Alzheimer disease with progressive impairment of memory and other cognitive functions is the common cause of dementia. It is an increasingly prevalent condition in an aging population with many oral- and dental-related implications. Primarily with a decline in mental status, Alzheimer disease presents with no motor, sensory, or coordination problems in the early stages. Dementia is a set of behavioral and psychological symptoms associated with the loss of memory, language, and recognition in various stages of the disease that reduce the ability to perform everyday activities. The patient’s stage of Alzheimer disease will be the determinant for the practitioner as to which precautions and procedures they will undertake in the best interest of the patient. Treatment options available for the condition have shown clinical success in terms of symptom improvement and cognitive function; however, they are not devoid of adverse effects. Collaboration with other health professionals is imperative for awareness of drug interactions, formulation of treatment plans, and improvement in the overall well-being of the patient.
Alzheimer disease is the common cause of dementia, with its insidious onset causing the progressive impairment of memory and other cognitive functions. Alzheimer diagnosis relies primarily on the mental decline, with no motor, sensory, or coordination problems evident in the early stages. Currently, neuroimaging with magnetic resonance imaging and computed tomography (CT) is able to confirm the absence of other possible causes. Today there is focus on biomarkers, easily detectable by molecular imaging, such as the PET scan. It is important to understand the disease so sufferers requiring dental treatment can be catered for effectively and efficiently.
Alzheimer disease (AD) is a progressive, degenerative brain disease, and is the most common form of dementia globally. It affects up to 70% of people that suffer from dementia, with an estimated 115.4 million people predicted as sufferers by the year 2050.1 Its incidence and prevalence is linked to the increase in age,2 with approximately 5% of sufferers developing symptoms before the age of 65, associated with early-onset Alzheimer disease (EOAD). Of those, 85 to 90% of sufferers present with sporadic Alzheimer disease, beginning at 50+ years of age, with mainly temporal profile, similar to that of late-onset Alzheimer disease (LOAD).2 LOAD occurs in people aged 65 and older. According to Toyota et al,3 few differences exist behaviorally and psychologically between EOAD and LOAD, with no cognitive or dementia severity differences being displayed. The remainder 10 to 15% will have the genetic form (aggressive in nature, starting at 40 years of age).4 Dementia is not a disease by itself, but rather a set of behavioral and psychological symptoms that are associated with specific diseases.5 The term dementia is generally used to describe the loss of memory, language and recognition in various stages of the disease, to such an extent that it interferes with daily life.6 According to Reisberg,7 there are seven stages of Alzheimer disease, which include preclinical (stage 1), mild dementia (stages 2 and 3), moderate dementia (stages 4 and 5), severe dementia (stage 6), and very severe dementia (stage 7). The patient’s stage of Alzheimer disease will be the determinant for the dental practitioner as to which precautions and procedures they will undertake in the best interest of the patient. This chapter will look at the background, description, epidemiology, pathogenesis/etiology, genetic components, identification, medical history, physical exams and lab testing, dental treatment of patients with the disease, and oral medicines available with regard to AD.
Early detection of AD is instrumental in slowing down the process and providing the necessary care.8 In addition, it provides the best response to treatments and quality of life when dealing with Huntington, Parkinson, and Pick that cause irreversible dementia. Early detection enables a person to function “normally” for longer periods of time, and in some cases, reversible symptoms that mimic dementia can be identified and handled effectively. Alzheimer disease damages the human brain affecting memory, thinking, and behavior. Statistics reveal that globally, approximately 33% of people over the age of 85 have some form of dementia (LOAD).9 However, sporadic Alzheimer disease can affect anyone of any age,10 and familial Alzheimer disease, a rare genetic condition, usually affects people under the age of 65 (EOAD).10
AD was first recorded by Dr. Alois Alzheimer in 1907 when he began studying Auguste Deter, a female patient in her 50s. Her symptoms of dementia were associated with changes taking place in her brain.11 Until the 1970s, Alzheimer disease was considered rare; however, it was Dr. Robert Katzman who realized that senile dementia and Alzheimer disease were the same thing, with both displaying symptoms not part of the normal aging process.12 He hypothesized that two types of AD existed: sporadic (occurring in people 65 years and older), and familial, a genetic condition affecting people in their 40s and 50s, both causing irreversible damage to the brain.
The brain, with its complex network of arteries and veins and capillaries that feed the brain its required blood and oxygen needed to survive, is the most complex part of the body to treat medically.13 As a result, the brain’s blood network is separated from the rest of the body, with its intricate blood barrier protecting it from infection. If an infection does infiltrate this barrier, treatment is difficult as the molecules in antibiotics are too large to penetrate the brain’s barrier. Any agent that could possibly treat Alzheimer disease needs to consist of small molecular structures able to target the brain.14 In addition, the brain is comprised of many parts, such as the temporal lobes responsible for speech, working memory, and “higher emotions” such as empathy, morality, and regret.15 The limbic system of the brain processes our desires and emotions,12 while the cerebellum stores our muscle memory responsible for involuntary muscle actions, such as walking, lifting, etc.16 The midbrain controls the heart rate and digestion and is the link between the spinal cord and the remainder of the brain. All tasks are carried out by sensitive connections via the brain’s neurons, called synapses. In an average adult human brain, 100 billion neurons exist, each connected to its neighbors by 5,000 to 10,000 synapses.17 Every second of our lives we make new connections, we learn new things, and it is in these changing connections that memories are stored, habits are formed, and personalities developed in a unique fashion as no two brains are the same.
Brain cells (neurons) communicate via the process of synapses, where signals move in chemical form across the synapse, called neurotransmitters. These pass from one neuron to the receiving neuron, which collects it using a receptor. The receiving neuron then, in turn, sends out a burst of neurotransmitters to various other brain neurons, and so the message gets relayed.18 What Dr. Alzheimer discovered with Auguste Deter was that the outer layer of the brain, known as the cortex, had visibly undergone a permanent shrinking process caused by dying brain cells. As this part of the brain became affected, so too did Ms. Deter’s ability to remember, to communicate, and to judge. Two types of plaque were also discovered in her brain, plaque outside the brain neurons, and the other inside the brain neurons, which are called “neurofibrillary tangles” (NFTs).19 These plaque deposits hinder synapses, and the NFTs starve the neurons of food and energy. By using the technique of magnetic resonance imaging (MRI), shrinking of the brain can be detected even in the early stages of AD.20 Alzheimer disease is progressive, initially affecting the outer portion of the brain, leading to a loss of short-term memory, and eventually long-term memory loss and other behavioral patterns become disturbed (Fig. 5.1).21
Not a great deal is known about Alzheimer disease, or what triggers the plaque and tangle formations, in addition to the other chemical changes that occur within the brain, as this disease causes irreparable damage. To date only suspected causes have been investigated, such as environment, biochemical disturbances, and the process of the body’s immune system. In the final stages of AD, the three main causes of death are pneumonia, dehydration, and malnutrition.12 The average time frame living with Alzheimer disease is 7 to 10 years.22 However, temporary improvement with regard to cognitive functioning, for those with mild-to-moderate Alzheimer disease, can be achieved by taking cholinergic drugs.23 However, early detection is important to relieve the anxiety of the unknown, allowing adequate time to develop an advanced care plan. The quality of life can be maximized, and with early treatment, there is a greater chance of a favorable response to treatment, thereby prolonging progressive symptoms, resulting in lower costs overall. A new cost-effective method for early preventative detection is now being trialed, with a noninvasive eye scan that can detect signs on the retina of the eye, which has a central nervous system similar to that of the brain.24 Early detection involves education about the symptoms and testing for those with a family history of Alzheimer disease.5 The three main risk factors include a family history,5 the apolipoprotein E4 (ApoE4) allele,25 and age.26 Currently, there are drugs that aim to prevent the formation of the beta-amyloid plaques by inhibiting the beta and gamma secretase. If beta-amyloid is not formed on the amyloid precursor protein (APP), it averts impairment of the synaptic function by neurodegeneration, limiting the progression of Alzheimer disease. This medication is not ideal, in that it also brings about cleavage of other proteins.27 Nontherapeutic interventions are proving effective, with cognitive therapy being able to minimize psychological symptoms of the disease.28
With the age increase of the global population and consequently rise in the prevalence of Alzheimer disease, dental treatment of such patients seems more important for reduction of its associated co-morbidities.29 Research has shown the link between periodontal disease and the progression of the neurological dysfunction in AD patients. This requires monitoring and treatment of the condition.30 , 31 As a dental professional, an initial dental plan is imperative with all AD patients so that all their present and future needs can be catered for, such as written consent by the patient in the early stages of AD, the use of saliva sprays to replace patient saliva, the use of dentures to prevent further dental issue, and the use of anesthesia during some procedures. By doing this, the dental practitioner can operate in a safe environment, ensuring the best outcome for their patient.
As human life expectancy increases so does the prevalence of Alzheimer disease (AD) among our ever-aging population. In 2016, it was estimated that 5.4 million people in America alone suffered from the disease and was most prevalent in individuals 65 years and older (5.4 million people) as opposed to individuals 64 years and younger (200,000 people).32 Of those individuals 65 years and older suffering from AD, it was found that 63% were female and 37% were male, showing an obvious trend between sexes.32
This data is found to be consistent with some of the three main risk factors reported for AD: age, a family history of AD, and the ApoE4 allele.32 Age is one of the greatest risk factors for AD, with numerous studies around the world showing a dramatic increase in the expression of the disease over the age of 65.32 The second risk factor, a family history of AD, has been proven by many studies to increase the likelihood of developing the disease. Whether the family history is related to the genetic presence of the ApoE4 protein or not is still currently being researched.33 Finally, a study conducted in 2014 found that the female carriers of the ApoE4 allele more frequently went on to suffer from AD. This can be supported by data generated from a study of the prevalence of AD in Europe (2013), which showed the prevalence of AD in women was nearly double than that in men (7.13 and 3.31%).34 Another identified risk factor for the development of AD is a periodontal disease. A retrospective cohort study was performed using the NHIRD (National Health Insurance Research Database) of Taiwan, which looked at the association between chronic periodontitis (CP) and the risk of AD, and it was concluded that patients who had CP for at least 10 years were 1.7 times more likely to develop AD than in patients who did not have CP.35
The 1984 guidelines and criteria published by National Institute on Aging and the Alzheimer’s Association has been the standard for diagnosing AD in America until it was reviewed in 2011.32 Traditionally, a person was diagnosed with the AD as soon as they expressed certain physical symptoms, until more recently it was suggested that the disease could be expressed even before the emergence of its symptoms,32 which is a concept now widely accepted by most researchers.36 If this indeed was the case, the inconsistency between definitions and diagnostic guidelines for AD makes it difficult to generate a precise figure of morbidity rates within a population, and it is thought that if there were a reliable mechanism to detect pre-symptomatic AD, there would be a much higher prevalence and incidence rates of the disease than currently reported.32
AD was first pathologically characterized by extracellular amyloid plaques and intracellular NFTs,37 resulting in impaired cognition characterized by memory loss, disorientation, lack of comprehension, reduced judgment, and more.38 Despite significant evidence to support the correlation between AD and plaques and NFTs, some histopathology studies have clinically diagnosed nondemented individuals with AD.37 A study on the molecular pathogenesis of AD in 2016 concluded that no single proposed theory can entirely clarify the pathogenesis of AD.38 Two proposed theories on the pathophysiology of AD are the cholinergic and amyloid hypotheses.38 Despite the fact that the mechanism of AD initiation and progression remains unclear,39 apolipoprotein E (ApoE) has demonstrated a significant role in the pathogenesis of AD.40
The earliest and most severe atrophy of the brain in AD patients is in the medial temporal lobe.41 Characteristic findings in autopsy reveal neuritic plaques (senile) and NFTs.41 Adjunct to typical plaques and NFTs, studies have revealed a significant imbalance between reactive oxygen species (ROS) and antioxidants in AD, resulting in neural cell damage.38 Though causation of elevated levels of ROS remains unclear, the amyloid hypothesis states that abnormal amyloid β accumulation results in the release of ROS, and released ROS may reversibly stimulate amyloid β production—resulting in a repetitive cycle that may be linked to the progression of Alzheimer disease.38 Abnormal amyloid β polymerization and production leads to amyloid angiopathy within cerebral arteries, linked to reduced cognition and seizures in AD patients.41
A study on memory impairment caused by extracellular amyloid β and tau protein (T protein: a proteins that stabilizes microtubules) has demonstrated that both proteins are dependent on the expression of APP, revealing a promising therapeutic target against AD.42 NFTs contain abnormally phosphorylated tau protein: an oligomer protein required to support axonal transport of organelles and neurotransmitters and stabilize microtubules.41 Protein phosphatase 2A (PP2A) acts to dephosphorylate tau protein; however, genetic abnormalities in PP2A lead to the abnormal phosphorylation of tau protein, compromising function and contributing to AD pathogenesis.43 Postmortem AD patients expressing at least one ApoE4 allele have demonstrated elevated tau phosphorylation.43 A study on the down-regulation of PP2A has linked abnormalities in PP2A to ApoE4, stating that ApoE4 allele inheritance is the most important genetic risk factor for AD.43 The ApoE4 allele binds to the PPP2RSE promoter region on DNA and consequently reduces PP2A activity by reducing its gene expression.43 Abnormal changes in tau and amyloid β protein in the CNS are responsible for neuronal dysfunction in the pathogenesis of Alzheimer disease.38
The cholinergic hypothesis of the pathogenesis of AD suggests that cognitive impairment is attributed to cholinergic dysfunction.44 AD is biochemically associated with a reduction in the neurotransmitter acetylcholine, choline acetyltransferase (CAT enzyme), and reduced expression of nicotinic and muscarinic receptors.41 Nonselective muscarinic antagonists have shown to induce cognitive impairment and increase production of amyloid β,38 supporting the cholinergic theory. In addition, amyloid β has shown to interact with cholinergic receptors and reduce their function (Fig. 5.2).38
Early-onset familial AD is an autosomal-dominant inheritance related to three genes: amyloid precursor protein (APP), presenilin 1 (PSEN-1), and presenilin 2 (PSEN-2).4 This particular variant of the disease develops between the ages of 30 and 60 and attributes to less than 10% of all Alzheimer cases.4 Early onset involves a single gene mutation on chromosomes 21, 14, and 1, resulting in abnormal protein formation.45 APP, PSEN-1, and PSEN-2 mutations have been found to play a key role in APP breakdown, increasing the production of aggregation-prone forms of AB peptide that subsequently triggers the pathological process.46 , 47 , 48
Abnormal APP is located on chromosome 21. APP is a type 1 integral-membrane protein, concentrated in the synapses of neurons. Ten to fifteen percent of the mutation of this protein occurs either in or next to the AB peptide sequence.46 The AB peptide is the main constituent of amyloid plaques found in AD-affected brains.46 Patients with Down syndrome (trisomy 21) have additionally been found to display neuropathological features of AD by the time they are in their forties, provided that they live that long.4
Presenilin-1 is a polytopic membrane protein and a component of the atypical aspartyl protease complex, which ultimately is liable for the cleavage of the AB peptide.4 Mutations of this protein occur on chromosome 14 and are the most common causations of early-onset Alzheimer; studies have found this to be approximately 40 to 70%.45 These mutations tend to cause an earlier age of onset, as early as 30 years old,45 and the most severe form as a short yet rapid course of progression of the disease (6–7 years) compared with 11 years in PSEN-2.46
Alike PSEN-1, presenilin 2 is also a component of the atypical aspartyl protease complex.4 PSEN-2 is found on chromosome 1 and mutations in this gene are an extremely rare cause of early-onset AD compared to PSEN-1, particularly in Caucasian populations.4 Age of onset is variable among members of the same family that have been affected by this missense mutation; conversely, PSEN-1 causes relatively similar age of onset. It is unlikely that presenilin mutations will lead to late-onset AD.
Late-onset AD occurring around 60 to 65 years has a higher incidence, with more than 90% patients identified in this category.4
It is likely that genetics play an essential role with this type, however, only in conjunction with other lifestyle and environmental factors.45 As yet, there has been no specific causative gene identified; however, having a form of the ApoE gene on chromosome 19 has been found to increase the risk of Alzheimer disease.4 , 45 , 46 Associations with this gene have been linked to both sporadic and familial late-onset AD4 and is vital in the pathogenesis of the disease.45
ApoE has different alleles including ApoE ε2, ApoE ε3, and ApoE ε4.4 ApoE ε4 leads to inefficient amyloid clearance and is capable of producing toxic fragments once the molecule is cleaved.4 ApoE ε4 falls into the category of a genetic risk-factor as it increases the risk of the development of AD, depending on the number of alleles a person has, the greatest being 2. However, this is not an accurate determination of the disease because some individuals expressing this allele do not present with AD, and, conversely, there are others who do not possess the ApoE ε4 allele but present with AD.4 Thus, having this allele alone is not a necessary causative factor, yet it remains to be the most significant and well-established biological marker associated with late-onset AD.45 Having the ApoE ε2 allele is rare and may even have a reducing effect on the disease,45 but if someone is found to have it, they are not likely to develop the disease until later in life.4
Genetic investigations have evolved considerably throughout the years, and ongoing research into the genetic components of AD is still being conducted. Recently, genome-wide association studies (GWAS) have found over 21 additional genetic risk loci to contribute to increased susceptibility of late-onset AD, supported by a sufficient level of evidence.49 , 50 , 51 These include clusterin (CLU), phosphatidylinositol-binding clathrin assembly proteins (PICALM), exocyst complex component3-like 2 (EXOC3L2), bridging integrator 1 (BIN1), complement component receptor 1 (CR1), sortilin-related receptor (SORL1), nonreceptor tyrosine kinase 1 (TNK1), interleukin 8 (IL8), low-density lipoprotein receptor (LDLR), cystatin C (CST3), CHRNB2 gene (on chromosome 1), SORCS1, tumor necrosis factor alpha (TNF), chemokine receptor 2 (CCR2).49 A number of these GWAS-identified risk genes are possibly linked with the AB cascade, but, notably, the majority of the associated genes accumulate within either of three pathways: endocytosis, inflammatory response, and cholesterol and lipid metabolism.50 , 51 These risk genes emphasize the multifactorial nature of AD; however, they play a lesser role compared with ApoE gene, APP, PSEN-1, and PSEN-2.49 , 50