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8.1 Introduction

Alzheimer’s disease (AD) is one of the leading causes of dementia [1]. In the United States alone, approximately 5.3 million patients have been diagnosed with AD [2] and in view of the country’s aging demographics, its prevalence and incidence will continue to increase as the population ages. One in 9 and one in 3 people older than 65 and 85, respectively, have AD, and approximately 61,000 and 240,000 new cases of AD in the 65–75 and 85 and older age groups, respectively, were reported in 2015 [2]. Notably, AD in the United States is ranked the 9th leading cause of mortality ahead of breast and colon cancer and is ranked 12th in contribution to years of disability [3]. It is estimated that delaying the onset of AD by 5 years could result in a 50 % decrease in prevalence 50 years later. Undoubtedly, as the population ages and life span increases, the prevalence of AD will increase even further, and in 50 years, AD is predicted to afflict approximately 16 million people [4]. Although the above statistics underscore AD as a major public health concern, the prevalence of AD will not significantly decrease unless novel approaches emerge to help prevent and slow the progression and manage AD. Therefore, efforts to “think out of the box” and identify novel, modifiable factors involved in the initiation and progression of AD are of paramount importance.

Two types of AD are recognized. Early onset AD is present in less than 5 % of the population and is genetically determined [5]. Late onset or sporadic AD (LOAD) is the most prevalent type of AD and is believed to result from the interaction of multiple genetic and environmental factors [6, 7]. As is true for atherosclerosis and hypertension, AD is thought to be a continuous process developing over many years and understanding the relative contributions of both genetic and environmental factors to AD pathogenesis is essential to determine disease susceptibility and prevention. Although risk factors such as age, race, family history, and disease-associated genes such as ApoE with an ε4 allele [5] are immutable, environmental risk factors may be modifiable and serve as a target for therapy. Despite the significant strives made in understanding the pathogenesis of AD, to date there are no drugs that can modify the course of AD. Therefore, emphasis has been placed on understanding the role of environmental risk factors. Among the risk factors recognized by The Alzheimer’s Association are: cerebrovascular disease, hypertension, diabetes, obesity, smoking, depression, psychological stress, and history of head trauma [8]. In addition to these established risk factors, novel factors such as periodontal disease have also been implicated in the pathogenesis of AD. Eradication of a single risk factor may not have a major effect but if several risk factors are removed the combined effect may substantially reduce or delay the onset of AD [9]. Delaying the onset of AD by only 1 year would constitute a major effect [10]. With this goal in mind, the objective of this chapter is to briefly summarize our current understanding of the pathogenesis of AD and the evidence potentially linking periodontal disease with AD.

8.2 Clinical Diagnosis of AD

For almost 30 years the clinical diagnosis of probable AD was made using criteria published by the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA) workgroup (NINCDS-ADRDA). By these criteria the diagnosis of AD was based on the presence of a dementia syndrome encompassing an array of symptoms and signs characterized by a decline in cognitive performance severe enough to interfere with daily activities. Although the specific signs and symptoms depend on the type of dementia, several symptoms are common to all types of dementia including loss of memory, difficulty in planning and executing tasks, inability to recognize faces and orient objects, difficulty in communicating, and behavior changes. A definite diagnosis of AD, however, required a neuropathologic evaluation.

Recently, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) workgroup updated the diagnostic criteria. The new diagnosis criteria acknowledged that pathophysiologic processes in AD begin early in life and can be present in cognitively normal (NL) individuals as well as individuals with mild cognitive impairment (MCI). For the diagnosis of AD, NIA-AA proposed the utilization of the following diagnostic classification groups: (1) probable AD dementia, (2) possible AD dementia, and (3) probable or possible AD dementia with evidence of the AD pathophysiological process [11]. The first two classifications are for clinical use. The third classifying criteria include evidence of AD-specific biomarkers obtained by techniques such as imaging or cerebrospinal fluid (CSF) analysis by lumbar puncture and are intended to be used in research settings. Common diagnostic criteria for these groups include:

  • The presence of a dementia syndrome (defined above) encompassing impairments affecting at least two of the following domains of cognition/behavior: memory, executive function, visuospatial, language, and behavior/personality.

  • The onset of the dementia is gradual and not acute. This feature differentiates a dementia syndrome from other acute cognitive conditions (such as delirium).

  • The course of dementia is progressive although not necessarily uniform.

  • The dementia syndrome is not due to cardiovascular diseases, Lewy body formation, frontotemporal pathology, or conditions affecting the brain (i.e., tumors, drugs). Therefore these conditions should be ruled out.

  • The presence of objective signs of cognitive decline or the presence of a genetic mutation known to be etiologic to AD (genes including APP, PSEN1, and PSEN2) strengthens the diagnosis.

The classification of possible AD dementia is recommended when the dementia has an atypical or mixed presentation. Probable or possible AD dementia with evidence of the AD pathophysiological process is defined as the clinical entity with a clinical diagnosis of probable/possible AD that present with evidence of an AD-specific pathophysiologic processes. This evidence encompasses the presence of AD-specific biomarkers that are classified into (a) biomarkers related to Aβ deposition, (b) biomarkers related to tau pathology, and (c) biomarkers related to neuronal damage. Markers of Aβ deposition are low levels of Aβ42 in subjects’ CSF and/or increased ligand retention by PET imaging such as [C-11]-(2-[4-methyl-amino phenyl]-1,3-benzothiazol-6-ol), or Pittsburgh Compound B (PiB), florbetapir F-18, flutemetamol F18, or florbetaben F18. These ligands bind to fibrillar amyloid in the brain and correlate with brain amyloid deposition. Tau pathology translates into increases in CSF P-tau (phosphorylated tau) and increases in CSF T-tau (total tau). PET based measures of tau are currently in clinical trials. Markers of increased neuronal degeneration include decreased [18F] FDG-PET signal (brain glucose metabolism) and brain atrophy by MRI.

Mild cognitive impairment (MCI) is an intermediate state between NL and dementia and has a high risk of progression to AD. MCI is also known as symptomatic pre-dementia. Patients with MCI present with impairment in memory, executive function, attention, language, or visuospatial skills. However, they do not have dementia and their cognitive impairments do not interfere with daily activities. MCI due to AD assumes that this clinical syndrome is due to pathophysiology characteristic of AD. In addition to clinical criteria, MCI includes AD-specific biomarkers [12]. Preclinical AD also includes cognitively NL individuals expressing AD-specific biomarkers [13, 14]. However the use of biomarkers is presently limited to research and not clinical settings.

8.3 Management of AD

Present FDA approved treatments regimens focus on symptoms and not etiology. Currently, two groups of drugs are used, acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. Acetylcholinesterase inhibitors act by preventing acetylcholine degradation, thus increasing the concentration of acetylcholine in the synaptic cleft and prolonging cholinergic neurotransmission. Acetylcholine inhibitors can be effective for 2–5 years and are usually indicated in mild to moderate AD although donepezil can be administered in all stages. N-methyl-D-aspartate (NMDA) receptor antagonists interfere with the sustained activation of NMDA receptors thus facilitating neuronal function. The noncompetitive NMDA-receptor antagonist memantine acts by regulating glutamate activity. Memantine may be effective in moderate to severe disease but only over shorter time periods. A combination therapy of donepezil and memantine has been approved recently for moderate to severe AD. In addition to cognition, AD patients may exhibit other symptoms such as depression, aggression, psychomotor agitation, and psychosis. Oral complications are not commonly encountered for acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists; however, medications used to treat depressive and psychiatric symptoms have oral complications including hyposalivation and xerostomia with associated sequelae.

8.4 Pathogenesis of AD

The pathologic hallmarks of AD are the presence of senile plaques, neurofibrillary tangles, neuronal and synaptic dysfunction, and neuronal loss. The senile plaques found in the brain parenchyma contain extracellular aggregates of amyloid β-peptide (Aβ) [15]. Associated with senile plaques are activated glial cells, reactive astrocytes, and inflammatory molecules [16]. Aggregates of Aβ also accumulate in brain vessel walls forming cerebral amyloid angiopathy. Neurofibrillary tangles are neuronal intracellular aggregates composed of phosphorylated tau proteins [17]. Macroscopically, neuronal loss and brain atrophy occurs in several sites including the hippocampus and temporal and parietal lobes resulting in the thinning of the cortex and enlargement of the ventricles.first atrophy observed was in the hippocampal formation, a discovery we published in the Lancet in 1989 and replicated in 1991. Afterwards the atrophy spreads to the neocortex. AD is thought to be a continuous process starting as early as 30 years of age although the steps involved in AD pathogenesis are not well understood. The amyloid and inflammatory hypotheses are the most prominent presently hypotheses forwarded to explain the pathogenesis of AD

The amyloid hypothesis posits the initiating event in AD is the presence of amyloid beta peptides (Aβ) that accumulate within the brain and initiate a cascade of events leading to neurodegeneration and neuronal death. The accumulation of Aβ in the brain in both parenchyma and blood vessels results from impairments in the Aβ hemostatic mechanisms. Several mechanisms involving Aβ synthesis and clearance have been proposed and include increased central (brain) synthesis, central degradation, decreased amyloid clearance (efflux) from the brain [18], increased peripheral synthesis [19], decreased peripheral degradation, and a combination of these mechanisms (Fig. 8.1) [20]. Substantial evidence from genetic studies exists for the role of increased amyloid brain synthesis. Several types of early-onset AD present genetic mutations that increase the production of brain amyloid. In patients with late-onset AD, brain amyloid synthesis accumulation appears to be mostly due to decreased clearance although increased synthesis cannot be excluded [21, 22]. Peripheral Aβ contribution to the brain amyloid accumulation is less certain; however current investigations are exploring these areas.

Fig. 8.1
figure 1

Model for peripheral inflammations/infections contribution to amyloid regulation. The accumulation of Aβ in the brain is the result of several mechanisms involving Aβ synthesis and clearance that can occur centrally and peripherally. BBB = blood brain barrier; RAGE = receptor for advanced glycation endproducts (mediates Aβ transport into the brain); LRP = receptor-related protein

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In addition to Aβ synthesis in the brain, Aβ can also be synthesized peripherally. Although the production of Aβ in the peripheral tissue is ubiquitous, the major peripheral producers of amyloid are platelets and perhaps endothelial cells, the liver and muscle. Up to 90 % of peripheral amyloid is attributed to platelets. The cleavage of APP into Aβ peptides occurs upon platelet activation. The released cleavage products are then stored in the alpha granules of platelets and released into the circulation thus Aβ contribute to the Aβ systemic pool [23].

Amyloid clearance from the brain is a complex, multimodal process with several pathways thought to contribute. In addition to enzymatic degradation and glial phagocytosis, these pathways include direct transport of the Aβ through the blood–brain barrier, its transport to the cerebrospinal fluid with absorption in the venous compartment, bulk flow of the interstitial fluid, and peripheral lymphatic system. Other transport pathways such as via optic and olfactory nerves have also been described. The specific contribution of these pathways to the Aβ clearance is not known and form active areas of investigations. Animal models showed that most Aβ clearance takes place at the blood–brain barrier by an active transport mechanism in which low-density lipoprotein receptor-related protein 1 (LRP1) transport receptor plays a crucial role.

The inflammatory hypothesis is a second prominent hypothesis for the pathogenesis of AD [24]. which believes inflammation can play an etiologic (primary) role or can be contributory (secondary) in AD pathogenesis. In an animal model acute as well as chronic inflammation was able to induce AD-related pathology [25] and cognitive decline. In contrast, other studies showed that AD associated molecules such as Aß, p-tau, and degenerating neurons are themselves pro-inflammatory. Whether brain inflammation is etiological or contributory, it is characterized by a self-reinforcing cycle in which pro-inflammatory molecules including TNF-α, Il-1ß, Il-6, and C-reactive protein (CRP) [26] act via paracrine and/or autocrine pathways to stimulate glial cells pathways to stimulate glial cells to further produce more inflammatory and pathogenic molecules such as Aß42, and P-Tau or impair their clearance [27, 28]. Multiple in vitro and animal studies support the role of cytokines and LPS in Aβ production and tau phosphorylation. In vitro, TNF-α, Il-1ß, and Il-6 have been shown to stimulate the synthesis of Aß42 and the phosphorylation of tau protein, while Aß42 and P-Tau have been shown to enhance the production of TNF-α, Il-1ß, and Il-6 by glial cells and the activation of the complement pathway. In animal studies, inflammation associated with LPS resulted in enhanced brain amyloid accumulation and tau phosphorylation and Aß enhanced the glial production of cytokines and cognitive dysfunction.

More importantly, evidence for a role of inflammation in AD also comes from clinical specimens and clinical studies. Senile plaques react with antibodies against TNF-α, Il-1ß, Il-6, CRP, and complement proteins and reactive astrocytes and activated micro-glial cells associate with senile plaques. Elevated CRP increased the risk of both developing AD and of cognitive decline in various populations. Pro-inflammatory cytokines as predictors of AD have also been investigated [29] however some studies report conflicting results [30]. The variation in results among studies is not unexpected for several reasons. Cytokines play important roles in mediating cognition and this effect is concentration and time dependent [31]. They also have beneficial effects on healing as well as amyloid phagocytosis. In addition, inflammation is the summation of multiple signaling and effecter pathways that interact with each. Therefore, the increase or decrease in the individual pro-inflammatory cytokine may not reflect the synergy or contribution from other inflammatory cytokines. Most epidemiological studies investigated only selected cytokines such as Il-6 IL-1ß and TNF-α, therefore reflecting only a limited aspect of inflammation.

Sources of peripheral inflammation that produce significant systemic inflammatory burden such as cardiovascular disease, diabetes, obesity, and the metabolic syndrome also associate with cognitive dysfunction and AD and are now accepted risk factors for AD. Infections with cytomegalovirus, Helicobacter pylori, spirochetes, and herpes simplex virus have also been associated with AD and cognitive dysfunction.

Genetic polymorphisms in the inflammatory/immune genes have also been associated with AD. For example, the presence of a composite genotype characterized by the presence of Il-1α-889 and Il-1β + 3953 polymorphisms conferred an almost 11-fold increased risk of developing AD [32] presumably due to increased Il-1 levels [33]. In addition, findings from genome-wide association studies reported that polymorphisms in immune and inflammatory genes PICALM, CLU, CR1, CR2, TREM2, CD33 were associated with AD. Interestingly, our own study showed that subjects with periodontal inflammation had lower cognition compared to those without periodontal disease [34] and among the subjects with periodontal inflammation, those having IL-1082 AA/AG genotype tested lower on the cognitive test compared to periodontal subjects with IL-1082 GG genotype or subjects without periodontal inflammation [35]. Since the IL-1082 AA/AG genotype has lower production of the anti-inflammatory cytokine IL-10 compared to the IL-1082 GG genotype, this study showed that when a peripheral infection is associated with a genotype predisposing to higher inflammatory response, it might have significantly more effect on the brain.

8.5 Peripheral Inflammatory Mechanisms in the Pathogenesis of AD

The brain is a privileged site whose homeostasis is maintained by the function of a structurally sound blood–brain barrier. However, peripherally derived pro-inflammatory molecules and bacteria or bacterial products can enter the brain by two mechanisms: via systemic circulation and/or neural pathways [36]. Peripherally produced pro-inflammatory molecules can enter the CNS in areas of the brain that lack a blood–brain barrier such as the circumventricular organs, cross through fenestrated capillaries of the brain blood barrier, use cytokine-specific transporters, or activate brain endothelial cells to induce the production of cytokine, nitric oxide, and prostanoids on the abluminal site of the brain (brain site). In addition the blood–brain barrier also expresses toll-like receptors including TLRs1-4 and LTR-6 [37] suggesting that pathogen-associated molecular patterns such a LPS-endotoxin can influence the brain upon blood–brain barrier stimulation. Once in the brain, pro-inflammatory molecules may directly increase the local pro-inflammatory cytokine pool, indirectly increase brain cytokine storage release and stimulate glial cells to synthesize additional pro-inflammatory cytokines [38].

Neurons may also provide an anatomic pathway through which peripherally expressed cytokines or bacteria or bacterial products may access the brain [39]. For example, the trigeminal neurons express TLR-4 and CD14 that could be bound by LPS produced peripherally [40]. This mechanism has been demonstrated in the oral cavity. Injection of interleukin IL-1β into the soft palate of rats induced a febrile response that was significantly attenuated by bilateral glossopharyngeal nerve transection [41].

Pro-inflammatory cytokines and bacteria or bacterial products can contribute to AD by augmenting Aß synthesis [42], disrupting the brain blood barrier and/or amyloid beta trafficking [43], inducing phosphorylation of tau protein, decreasing synaptic strength and neuronal degeneration, and ultimately contributing to cognitive decline [44]. Consistent with these mechanisms, we reported that periodontitis, a chronic infection with significant inflammatory and infectious burden was associated with amyloid accumulation in the brain as assayed by PIB uptake [45]. In addition, subjects with periodontal disease had increased p-tau and t-tau in their CSF (unpublished data) again suggesting that inflammation and inflammatory conditions can contribute to AD-related pathology. If glial cells were already primed as occurs in aging or genetic predisposition, stimulation by peripherally produced pro-inflammatory cytokines would result in amplified effect.

8.6 Periodontitis and AD

Periodontitis is a chronic, polymicrobial, inflammatory disease. In the United States alone, approximately 141 million adults ≥30 years old comprising 46 % of the dentate US adults have periodontitis, and among them 9–12 % have severe periodontitis [46]. In addition to adults, 2–3 % of children have chronic periodontitis and another 0.2–2 % have a severe form called aggressive periodontitis [47].

Clinical data from our studies as well as others using a range of exposure indexes and study designs have reported that measures of periodontal infection were associated with cognitive impairment, cognitive decline, dementia, and AD with odd and hazard ratios of mild to moderate strength [34, 45, 48]. Using the NHANES III data set, high titers of antibodies against P. gingivalis were associated with lower cognitive function [49]. Furthermore, antibodies to A. actinomycetemcomitans, T. forsythus, and T. denticola were predictive of the development of AD years before its clinical diagnosis [50]. Taken together these studies strongly support an infection and/or immune response role of periodontitis in AD pathogenesis. Since the end result of periodontitis is tooth loss, this index has been used as a proxy of the presence of periodontal disease as well as periodontal treatment outcome. Considering the high prevalence of periodontal disease in the general population, even if periodontal effect on AD risk is modest, the numbers of people whose disease could be prevented are staggering.

8.7 Proposed Model for the Effect of Periodontal Disease on AD

Chapter 2 of this volume described the pathogenesis of periodontal diseases. Important to its role in the pathogenesis of AD are its infections and inflammatory burden, both of which can contribute to AD pathogenesis by contributing to the brain inflammation, neurodegeneration by increasing AD-specific pathology, and inducing cognitive decline. The AD-specific pathology commences as early as 30 years of age, and therefore periodontal disease-associated effects on AD pathology can occur before or throughout its progression (Fig. 8.2).

Fig. 8.2
figure 2

Model for periodontal disease contribution to AD progression. The central theme of AD pathogenesis is the presence of brain inflammation characterized by increased proinflammatory cytokines. The periodontal disease-derived pro-inflammatory molecules and bacterial products can contribute to the brain inflammatory pool via systemic circulation and/or neural pathways. In the brain, the pro-inflammatory molecules may stimulate glial cells to synthesize additional pro-inflammatory cytokines, and increase AD-specific pathology, induce neurodegeneration and subsequent cognitive decline

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Periodontal bacteria frequently gain access to the circulatory system. Bacteremia can occur during manipulations of the oral tissues and daily procedures such as flossing, brushing, and mastication particularly when periodontitis is present. Under normal physiologic conditions, bacteremia lasts approximately 30 min until cleared by the immune system. However, if the immune response is weakened, keystone pathogens such as P. gingivalis, B. forsythus, and T. denticola can evade, subvert the immune system, and metastasize at distant sites such as the brain and induce local inflammation. They may also assist other bacteria in doing the same. Several periodontal species can invade proximal tissue. By invading monocytes, bacteria can use these cells as transport mechanisms to reach the brain [51]. At the local periodontal tissue, the pathobionts assisted by the keystone bacteria maintain a continuous dysbiotic, inflammatory milieu thus perpetuating this vicious circle.

Infection-induced effects on AD have been critically reviewed [52]. Miklossy proposed that oral spirochetes could be possible candidates to invade the brain and cause cognitive impairment in AD. Indeed, Riviere et al. detected six different periodontal treponemes in the brains in more than 90 % of the 16 AD cases analyzed [53]. In addition, P. gingivalis-derived LPS was detected in the brains of AD patients [54].

Moderate to severe periodontitis is associated with increased systemic inflammation characterized by elevated levels of IL-1β, IL-6, and TNF-α and CRP [55]. In fact the elevation of the CRP in subjects with periodontitis can reach values that are considered high risk for cardiovascular disease. When these intense host responses associated with periodontal bacterial infections, the periodontal disease systemic effect was significantly increased than when the indexes of periodontal infection and systemic inflammation were absent [56], showing that the host response to the infectious challenge is of significance [57–59].

Cytokines and LPS are found to consistently stimulate amyloid synthesis in the brain and induce cognitive impairment [60]. Spirochetes were found to contribute to amyloid deposition in the brain and cognitive decline [52] and possibly tau pathology [45], findings consistent with our own studies [45].

In addition to central effects, periodontal-derived pro-inflammatory molecules [61] and bacterial products may exert their effects by increasing the production of amyloid peripherally and/or upregulating its transport into the brain. Although direct evidence for this hypothesis does not exist, several possibilities exist that need further investigations. Periodontal disease associates with platelet activation [62]. Since platelet activation increases APP proteolysis, periodontal disease-platelet activation may lead to increased peripheral production of Aβ. Another possible mechanism that could contribute to the brain amyloid accumulation is the upregulation of the Aβ transport into the brain. Upregulating RAGE by periodontal-induced inflammatory molecules or bacteria/bacterial products may enhance the Aβ influx into the brain. It is known that bacterial products and inflammatory molecules can increase RAGE production [63], and this has been also documented in periodontal tissue of nondiabetic subjects [64]. In addition, animal models of nondiabetic-related periodontitis showed increased production of RAGE. AGE is one of the RAGE ligands, and a positive regulator of RAGE and AGE is increased in serum of subjects with periodontitis.

In summary, we suggest that periodontal disease may constitute a risk for AD. Assessing the role of risk factors and their preventive effect in AD pathogenesis requires longitudinal cohort studies in which clinicians and researchers from medical and dental fields collaborate. We recognize that these cohort studies are difficult and expensive to implement. However, the benefits would outweigh the difficulties.