Hanson LR, Frey WH (2010) trigeminal path- 919. 1338
P
1274 way delivers a low molecular weight drug from the nose [113] Gautam DK, Jindal V, Gupta SC, Tuli A, Kotwai B, Thakur R 1339
1275 to the brain and orofacial structures. Mol Pharm 7, 884- (2011) Effect of cigarette smoking on the periodontal health 1340
1276 893. status: A comparative, cross-sectional study. J Indian Soc 1341
1277 [97] Foschi F, Izard J, Sasaki H, Sambri V, Prati C, Muller R, Periodontol 15, 383-387. 1342
1278
1279
1280
1281
[98]
Stashenko P (2006) Treponema denticola in disseminating
endodontic infections. J Dent Res 85, 761-765.
Haraszthy V, Zambon J, Trevisan M, Zeid M, Genco R
(2000) Identification of periodontal pathogens in atheroma-
[114]
or
White HK, Levin ED (2004) Chronic transdermal nicotinic
patch treatment effects on cognitive performance in age-
associated memory impairment. Psychopharmacology 171,
465-471.
1343
1344
1345
1346
uth
1282 tous plaques. J Periodontol 71, 1554-1560. [115] Borrell LN, Burt BA, Taylor GW (2005) Prevalence and 1347
1283 [99] Belstrm D, Holmstrup P, Damgaard C, Borch TS, Skjdt trends in periodontitis in the USA: From the NHANES III 1348
1284 MO, Bendtzen K, Nielsen CH (2011) The atherogenic to the NHANES 1988 to 2000. J Dent Res 84, 924-930. 1349
1285 bacterium Porphyromonas gingivalis evades circulating [116] Borrell LN, Crawford ND (2008) Social disparities in 1350
1286 phagocytes by adhering to erythrocytes. Infect Immun 79, periodontitis among United States adults 1999-2004. Com- 1351
1287 1559-1565. munity Dent Oral Epidemiol 36, 383-391. 1352
dA
1288 [100] Arrive E, Letenneur L, Matharan F, Laporte C, Helmer C, [117] Sabbah W, Tsakos G, Sheiham A, Watt RG (2009) The role 1353
1289 Barberger-Gateau P, Miquel JL, Dartigues JF (2012) Oral of health-related behaviours in the socioeconomic dispari- 1354
1290 health condition of French elderly and risk of dementia: A ties in oral health. Soc Sci Med 68, 298-303. 1355
1291 longitudinal cohort study. Community Dent Oral Epidemiol [118] Sharp ES, Gatz M (2011) The relationship between educa- 1356
1292 40, 230-238. tion and dementia: An updated systematic review. Alzheimer 1357
1293 [101] Syrjala AM, Ylostalo P, Ruoppi P, Komulainen K, Har- Dis Assoc Disord 25, 289-304. 1358
1294 tikainen S, Sulkava R, Knuuttila M (2012) Dementia and [119] Kornman KS, Crane A, Wang HY, di Giovine FS, Newman 1359
cte
1295 oral health among subjects aged 75 years or older. Gerodon- MG, Pirk FW, Wilson TG Jr, Higginbottom FL, Duff GW 1360
1296 tology 29, 36-42. (1997) The interleukin-1 genotype as a severity factor in 1361
1297 [102] Yamamoto T, Kondo K, Nakada M, Aida J, Hirata Y (2012) adult periodontal disease. J Clin Periodontol 24, 72-77. 1362
1298 Association between self-reported dental health status and [120] Galbraith GMP, Hendley TM, Sanders JJ, Palesch Y, Pandey 1363
1299 onset of dementia: A 4-year prospective cohort study of JP (1999) Polymorphic cytokine genotypes as markers of 1364
1300 older Japanese adults from the Aichi Gerontological Evalu- disease severity in adult periodontitis. J Clin Periodontol 1365
rre
1301 ation Study (AGES). Project Psychosom Med 74, 241-248. 26, 705-709. 1366
1302 [103] Mooijaart SP, Gussekloo J, Frolich M, Jolles J, Stott DJ, [121] Shao MY, Huang P, Cheng R, Hu T (2009) Interleukin-6 1367
1303 Westendorp RGJ, de Craen AJM (2005) Homocysteine, polymorphisms modify the risk of periodontitis: A system- 1368
1304 vitamin B-12, and folic acid and the risk of cognitive decline atic review and meta-analysis. J Zheijang Univ Sci B 10, 1369
1305 in old age: The Leiden 85-plus study. Am J Clin Nutr 82, 920-927. 1370
co
1306 866-871. [122] Shearer DM, Thomson WM, Caspi A, Moffitt TE, Broadbent 1371
1307 [104] Engelborghs S, Gilles C, Ivanoiu A, Vandewoude M (2014) JM, Poulton R (2011) Inter-generational continuity in peri- 1372
1308 Rationale and clinical data supporting nutritional interven- odontal health: Findings from the Dunedin Family History 1373
1309 tion in Alzheimers disease. Acta Clin Belg 69, 17-24. Study. J Clin Periodontol 38, 301-309. 1374
1310 [105] Sparks Stein P, Steffen MJ, Smith C, Jicha G, Ebersole [123] Selye H (1974) Stress without Distress, Lippincott, New 1375
Un
1311 JL, Abner E, Dawson D (2012) Serum antibodies to peri- York. 1376
1312 odontal pathogens are a risk factor for Alzheimers disease. [124] Miller DB, OCallaghan JP (2002) Neuroscience aspects of 1377
1313 Alzheimers Dement 8, 196-203. the response to stress. Metabolism 51(6 Suppl 1), 5-10. 1378
1314 [106] Chen JQ, Cammarata PR, Baines CP, Yager JD (2009) Reg- [125] Lupien SJ, Gillin CJ, Hauger RL (1999) Working memory is 1379
1315 ulation of mitochondrial respiratory chain biogenesis by more sensitive than declarative memory to the acute effects 1380
1316 estrogens/estrogen receptors and physiological, patholog- of corticosteroids: A dose-response study in humans. Behav 1381
1317 ical and pharmacological implications. Biochem Biophys Neurosci 113, 420-430. 1382
1318 Acta 1793, 1540-1570. [126] Hoffman R, AlAbsi M (2003) The effect of acute stress on 1383
1319 [107] Desvarieux M, Schwahn C, Volzke H, Demmer RT, Lude- subsequent neuropsychological test performance. Arch Clin 1384
1320 mann J, Kessler C, Jacobs DR, John U, Kocher T (2004) Neuropsychol 19, 497-506. 1385
1321 Gender differences in the relationship between periodontal [127] Wolf OT, Schommer NC, Hellhammer DH, Reischies FM, 1386
1322 disease, tooth loss and atherosclerosis. Stroke 35, 2029- Kirschbaum C (2002) Moderate psychosocial stress appears 1387
1323 2035. not to impair recall of words learned 4 weeks prior to stress 1388
1324 [108] Jagannathachary S, Kamaraj D (2010) Obesity and exposure. Stress 5, 59-64. 1389
1325 periodontal disease. J Indian Soc Periodontol 14, 96- [128] Dhabhar FS, McEwen BS (1997) Acute stress enhances 1390
1326 100. while chronic stress suppresses cell-mediated immunity in 1391
1392 vivo: A potential role for leukocyte trafficking. Brain Behav [137] McEwan BS (2007) Physiology and neurobiology of stress 1420
1393 Immun 11, 286-306. and adaptation: Central role of the brain. Physiol Rev 87, 1421
1394 [129] Oitzl MS, Champagne DL, van der Veen R, de Kloet ER 873-904. 1422
1395 (2010) Brain development under stress: Hypotheses of glu- [138] Gouin JP, Hantsoo L, Kiecolt-Glaser JK (2008) Immune 1423
cocorticoid actions revisited. Neurosci Biobehav Rev 34, dysregulation and chronic stress among older adults: A
f
1396 1424
1397 853-866. review. Neuroimmunomodulation 15, 251-259. 1425
roo
1398 [130] Pomerleau CS, Pomerleau OF (1987) The effects of a psy- [139] Gusev NB, Bogatcheva NV, Marston SB (2002) Structure 1426
1399 chological stressor on cigarette smoking and subsequent and properties of small heat shock proteins (sHsp) and their 1427
1400 behavioral and physiological responses. Psychophysiology interaction with cytoskeletal proteins. Biochemistry 67, 511- 1428
1401 24, 278-285. 519. 1429
1402 [131] Cooper ML, Russell M, Skinner JB, Frone MR, Mudar P [140] Dou F, Netzer WJ, Tanemura K, Li F, Hartl FU, Takashima 1430
1403 (1992) Stress and alcohol use: Moderating effects of gender, A, Gouras GK, Greengard P, Xu H (2003) Chaperones 1431
P
1404 coping, and alcohol expectancies. J Abnorm Psychol 101, increase associations of tau protein with microtubules. Proc 1432
1405 139-152. Natl Acad Sci U S A 100, 721-726. 1433
1406 [132] Torres SJ, Nowson CA (2007) Relationship between stress, [141] Obata T, Yaffe MB, Leparc GG, Piro ET, Maegawa H, 1434
1407 eating behaviour, and obesity. Nutrition 23, 887-894. Kashiwagi A, Kikkawa R, Cantley LC (2000) Peptide and 1435
1408
1409
1410
1411
[133]
[134]
Akcali A, Huck O, Tenebaum H, Davideau JL, Buduneli
N (2013) Periodontal diseases and stress: A brief review. J
Oral Rehabil 40, 60-68.
Giannopoulou C, Kamma JJ, Mombelli A (2003) Effect
[142] or
protein library screening defines optimal substrate motifs
for AKT/PKB. J Biol Chem 17, 108-115.
Scheinfeld M H, Roncarati R, Vito P, Lopez P A, Abdal-
lah M, DAdamio L (2002) Jun NH2 -terminal kinase (JNK)
1436
1437
1438
1439
uth
1412 of inflammation, smoking and stress on gingival crevicular interacting protein 1 (JIP1) binds the cytoplasmic domain 1440
1413 fluid cytokine level. J Clin Periodontol 30, 145-153. of the Alzheimers beta-amyloid precursor protein (APP). J 1441
1414 [135] Turnbull AV, Rivier CL (1999) Regulation of the Biol Chem 277, 3767-3775. 1442
1415 hypothalamic-pituitary-adrenal axis by cytokines: Actions [143] Zhu X, Raina AK, Lee HG, Casadesus G, Smith MA, Perry 1443
1416 and mechanisms of action. Physiol Rev 79, 1-71. G (2004) Oxidative stress signaling in Alzheimers disease. 1444
1417 [136] Li G, Cherrier MM, Tsuang DW, Petrie EC, Colasurdo Brain Res 1000, 32-39. 1445
dA
1418 EA, Craft S, Schellenberg GD, Peskind ER, Raskind MA,

1419 Wilkinson CW (2006) Salivary cortisol and memory func-
tion in human aging. Neurobiol Aging 27, 1705-1714.
cte
rre
co
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Journal of Alzheimers Disease xx (20xx) xxx 1

6 and StJohn Creanb,1,

Accepted 14 April 2014

28 Keywords: Alzheimers disease, inflammation, oral health, periodontal disease

Alzheimers disease (AD), a form of dementia, is the 30

derived from Streptomyces species of bacteria [28]. It 116

is, therefore, plausible to suggest that an initial micro- 117

68 ALZHEIMERS DISEASE and the subsequent deposition of A in late-onset AD. 119

A plaques can be observed in the brains of cogni- 120

microglia) bearing the LPS receptor (CD14) and the 177

highly conserved toll-like receptors 2 and 4 (TLR 2 178

154 WHAT IS INTRA-CEREBRAL and 4) undergo a number of phenotypic (resting to 179

logical changes include thickening and shortening of 181

309 spp., [72] Borrelia burgdorferi [73], and more recently

world population and is a major cause of tooth loss. 358

The prevalence of PD increases with age, affecting 359

interaction of specific bacteria and the hosts immune 362

401 ANATOMICAL RELATIONSHIP OF FACIAL

using local anesthesia (e.g., novocaine, xylocaine), the 455

Nutritional deficiencies are documented in the 556

ciencies also correlates with cognitive decline, but as 560

516 and motility of the low virulence strains of periodontal

517 pathogens may not be sufficient for them to access the

522 Our unpublished data demonstrates that P. gingivalis

[109]. Smoking is thought to affect neutrophil func- 644

tion, reducing the hosts ability to eliminate periodontal 645

pathogenic microbial profile than non-smokers with 647

present as dementia-like even within a cognitively nor- 742

698 AND PERIODONTITIS to impairments in attention [125], working memory 745

and inhibitory control [126], and declarative memory 746

709 pathogenesis [59], it is thought that PD itself may have

vulnerability of periodontal tissue to microorganisms 770

leading to further tissue destruction [133]. Inhibition of 771

725 FACTORS in part, susceptibility to PD and pro-inflammatory 773

cytokines are potent activators of the HPA axis [134, 774

IL-6 and IL-1 levels in gingival crevicular fluid [133]. 776

periodontal status of the cases analyzed. 833

785 High levels of environmental stressors could lead to

ing periodontal status of the individual? Or common

between parents with AD and their children at a much

our current understanding of the causal association 855

809 pathways can also be activated by oxidative stress [142,

AD. Although various types of neurotropic spirochetes 858

including oral (Treponema spp) and non-oral spiro- 859

chetes (B. burgdorferi) have been detected directly in 860

ined the role of periodontal bacteria during chronic 865

with the development of AD pathology. Even though 868

[14] Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole 940

899 48, 626-632. 1094-1099. 964

[17] Braak H, Braak E (1995) Staging of Alzheimers disease-

921 Stek ML, Scheltens P, Eefsting JE, Westendorp RG (2009) 986

1008 fibrillar Abeta-stimulated microglial activation. J Neurosci 119-125. 1072

1024 la Monte SM (2006) Intracerebral streptozotocin model of 257, 72-79. 1088

1418 EA, Craft S, Schellenberg GD, Peskind ER, Raskind MA,

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