Megan J. Ehret, Gary M. Levin, and Toya M. Bowles
Upon completion of the chapter, the reader will be able to:
1. Describe the epidemiology of Alzheimer’s disease (AD) and its effects on society.
2. Describe the pathophysiology including genetic and environmental factors that may be associated with the disease.
3. Detail the clinical presentation of the typical patient with AD.
4. Describe the clinical course of the disease and typical patient outcomes.
5. Describe how nonpharmacologic therapy is combined with pharmacologic therapy for patients with AD.
6. Recognize and recommend treatment options for disease-specific symptoms as well as behavioral/noncognitive symptoms associated with the disease.
7. Develop an alternative treatment plan for patients with AD.
8. Educate patients and/or caregivers about the expected outcomes for patients with AD, and provide contact information for support/advocacy agencies.
Alzheimer’s disease (AD) is characterized by progressive cognitive decline including memory loss, disorientation, and impaired judgment and learning.
Pathologic hallmarks of the disease in the brain include neurofibrillary tangles and neuritic plaques (senile plaques) made up of various proteins, which result in a shortage of the neurotransmitter acetylcholine.
A diagnosis can be made only at autopsy; therefore, the diagnosis is established following an extensive history and physical examination, and by ruling out other potential causes of dementia.
Treatment is focused on delaying disease progression and preservation of functioning as long as possible.
The current gold standard of treatment for cognitive symptoms includes pharmacologic management with a cholinesterase inhibitor and/or an N-methyl-D-aspartate (NMDA) receptor antagonist.
Future therapies for AD may be based on disease-modifying therapies.
The general approach to treatment of cognitive symptoms includes both pharmacologic and nonpharmacologic management.
Treatment of behavioral symptoms should begin with nonpharmacologic treatments, but may also include antipsychotic agents and/or antidepressants.
Therapeutic response in AD is genotype-specific depending on the genes associated with pathogenesis and/or genes responsible for drug metabolism.
Alzheimer’s disease (AD) is a nonreversible, progressive dementia manifested by gradual deterioration in cognition and behavioral disturbances. AD is primarily diagnosed by exclusion of other potential causes for dementias. There is no single symptom unique to AD; therefore, diagnosis relies on a thorough patient history. The exact pathophysiologic mechanism underlying AD is not entirely known, although certain genetic and environmental factors may be associated with the disease. There is currently no cure for AD; however, drug treatment can slow symptom progression over time.
Family members of AD patients are profoundly affected by the increased dependence of their loved ones as the disease progresses. Referral to an advocacy organization, such as the Alzheimer’s Association, can provide early education and social support of both the patient and family, which is also important treatment. The Alzheimer’s Association has developed a checklist of common symptoms (Table 35–1).1
Table 35–1 Ten Warning Signs of AD
1. Memory loss: more than typical forgetfulness without remembering later
2. Difficulty performing familiar everyday tasks (e.g., preparing a meal and grooming)
3. Problems with language: forgetting simple words or substituting unusual words
4. Disorientation to time and place: may forget where they are and/or how they got there
5. Poor or decreased judgment: dress without regard to weather or falling prey to scam artists
6. Problems with abstract thinking: not just difficulty balancing a checkbook, but forgetting what the numbers represent
7. Misplacing things in unusual places: such as placing an iron in a freezer
|8. Changes in mood or 'padding:.75pt .75pt .75pt .75pt'>
9. Changes in personality: extreme confusion, suspicion, or fearfulness
10. Loss of initiative: passivity and loss of interest in usual activities
From Ref 1.
EPIDEMIOLOGY AND ETIOLOGY
AD is the most common type of dementia, affecting approximately 4.5 million Americans in the year 2000.2 Various classifications of dementia include dementia of the Alzheimer’s type, vascular dementia, and dementia due to HIV disease, head trauma, Parkinson’s disease, Huntington’s disease, Pick’s disease, or Creutzfeldt-Jakob disease.3 This chapter will address only dementia of the Alzheimer’s type.
The prevalence of AD increases with age, and it is most prevalent in persons aged 65 years and older. In the year 2000, it was estimated that there were 4.5 million people with AD in the United States. Of those affected, 7% were 65 to 74 years of age, 53% were between 75 and 84 years of age, and 40% were persons over 85 years of age.2 It is projected that by the year 2050, there will be a threefold increase in prevalence yielding potentially 13.4 million AD patients due to a population increase in persons over 65 years of age. It is projected that three out of five individuals greater than or equal to 85 years of age will have AD. Additionally, the cost to society due to rising Medicare spending for AD is projected to increase from $62 billion in 2000 to over $1 trillion in 2050. Furthermore, the costs associated with nursing home care alone are projected to increase from $19 billion in 2000 to $118 billion in 2050 (Fig. 35–1).4,5 The severity of AD also correlates with increasing age and is classified as mild, moderate, or severe. Other risk factors associated with AD besides age include family history, female gender, and vascular risk factors such as diabetes, hypertension, heart disease, and current smoking.6,7 However, it is unknown how other factors such as environment contribute and interact with the genetic predisposition for AD.
FIGURE 35–1. Projected increases in the population of patients with AD, Medicare nursing home spending, and total Medicare spending. (AD, Alzheimer’s disease.) (From Refs. 4 and 5.)
The mean survival time of persons with AD is reported to be approximately 6 years from the onset of symptoms until death. However, age at diagnosis, severity of AD, and other medical conditions affect survival time.8 Although AD does not directly cause death, it is associated with an increase in various risk factors which often contribute to death such as senility, sepsis, stroke, pneumonia, dehydration, and decubitus ulcers.
The exact etiology of AD is unknown; however, it has been suggested that genetic factors may contribute to errors in protein synthesis resulting in the formation of abnormal proteins involved in the pathogenesis of AD.9 Early onset, which is defined as AD prior to age 60, accounts for approximately 1% of all AD. This type is usually familial and follows an autosomal dominant pattern in approximately 50% of cases of early-onset AD. Mutations in three genes, presenilin 1 on chromosome 14, amyloid precursor protein (APP) on chromosome 21, and presenilin 2 on chromosome 1, lead to an increase in the accumulation of amyloid beta (Aβ) in the brain, resulting in oxidative stress, neuronal destruction, and the clinical syndrome of AD.10,11
The genetic basis for the more common late-onset AD appears more complex. Genetic susceptibility is more sporadic and it may be more dependent on environmental factors.9 The apolipoprotein E (apo E) gene on chromosome 19 has been identified as a strong risk factor for late-onset AD. There are three variants of apo E; however, carriers of two or more of the apo E4 allele have an earlier onset of AD (approximately 6 years earlier) compared with noncarriers.9 Only 50% of AD patients have the apo E4 allele, thus indicating it is only a susceptibility marker.
The pathologic hallmarks of the disease in the brain include neurofibrillary tangles and neuritic plaques made up of various proteins, which result in a shortage of the neurotransmitter acetylcholine (Ach).These are primarily located in brain regions involved in learning, memory, and emotional behaviors such as the cerebral cortex, hippocampus, basal forebrain, and amygdala.12
Neurofibrillary tangles are intracellular and consist of abnormally phosphorylated τ protein, which is involved in microtubule assembly. Tangles interfere with neuronal function, resulting in cell damage, and their presence has been correlated with the severity of dementia.13 Unfortunately, these tangles are insoluble even after the cell dies, and they cannot be removed once established. The neurons that provide most of the cholinergic innervation to the cortex are most prominently affected.14 Therefore, prevention is the key to targeted therapy of these tangles.
Neuritic or senile plaques are extracellular protein deposits of fibrils and amorphous aggregates of β-amyloid protein.12 This formed protein is central to the pathogenesis of AD. The β-amyloid protein is present in a nontoxic, soluble form in human brains. In AD, conformational changes occur that render it insoluble and cause it to deposit into amorphous diffuse plaques associated with dystrophic neuritis.15Over time, these deposits become compacted into plaques and the β-amyloid protein becomes fibrillar and neurotoxic. Inflammation occurs secondary to clusters of astrocytes and microglia surrounding these plaques.
The neurotransmitter Ach is responsible for transmitting messages between certain nerve cells in the brain. In AD, the plaques and tangles damage these pathways, leading to a shortage of Ach, resulting in learning and memory impairment.16 The loss of Ach activity correlates with the severity of AD. The basis of pharmacologic treatment of AD has been to improve cholinergic neurotrans-mission in the brain. Acetylcholinesterase is the enzyme that degrades Ach in the synaptic cleft. Blocking this enzyme leads to an increased level of Ach with a goal of stabilizing neurotransmission.17
Glutamate is the primary excitatory neurotransmitter in the CNS involved in memory, learning, and neuronal plasticity. It acts by providing information from one brain area to another and affects cognition through facilitation of connections with cholinergic neurons in the cerebral cortex and basal forebrain.18 In AD, one type of glutamate receptor, N-methyl-D-aspartate (NMDA), is less prevalent than normal. There also appears to be overactivation of unregulated glutamate signaling. This results in a rise in calciumions that induces secondary cascades, which lead to neuronal death and an increased production of APP.17 The increased production of APP is associated with higher rates of plaque development and hyperphosphorylation of τ protein.19 Memantine is a noncompetitive NMDA antagonist that targets this path-ophysiologic mechanism.20
Increased cholesterol concentrations have been associated with AD. The cholesterol increases β-amyloid protein synthesis which can lead to plaque formation.17 Also, the apo E4 allele is thought to be involved in cholesterol metabolism and is associated with higher cholesterol levels.17
Estrogen appears to have properties that protect against memory loss associated with normal aging. It has been suggested that estrogen may block β-amyloid protein production and even trigger nerve growth in cholinergic nerve terminals.21,22 Estrogen is also an antioxidant and helps prevent oxidative cell damage.21 It is important to note, however, that the Women’s Health Initiative Memory Study reported that hormone replacement with either estrogen alone or estrogen plus medroxyprogesterone resulted in negative effects on memory.23
CLINICAL PRESENTATION AND DIAGNOSIS
Diagnosing AD relies on a thorough medical and psychological history, mental status testing, and laboratory data to exclude other possible causes of dementia. There are no biological markers other than those pathophysiologic changes found at autopsy that can confirm AD.
The American Academy of Neurology has adopted practice guidelines for the diagnosis and management of AD.24 The diagnostic criteria are based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) (Table 35–2)25 or the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA).
AD is a progressive disease that, over time, affects multiple areas of cognition. The symptoms of AD can be divided into cognitive symptoms, noncognitive symptoms, and functional symptoms for assessment and treatment purposes. Table 35–3 describes the stages of cognitive decline.26,27
Clinical Presentation and Diagnosis of AD
The diagnosis of AD relies on thorough mental status testing and neuropsychological tests, medical and psychiatric history, neurologic examination, interview of caregivers and family members, and laboratory and imaging data to support the diagnosis and exclude other causes.
Signs and Symptoms
• Cognitive: memory loss, problems with language, disorientation to time and place, poor or decreased judgment, problems with learning and abstract thinking, misplacing things
• Noncognitive: changes in mood or behavior, changes in personality, or loss of initiative
• Functional: difficulty performing familiar tasks
• MRI or CT is used to measure changes in brain size and volume and rule out stroke, brain tumor, or cerebral edema.
• Tests to exclude possible causes of dementia include a depression screen, vitamin B12 deficiency, thyroid function tests (thyroid-stimulating hormone and free triiodothyronine and thyroxine), CBC, and chemistry panel.21
• Other diagnostic tests to consider for differential diagnosis: erythrocyte sedimentation rate, urinalysis, toxicology, chest x-ray, heavy metal screen, HIV testing, CSF examination, electroencephalography, and neuropsychological tests such as the Folstein Mini Mental Status Examination.
Table 35–2 Diagnostic Criteria for AD Based on DSM-IV-TR
Dementia of the Alzheimer’s type
A. The development of multiple cognitive deficits manifested by both
1. Memory impairment (impaired ability to learn new information or to recall previously learned information)
2. One or more of the following cognitive disturbances:
(a) Aphasia (language disturbance)
(b) Apraxia (impaired ability to carry out motor activities despite intact motor function)
(c) Agnosia (failure to recognize or identify objects despite intact sensory function)
(d) Disturbance in executive funning (e.g., planning, organizing, sequencing, abstracting)
B. The cognitive deficits in criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning
C. The course is characterized by gradual onset and continuing cognitive decline
D. The cognitive deficits in criteria A1 and A2 are not due to any of the following:
1. Other CNS conditions that cause progressive deficits in memory and cognition
2. Systemic conditions that are known to cause dementia
3. Substance-induced conditions
E. The deficits do not occur exclusively during the course of delirium
F. The disturbance is not better accounted for by another Axis I disorder
From Ref. 3.
Desired and Expected Outcomes
Although there are currently five agents approved for the treatment of AD, none of these agents are curative or are known to directly reverse the disease process.
Consequently, the primary desired outcome of treatment of AD is to symptomatically treat the cognitive symptoms of the patient and preserve the patient’s functioning for as long as possible. Secondary goals include treating psychiatric and behavioral symptoms that may occur during the course of the disease.
General Approach to Treatment
The current gold standard of treatment for cognitive symptoms includes pharmacologic management with a cholinesterase (ChE) inhibitor and/or an NMDA antagonist. The following are four ChE inhibitors: tacrine, donepezil, rivastigmine, and galantamine. The use of tacrine is limited due to its propensity for hepatotoxicity, difficult titration schedule, four times daily dosing, poor bioavailability, and increased adverse events of nausea, diarrhea, and urinary incontinence. There is only one NMDA antagonist, memantine. Psychiatric and behavioral symptoms that occur during the course of the disease should be treated as they occur.
Essential elements in the treatment of AD include education, communication, and planning with the family/caregiver of the patient. Treatment options, legal and financial decisions, and course of the illness need to be discussed with the patient and family members. In this regard, the clinician’s emphasis should be on helping to maintain a therapeutic living environment while minimizing the burden of care resulting from the disease.
Treatment of AD involves both pharmacologic and nonpharmacologic methods. Upon the initial diagnosis, the patient and family should be counseled on the course of the illness, prognosis, available treatments, legal decisions, and quality-of-life issues. The life of a patient with AD must become progressively more simple and structured as the disease progresses, and the caregiver must learn to keep requests and demands on the patient simple. The family of the patient will need to be prepared to face changes in life that will occur as the disease becomes worse. Basic principles in the treatment of patients with AD are shown in Table 35–4.
Table 35–3 Stages of Cognitive Decline
Patient Encounter, Part 1
A woman arrives at the clinic with her 80-year-old mother, LB, complaining that her mother is becoming increasingly forgetful and confused with old age. The woman complains that her mother sometimes takes her diabetes and hypertension medications at a frequency greater than that prescribed. This has become more frequent in the last 6 months and the mother has been getting very agitated when her daughter confronts her. The woman asks for a pill organizer and if any of the over-the-counter drugs claiming to help with memory would help her mother.
What information is suggestive of AD?
Does the mother have any risk factors for AD?
How would you approach and address the daughter’s question?
Table 35–4 Basic Principles in the Treatment of Patients With AD
• Using a gentle, calm approach to the patient
• Giving reassurance when needed
• Empathizing with the patient’s concerns
• Using distraction and redirection
• Maintaining daily routines
• Providing a safe environment
• Providing daytime activities
• Avoiding overstimulation
• Using familiar decorative items in the living area
• Bringing abrupt declines in function and the appearance of new symptoms to professional attention
Conventional Pharmacologic Treatment for Cognitive Symptoms
ChE Inhibitors (Donepezil, Rivastigmine, and Galantamine)
The ChE inhibitors all have the indication for the treatment of dementia of the Alzheimer’s type. Guidelines for the treatment of AD recommend the use of ChE inhibitors as a valuable treatment for AD and the use of memantine for moderate-to-severe AD.28–30 None of the ChE inhibitors have been compared in head-to-head studies, so the decision to use one over another is based on differences in mechanisms of action, adverse reactions, and titration schedules.
Treatment should begin as early as possible in patients with a diagnosis of AD.31 Figure 35–2 provides a recommended treatment algorithm for AD.32 Patients should be switched to another ChE inhibitor from their initial ChE inhibitor if they show an initial lack of efficacy, initially respond to treatment but lose clinical benefit, or experience safety/tolerability issues. This switch should not be attempted until the patient has been on a maximally tolerated dose for a period of 3 to 6 months. The switch should also be based on realistic expectations of the patient and/or caregiver.33 ChE inhibitor therapy should be discontinued in patients who experience poor tolerance or adherence, who show a lack of clinical improvement after 3 to 6 months at optimal dosing, who continue to deteriorate at the pretreatment rate, or who demonstrate dramatic clinical deterioration following initiation of treatment.34
Donepezil is a piperidine ChE inhibitor, which rever-sibly and noncompetitively inhibits centrally active acetylcholinesterase.35
Donepezil is approved for the treatment of dementia of the Alzheimer’s type at a dose of 5 mg/day. This dose should be increased to 10 mg/day if needed after 4 to 6 weeks. Efficacy has been demonstrated in patients with mild-to-moderate and -severe AD. Table 35–5 describes the dosing strategies for all of the approved agents for AD.35–39
Adverse reactions with donepezil include nausea, vomiting, and diarrhea. Table 35–6 compares the major side effects for all of the approved agents for AD.35–39
Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P450 (CYP)3A4 or 2D6. Whether donepezil has the potential for enzyme induction is not known. Monitoring for possible increased peripheral side effects is advised when adding a CYP2D6 or 3A3/4 inhibitor to donepezil treatment. Also, inducers of CYP2D6 and 3A4 could increase the rate of elimination of donepezil.35
Rivastigmine has central activity for both the acetylcholinesterase and butyrylcholinesterase enzymes.37 Acetylcholinesterase is found in two forms: globular 4 and globular 1. In postmortem studies, globular 4 is significantly depleted, while globular 1 is still abundant. Thus, blocking metabolism of globular 1 may lead to higher concentrations of Ach. Rivastigmine has higher activity at globular 1 than at globular 4. Theoretically this may be advantageous, as rivastigmine prevents the degradation of Ach via the acetylcholinesterase globular 1 over the course of the disease as compared to the other ChE inhibitors.
The dual inhibition of acetylcholinesterase and butyrylcholinesterase may lead to broader efficacy. As acetyl-cholinesterase activity decreases with disease progression, the acetylcholinesterase-selective agents may lose their effect, while the dual inhibitors may still be effective due to the added inhibition of butyrylcholinesterase. However, this has not been demonstrated clinically.
FIGURE 35–2. Treatment algorithm for AD. A. Cognitive treatment. B. Treatment of psychiatric or behavioral symptoms. (AD, Alzheimer’s disease; MMSE, Mini Mental Status Examination; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association.) (From Faulkner JD, Bartlett J, Hicks P. Alzheimer’s disease. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill, 2005:1164, with permission.)
Table 35–5 Dosing Strategies for Cognitive Agents
Table 35–6 Comparative Common Adverse Effects of AD Medications From Clinical Trial Dataa
Rivastigmine is approved for the treatment of mild-to-moderate dementia of AD at an initial dose of 1.5 mg twice daily; if this dose is tolerated for at least 2 weeks, then the dose can be increased to 3 mg twice daily. Increases to 4.5 mg twice daily and 6 mg twice daily should be attempted only after at least 2 weeks at the previous dose. Tolerability and absorption are improved when the dose is given with food.
Rivastigmine is also available in a patch formulation, with an initial dose of 4.2 mg/24 hours applied once daily. The maintenance dose of the patch is 9.5 mg/24 hours applied once daily. A minimum of 4 weeks of treatment and good tolerability with the previous dose should be observed before consideration of an increase in dose. When switching from the oral formulation to the patch, if the patient is taking less than 6 mg/day of oral, then the 4.2 mg/24 hours patch is recommended. If the patient is taking 6 to 12 mg/day of oral, then the 9.5 mg/24 hours patch is recommended. The first patch should be applied on the day following the last oral dose.37
Cholinergic side effects are common with rivastigmine, but are usually well tolerated if the recommended dosing schedule is followed. If side effects cause intolerance, several doses can be held, then dosing can be restarted at the same or next lower dose. There are no pharmacokinetic drug interactions with drugs metabolized via CYP1A2, 2D6, 3A4/5, 2E1, 2C9, 2C8, or 2C19. Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine.37
Galantamine is a ChE inhibitor, which elevates Ach in the cerebral cortex by slowing the degradation of Ach.38 It also modulates the nicotinic Ach receptors to increase Ach release from surviving presynaptic nerve terminals. In addition, it may increase glutamate and serotonin levels. The clinical benefit of action of these additional neurotransmitters is unknown.
Galantamine is approved for the treatment of mild-to-moderate dementia of AD. It can be dosed once or twice daily (if using the immediate-release tablet or extended-release capsule). The initial dose is 8 mg daily (or 4 mg twice daily) for 4 weeks. If tolerated the dose can be increased if needed to 16 mg daily (or 8 mg twice daily) for at least 4 weeks. Again, if this dose is tolerated, the dose can be increased if needed to 24 mg daily (or 12 mg twice daily).
The adverse reactions associated with galantamine are similar to that observed with the ChE inhibitors.
CYP3A4 and 2D6 are the major enzymes involved in the metabolism of galantamine. Pharmacokinetic studies with inhibitors of this system have resulted in increased galantamine concentrations or reductions in clearance. Similarly to donepezil, if inhibitors are given concurrently with galantamine, monitoring for increased cholinergic side effects should be done.38
NMD A Receptor Antagonist
Memantine is a noncompetitive antagonist of the NMDA type of glutamate receptors, which are located ubiquitously throughout the brain. It regulates activity throughout the brain by controlling the amount of calcium that enters the nerve cell, a process essential for establishing an environment required for information storage. Overstimulation of the NMDA receptor by excessive glutamate allows too much calcium into the cell, disrupting information processing. Blocking NMDA receptors with memantine may protect neurons from the effects of excessive glutamate without disrupting normal neurotransmission.39
Memantine is indicated for the treatment of moderate-to-severe dementia of the Alzheimer’s type. The initial dose is 5 mg/day with increases to 20 mg/day if needed, with a minimum of 1 week between dosage increases. Doses greater than 5 mg/day should be given in two divided doses. A suggested titration is: 5 mg/day for at least 1 week, 5 mg twice daily for at least 1 week, 15 mg/day (5 mg in the morning and 10 mg in the evening) for at least 1 week, then 10 mg twice daily. If the patient has a creatinine clearance of 5 to 29 mL/min, then the target dose should be 5 mg twice daily. It is likely to be given as monotherapy, but can be given in combination with ChE inhibitors.
Adverse reactions associated with memantine include constipation, confusion, dizziness, headache, coughing, and hypertension. Extra monitoring should be done if memantine is given concurrently with a ChE inhibitor.
In vitro studies have shown that memantine produces minimal inhibition of CYP450 enzymes CYP1A2, 2A6, 2C9, 2D6, 2E1, and 3A4. These data indicate that no pharmacokinetic interactions with drugs metabolized by these enzymes should be expected.39
Future therapies for AD may be based on disease-modifying therapies. Current investigations involving the amyloid hypothesis are reviewing various compounds in the secondary prevention of AD. Mechanisms by which these compounds are thought to work include10:
• Decreasing the production of Aβ
• Stimulation of clearance of Aβ formed
• Prevention of aggregation of Aβ into amyloid plaques
• Prevention of neuronal damage by limiting inflammation and neurotoxicity caused by Aβ
Nonconventional Pharmacologic Treatment
Many other nonconventional treatments have been used as adjunctive treatments during the course of AD. Vitamin E has often been recommended for use as an adjunctive treatment because of its antioxidant properties.40 It has potential effectiveness, a favorable side-effect profile, and low cost. The maintenance dose of vitamin E should be titrated to 1,000 IU twice daily. However, a recent meta-analysis suggests that high doses (greater than 400 IU/day) of vitamin E should be avoided due to an increased all-cause mortality.41 Estrogen has been investigated for use in AD, but as mentioned previously, was associated with an increased risk of dementia. Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been investigated for their place in the therapy of AD. There is a lack of convincing data and significant adverse effects (gastritis and GI bleeds) associated with their use, so they are not recommended for general use in the treatment or prevention of AD at this time.42 Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) should be reserved for those patients who have other indications for their use.43 Ginkgo biloba has also been studied for its potential use in AD. Until this product has a more standardized manufacturing process and until its long-term safety and efficacy are established, it should be recommended with caution.44
Treatment for Behavioral Symptoms
Treatment of behavioral symptoms should begin with nonpharmacologic treatments, but may also include antipsychotic agents and/or antidepressants. Nonpharmaco-logic recommendations for treatment include45:
Patient Encounter, Part 2: Medical History, Physical Examination, and Diagnostic Tests
HPI: LB has seen a neurologist to address her cognitive decline and behavioral issues and is at the clinic for follow-up after obtaining her assessments and labs
• Diabetes mellitus since age 55; it was well controlled until last year when it worsened because of increased confusion of when to take her medication
• Hypertension treated for 20 years and well controlled; has been hypotensive on a few occasions recently during physicals
• Insomnia which is getting worse
FH: Father died of myocardial infarction at age 76; mother died of breast cancer at age 79
SH: Lives alone; denies drinking alcohol or smoking
• Hydrochlorothiazide 25 mg orally once daily
• Losartan 50 mg orally twice daily
• Metformin 1,000 mg orally twice daily
• Lorazepam 1 mg orally at bedtime
ROS: (+) weight loss of 5.5 kg (12 lb); (-) N/V/D, change in appetite, heartburn, chest pain, or shortness of breath
VS: BP 128/62 mm Hg supine, P 77 bpm, RR 15/min, T 37°C (98.6°F)
Gen: Poorly groomed, thin woman looks stated age
Neuro: Folstein Mini Mental Status Exam score 16/30; disoriented to month, date, and day of week, clinic name and floor; poor registration with impaired attention and short-term memory; recalled zero out of three items; good language skills but problems with commands
CT scan: Mild-to-moderate generalized cerebral atrophy
Based on the new information, what is your assessment of the patient?
What nonpharmacologic and pharmacologic interventions could be recommended?
What are the short-term and long-term treatment goals?
• Videotapes of family members
• Audio tapes of the voices of caregivers
• Walking and light exercise
• Sensory stimulation and relaxation
The atypical antipsychotics are the preferred agents for the treatment of psychosis (hallucinations, delusions, and suspiciousness) and the disruptive behaviors (agitation and aggression) of AD. Double-blind, controlled trials support the efficacy of risperidone and olanzapine in reducing the rate of psychosis and agitation.46–48 Risperidone should be initiated at 0.25 mg/day and titrated in 0.25 to 0.5 mg/day increments to 1 mg/day, with a maximum dose of 2 mg/day.46,47,49 Olanzapine has been studied with modest results at doses of 5 to 10 mg/day, and 15 mg/day has not been shown to be any better than placebo.48
In April 2005, the FDA issued a statement requesting black-box warnings on all atypical antipsychotics stating that elderly people with dementia-related psychosis treated with an atypical antipsychotic are at an increased risk of death compared to those treated with placebo. Of a total of 17 placebo-controlled trials investigating olanzapine, aripiprazole, quetiapine, and risperidone in elderly demented patients with behavioral disorders, 15 showed a numerical increase in mortality in the drug-treated group compared to the placebo-treated groups (1.6–1.7 times increased risk of death). Specific causes for these deaths were heart-related events (heart failure and sudden death) and infections (mostly pneumonia). The atypical antipsychotics are not currently approved for the treatment of elderly patients with dementia-related psychosis. Therefore, it is important to individually assess and balance the risk versus benefit of antipsychotic use in this population.
Differentiating between depression and dementia can be difficult, so symptoms of depression should be documented for several weeks prior to initiating therapy for the treatment of depression with AD. Citalopram and sertraline are recommended as first-line agents because of their efficacy in placebo-controlled trials.50 Indications for the use of antidepressants include depression characterized by poor appetite, insomnia, hopelessness, anhedonia, withdrawal, suicidal thoughts, and agitation.
Other miscellaneous therapies for AD include benzo-diazepines for anxiety, agitation, and aggression. However, their routine use is not advised.29 Additionally, benzodiaze-pines have been associated with an increase in falls leading to the potential for hip fractures in the elderly.51 Buspirone has shown benefit in treating agitation and aggression in a limited number of patients with minimal adverse effects.52,53 In open-label and controlled studies, selegiline decreased anxiety, depression, and agitation.54,55 Finally, trazodone has been shown to decrease insomnia, agitation, and dysphoria, and has been used to treat sundowning in Alzheimer’s patients. Figure 35–2 also provides a treatment algorithm for the behavioral symptoms of AD.32
Therapeutic response in AD is genotype-specific depending upon the genes associated with pathogenesis and/or genes responsible for drug metabolism. Recent investigations have demonstrated that the therapeutic response in AD is genotype-specific, depending upon genes associated with AD pathogenesis and/or genes responsible for drug metabolism. apo E-4/4 carriers tend to show a faster disease progression and a poorer therapeutic response to all available treatments than any other polymorphic variant associated with AD. Extensive and intermediate metabolizers of CYP450 enzymes are the best responders to pharmacotherapy, while poor and ultrarapid metabolizers are the worst responders. The pharmacogenetic response in AD may depend upon the interaction of genes involved in drug metabolism and the genes associated with AD pathogenesis.56
• The success of therapy is measured by the degree to which the care plan decreases the pretreatment deterioration rate, preserves the patients’ functioning, and treats psychiatric and behavioral symptoms. The primary outcome measure is thus subjective information from the patient and the caregiver, although the Mini Mental Status Examination (MMSE) can be a helpful tool. There are no physical examination or laboratory parameters that are used to evaluate the success of therapy.
• Once a tolerated agent is found, continue that therapy until poor tolerance or poor adherence occurs, no clinical improvement is seen with 3 to 6 months of optimal dosing, or the pretreatment deterioration rate continues. Inform the patient and the caregiver that the treatments available for AD are not curative, but may slow the deterioration rate of the patient.
• Treat behavioral and psychiatric issues as they arise. Consider the patient’s choices of nonpharmacologic and pharmacologic options before recommending a treatment. Discontinue the pharmacologic treatments periodically to reevaluate the need for continued treatment.
• Develop a plan to assess the effectiveness of the ChE inhibitor in slowing the deterioration of cognitive functioning after an appropriate interval (3–6 months). Assess improvement in quality-of-life measures such as ability to function independently and for slowing of memory deterioration. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions at appropriate intervals. Continue to be a resource for the patient and caregiver throughout the long course of the disease.
Patient Care and Monitoring
1. Assess the frequency and duration of the patient’s cognitive and noncognitive symptoms. Could the patient be depressed?
2. Review any available diagnostic data from the medical and psychiatric history including interviews from family, neuropsychologic testing, and other labs.
3. Obtain a thorough history of prescription, nonprescription, and natural drug product use. Is the patient taking any medications that could contribute to cognitive changes in the elderly?
4. Educate both the patient and caregivers about lifestyle modification and refer them to support when needed.
5. Monitor pharmacotherapy initiation. Is it titrated correctly?
6. Develop a plan to monitor cognitive response to treatment over time.
7. Routinely assess medication adherence.
8. Educate patient and caregivers on what to expect from pharmacotherapy.
9. Regularly evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug-drug and drug-disease interactions.
10. Be a resource and give continuous support to the patient and caregivers throughout the long course of the disease.
Table 35–7 Living With AD: Ten Quick Tips
1. Carry with you a book of important notes and photos
2. Enroll in Alzheimer’s Association Safe Return
3. Be open to accepting help from others
4. Keep doing the things you most enjoy
5. Talk to others who have AD
6. Find ways to laugh as often as you can
7. Maintain your physical health
8. Take steps to make your home safe
9. Extend the time you can live safely in your home with help from your family and friends
10. Put plans in place now for your future
From Ref. 57
AD is a progressive deterioration of cognitive abilities, and patients are likely to have behavioral disturbances and personality changes in the later stages of the disease. In an effort to help prepare patients and their caregivers for the inevitable, the Alzheimer’s Association has developed ten quick tips on “Living with Alzheimer’s disease” (Table 35–7).57 The Alzheimer’s Association can provide many resources as well as facilitate contacts with other organizations. Contact the association at:
Contact Center: 1.800.272.3900
TDD Access: 1.312.335.8882
National Office: 225 N. Michigan Ave., Fl. 17
Chicago, IL 60601–7633
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
1. Alzheimer’s Association. Available at: www.alz.org/alzheimers_disease_symptoms_of_alzheimers.asp.
2. Hebert LE, Scherr PA, Bienias JL, et al. Alzheimer disease in the U.S. population: Prevalence estimates using the 2000 census. Arch Neurol 2003;60:1119–1122.
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text revision. Washington, DC: American Psychiatric Association, 2000:147–154.
4. U.S. Census Bureau. Available at: http://www.census.gov/population/projections/nation/summary/np-t3-g.pdf.
5. Report of the Lewin Group to the Alzheimer’s Association. Available at www.alz.org/news_and_events_alzheimers_news_12-5-2005.asp.
6. Luchsinger JA, Reitz C, Honig LS, et al. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 2005;65: 545–551.
7. Gorelick PB. Risk factors for vascular dementia and Alzheimer disease. Stroke 2004;35:S2620–S2622.
8. Ganguli M, Dodge HH, Shen C, et al. Alzheimer disease and mortality. Arch Neurol 2005;62:779–784.
9. Kamboh MI. Molecular genetics of late-onset Alzheimer’s disease. Ann Hum Genet 2004;68:381–404.
10. van Marum RJ. Current and future therapy in Alzheimer’s disease. Fundam Clin Pharmacol 2008;22:265–274.
11. Holmes C. Genotype and phenotype in Alzheimer’s disease. Br J Psychiatry 2002;180:131–134.
12. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature 2004;430:631–639.
13. DeKosky ST. Pathology and pathways of Alzheimer’s disease with an update on new developments in treatment. J Am Geriatr Soc 2003;51:S314–S320.
14. Munoz DG, Feldman H. Causes of Alzheimer’s disease. Can Med Assoc J 2000;162:65–72.
15. Yanker BA, Lu T. Amyloid β-protein toxicity and the pathogenesis of Alzheimer’s disease. J Biol Chem Epub Nov 13, 2008.
16. Gauthier S. Advances in the pharmacotherapy of Alzheimer’s disease. Can Med Assoc J 2002;166:616–623.
17. Pietrzik C, Behl C. Concepts for the treatment of Alzheimer’s disease: Molecular mechanisms and clinical application. Int J Exp Path 2005;86:173–185.
18. Sze C, Bi H, Kleinschmidt-DeMasters BK, et al. N-Methyl-D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer’s disease. J Neurol Sci 2001;182: 151–159.
19. Parsons CG, Danysz W, Quack G. Glutamate in CNS disorders as a target for drug development: An update. Drug News Perspect 1998; 11:523–569.
20. Parsons CG, Stoffler A, Danysz W. Memantine: A NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system—too little activation is bad, too much is even worse. Neuropharmacology 2007;53:699–723.
21. Czlonkowaka A, Ciesielska A, Joniec I. Influence of estrogens on neurodegenerative processes. Med Sci Monit 2003;10:247–256.
22. Simpkins JW, Singh M, Bishop J. The potential role for estrogen replacement therapy in the treatment of the cognitive decline and neurodegeneration associated with Alzheimer’s disease. Neurobiol Aging 1994;15:S195–S197.
23. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women (Women’s Health Initiative Memory Study). JAMA 2004;291:2947–2958.
24. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2001;56:1143–1153.
25. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Text revision. Washington, DC: American Psychiatric Association, 2000:154–157.
26. Alzheimer’s Association. Available at www.alz.org/alzheimers_disease_causes_risk_factors.asp.
27. Reisberg B. Alzheimer’s disease. Stages of cognitive decline. Am J Nurs 1984;84:225–228.
28. Doody RS, Stevens JC, Beck C, et al. Practice parameter: Management of dementia (an evidence-based review). Neurology 2001;56: 1154–1166.
29. APA Working Group on Alzheimer’s Disease and other Dementias, Rabins PV, Blacker D, et al. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer’s disease and other dementias, 2nd ed. Am J Psychiatry 2007;164:5–56.
30. Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer’s disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA 1997;278: 1363–1371.
31. Cummings JL. Use of cholinesterase inhibitors in clinical practice: Evidence-based recommendations. Am J Geriatr Psych 2003;11: 131–145.
32. Slattum PW, Swerdlow RH, Massey Hill A. Alzheimer’s disease. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill, 2008: 1051–1065.
33. Gauthier S, Emre M, Farlow MR, et al. Strategies for continued successful treatment of Alzheimer’s disease: Switching cholinesterase inhibitors. Curr Med Res Opin 2003;19(8):707–714.
34. Swanwick GR, Lawlor BA. Initiating and monitoring cholinesterase inhibitor treatment for Alzheimer’s disease. Int J Geriatr Psych 1999; 14:244–248.
35. Product Information. Aricept (donepezil hydrochloride). Teaneck, NJ: Eisai; 2006 (Nov).
36. West-ward Pharmaceutical Corp. Cognex (tacrine hydrochloride) [product information]. Eatontown, NJ: Author; 2002 (Jan).
37. Novartis. Exelon (rivastigmine tartrate) [product information]. East Hanover, NJ: Author; 2007 (July).
38. Ortho-McNeil Neurologics. Razadyne ER/Razadyne (galantamine hydrobromide) [product information]. Titusville, NJ: Author; 2007 (April).
39. Forest Pharmaceutica, Inc. Namenda (memantine hydrochloride) [product information]. St. Louis, MO: Author; 2007 (April).
40. Sano M, Ernest C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med 1997;336:1216–1222.
41. Miller ER, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37–46.
42. Aisen PS, Schafer KA, Grundman M, et al. Effects of rofecoxib or naproxen versus placebo on Alzheimer’s disease progression. JAMA 2003;289:2819–2826.
43. Cooper JL. Dietary lipids in the etiology of Alzheimer’s disease. Drugs Aging 2003;20:399–418.
44. Dekosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA 2008;300:2253–2262.
45. Cummings J. Drug therapy: Alzheimer’s disease. N Engl J Med 2004;351:56–67.
46. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: A randomized, double-blind trial. J Clin Psych 1999;60: 107–115.
47. De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53:946–955.
48. Street JS, Clark WS, Gannon KS, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer’s disease in nursing care facilities: A double-blind, randomized, placebo-controlled trial. Arch Gen Psych 2000;57:968–976.
49. Brodaty H, Ames D, Snowdon J, et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia. J Clin Psych 2003;64:134–143.
50. Lyketsos CG, Olin J. Depression in Alzheimer’s disease: Overview and treatment. Biol Psychiatry 2002;52:243–252.
51. Allain H, Bentue-Ferrer D, Polard E, et al. Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: A comparative review. Drugs Aging 2005;22:749–765.
52. Sakuye KM, Camp CJ, Ford PA. Effects of buspirone on agitation associated with dementia. Am J Geriatr Psych 1993;1:82–84.
53. Hermann N, Eryavec G. Buspirone in the management of agitation and aggression associated with dementia. Am J Geriatr Psych 1993;1: 249–253.
54. Tariot PN, Cohen RM, Sunderland T, et al. L-deprenyl in Alzheimer’s disease. Arch Gen Psych 1987;44:427–433.
55. Schneider LS, Pollock VE, Zemansky MF, et al. A pilot study of low dose L-deprenyl in Alzheimer’s disease. J Geriatr Psych Neurol 1991;4:143–148.
56. Cacabelos R. Pharmacogenomics and therapeutic prospects in dementia. Eur Arch Psychiatry Clin Neurosci 2008;258:28–47.
57. Alzheimer’s Association. 10 quick tips: Living with Alzheimer’s. Available at www.alz.org/espanol_11842.asp.