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Alzheimer's Disease in the Primary Care Setting
Author: Larry W. Lawhorne, MD, Chair, Department of Geriatrics, Boonshoft School of Medicine, Wright State University, Dayton, OH.
Peer Reviewer: M. Flint Beal, MD, Department of Neurology and Neuroscience, Weill Medical College of Cornell University/New York Presbyterian Hospital, New York, NY.
Dementia is a clinical syndrome describing a constellation of cognitive deficits that adversely affect a person's day-to-day function.1,2 While dementia can be caused by a number of disorders of the brain, Alzheimer's disease is the most common1,2 and is the focus of this article in Primary Care Reports. Primary care will play a critical role in providing medical services for older adults with the aging of the U.S. population.3,4 Furthermore, the primary care physician's ability to diagnose and manage Alzheimer's disease will become increasingly important for at least two reasons. First, it is prevalent, and the absolute number of people with Alzheimer's disease is expected to increase dramatically. There are now 4.5 million Americans with Alzheimer's disease, with an expected increase to 13.2 million by 2050.5 Second, Alzheimer's disease has a devastating effect on the people who have it, on those around them, especially their caregivers, and on society as a whole.1-6
Two inter-related hypotheses about the pathophysiology of Alzheimer's disease are generally accepted: the amyloid hypothesis and the cholinergic hypothesis. The pathophysiology of Alzheimer's disease is complex, however, and future research could modify these hypotheses.2 According to the amyloid hypothesis, amyloid precursor protein (APP) is processed incorrectly in the beta-secretase pathway in neurons leading to the deposition of insoluble products called beta amyloid plaques (senile plaques). Eventually, these deposits lead to synaptic failure, neuronal injury, formation of tangles of hyperphosphorylated tau protein (neurofibrillary tangles), and finally neuronal death.2 Because the amyloid cascade initially involves neurons that synthesize the neurotransmitter acetylcholine, a cholinergic deficit is a prominent feature in the brains of people with Alzheimer's disease, hence the cholinergic hypothesis.2,7 However, injured or dying glutamate-producing neurons also may be involved in the pathogenesis of Alzheimer's disease.2,8 Under certain conditions, these neurons may release excessive amounts of glutamate causing excitotoxicity and death in neurons that are downstream to their synaptic connections.2,8 As will be seen in the section on the management of Alzheimer's disease, these observations about the activity of acetylcholine and glutamate figure prominently in current approaches to pharmacotherapy.
Demography, Epidemiology, and Primary Care
Managing the chronic health care needs of older adults, including those with Alzheimer's disease, will place an enormous burden on the health care system in the United States.3-6 The graph in Figure 1 shows that the number of people 65 years of age and older will essentially double between now and 2030 (from approximately 36 million to 72 million) representing an increase from approximately 12% to 20% of the U.S. population.9 The increase in the over-85 age group is noteworthy as well, reaching over 10 million by 2030.9 Both the relative and absolute increase in the number of older adults will affect the health care delivery system, including the relationship that exists between the primary care provider and the older consumer of health services.3,4 Family physicians, internists, nurse practitioners, and physician assistants will see more and more patients who are older and older as each wave of aging baby boomers becomes Medicare-eligible. The challenge of their increasing numbers will be matched by the heterogeneity of their health care expectations and needs, ranging from requests for anti-aging therapies and health maintenance on one end of the spectrum to management of frail elders with multiple medical and neuropsychiatric conditions on the other. Figure 2 provides a glimpse of what health care and social services professionals will face as they provide services for older adults. The percentage of men with moderate to severe memory impairment rises steadily from 8% in the 65 to 69 age group to 34% among those 85 and over.9 A similar increase is seen in women (from 3% to 31%).9
Since the prevalence of Alzheimer's disease and most other disorders causing dementia increases with age,5,6 the influx of older patients poses additional challenges for primary care providers. While the recognition, assessment, and management of dementia are difficult in their own right, the presence of dementia also affects the management of co-existing illnesses as well as the types of interventions that are recommended for the physical, psychosocial, and spiritual changes that occur with aging.4 Therefore, the primary care physician not only must be able to recognize that cognitive decline is present but also to determine the cause or causes of the decline either by performing the appropriate evaluation or referring the patient to a consultant.
Each office visit by an older adult at risk for developing Alzheimer's disease offers opportunities to improve the frequency with which symptoms and signs suggesting Alzheimer's disease can be recognized and to perform the evaluations necessary to establish a diagnosis. In addition, the primary care physician is in a pivotal position to initiate appropriate interventions to slow progression early in the course of the disease and to coordinate the long-term care of patients as the disease progresses. The objectives of the remainder of this article are to describe a process whereby primary care providers can: recognize risk factors and signs and symptoms suggestive of Alzheimer's disease; conduct or coordinate an assessment to establish the diagnosis; and manage Alzheimer's disease by developing a person-centered plan of care.
A number of publications suggest that primary care physicians fail to recognize or identify a substantial proportion of their patients who have cognitive impairment or fail to carry out appropriate assessments when they do recognize it.10-16 However, many of these reports focus on whether primary care physicians' screening activities and other processes and practices are consistent with existing clinical practice guidelines on dementia, specifically Alzheimer's disease. The question becomes, then, does the primary care physician fail to recognize and assess the problem or fail to use guidelines? Many of the older patients seen in the primary care setting have several medical and neuropsychiatric conditions, and there are potential pitfalls to applying multiple clinical practice guidelines to a single individual.17,18 In addition, many of the guidelines used to address Alzheimer's disease and other dementias were developed by specialists and academic centers and may suffer from limitations described by Kerr White and colleagues almost a half century ago. White's seminal article in the New England Journal of Medicine provided an elegant scheme for thinking about medical care from a population-based perspective.19 Using data collected by British general practitioners, White and his co-authors described the ecology of medical care in a population of 1000 adults. In an average month, 750 reported an illness but only 250 visited a physician. Of these 250, nine would be hospitalized, five referred to another physician, and one referred to an academic medical center. An overarching theme in 1961 and again in 2001 when White's medical care ecology construct was revisited20 is that what is happening in the academic medical center may not be reflective of what is happening in the community. An unintended effect, therefore, may be that medical research and medical education may not provide appropriate guidance for community-based primary care physicians, advance practice nurses, and other clinicians. Primary care practice-based research networks have addressed this potentially incongruent situation and ultimately changed the way common conditions are evaluated and managed.21,22
Applying the ecology of medical care model to Alzheimer's disease may be instructive. In a hypothetical town of 10,000 people in rural America, about 1,500 will be over the age of 65. How many of the 1,500 have cognitive impairment and what signs and symptoms can be expected? How many of those with cognitive impairment will see a primary care provider? How many with cognitive impairment will be recognized by the primary care provider as having impaired cognition? How many of those recognized as cognitively impaired will be assessed and diagnosed at the primary care level and how many will be referred to academic centers or experts specializing in the diagnosis and treatment of the dementing illnesses? Finally, how many will be treated using a systematic care and treatment model? Answers to these questions are important from a public health perspective because of the anticipated increase in the number of people with Alzheimer's disease noted earlier.5
Given these considerations, what should the primary care physician do to enhance the process of identification of potential cases of Alzheimer's disease? Is screening the answer? The Mini-Mental State Examination (MMSE)23 has been used for many years and is well validated. However, the MMSE was recently copyrighted, and according to the Web site for Psychological Assessment Resources, Inc., purchase price for 50 copies of the MMSE is $58.00.24 The Mini-Cog screen compares favorably with the MMSE with respect to sensitivity (76% vs. 79%) and specificity (89% vs. 88%).25 In the Mini-Cog, the patient is given three items to remember, is then distracted by a clock drawing test, and finally is asked to recall the three items without being cued. The test requires about 3 minutes to administer and is relatively uninfluenced by level of education or language differences.25
The U.S. Preventive Services Task Force concludes that there is insufficient evidence to recommend for or against routine screening for dementia in older adults.26 The Task Force reasoned that while some screening tests have good sensitivity and fair specificity, and that while there is good evidence that drug therapy has a beneficial effect on cognitive function, evidence for beneficial effect on instrumental activities of daily living is mixed.26 In addition, little is known about the potential harm of screening, such as labeling effect.26 Focus groups of primary care physicians in Michigan provided similar findings with concerns about time and resources, the potential adverse effects of labeling, and the belief that nothing could be done for the patient with Alzheimer's disease.4
If screening all older adults is not recommended, then what can be done to increase the frequency with which primary care physicians recognize risk factors and early signs and symptoms of Alzheimer's disease? Some authors suggest that targeted educational programs and enhanced support for clinical decision making would increase the number of people who are accurately diagnosed and for whom both disease-specific and supportive interventions can be implemented in a timely manner.15,27 Others have suggested that a constellation of symptoms are associated with early Alzheimer's disease: missing recall items on the Mini-Mental State Exam, difficulty doing calculations, repetition, getting lost while driving, forgetting the names of relatives, and having poor judgment.28
Based on existing literature and clinical practice guidelines, the dementia-prepared primary care practice should be knowledgeable about the risk factors for Alzheimer's disease and be aware of the warning signs and triggers that may suggest dementia.4,29-32 (See Table 1.) Finally, knowledge about the patient's Instrumental Activities of Daily Living (IADL) performance may help the primary care clinician with both recognition of dementia and prognosis. A study from the early 1990s reported that four IADLs correlated with cognitive impairment: telephone use, use of transportation, responsibility for taking medications, and handling finances.33 These correlations were noted to be independent of age, gender, and education.33 Not only was the inability to do one or more of these IADLs suggestive of the presence of dementia but also appeared to be predictive of further decline and health care utilization.33,34
To summarize his or her role in the recognition phase of Alzheimer's disease, the primary care physician should consider the following questions:
If the answer to any of these questions is yes, an assessment to determine the etiology of the cognitive deficits should be initiated as soon as possible.
Assessment and Diagnosis
If Alzheimer's disease is suspected because of the presence of warning signs, triggers, or IADL deficiencies, the primary care physician should consider measuring baseline cognition using the MMSE, Mini-Cog, 7-minute neurocognitive screen for Alzheimer's disease, or some other standard test of cognitive function that can be administered in the office. The 7-minute screen tests memory, verbal fluency, visuospatial ability, visuoconstruction, and orientation to time.35 Good evidence supports the use of the MMSE (adjusted for age and education) and neuropsychological batteries.36 Evidence is weaker for the Mini-Cog and the 7-minute screen.36
The National Guideline Clearinghouse (www.guideline.gov) lists 38 practice guidelines related to Alzheimer's disease. The American Academy of Neurology (AAN) guideline36 (published in 2001 and reviewed in 2004) provides a reasonable framework for the primary care practice. The AAN guideline recommends using the DSM-IV criteria to establish the diagnosis of Alzheimer's disease, and the American Association for Geriatric Psychiatry (AAGP) position statement on the principles of care for patients with Alzheimer's disease proposes a similar approach using the criteria in the DSM-IV-TR.2 The DSM-IV-TR criteria for Alzheimer's disease require the presence of multiple cognitive deficits manifested by memory impairment and aphasia and/or apraxia and/or agnosia, along with disturbances in executive functioning. In addition, the cognitive deficits represent a decline from previous functioning and cause significant impairment in social or occupational functioning with a course that is characterized by gradual onset and continuing decline. To meet criteria for Alzheimer's disease, the cognitive deficits cannot be due to other central nervous system, systemic, or substance-induced conditions that cause progressive deficits in memory and cognition and cannot be better accounted for by another psychiatric disorder.37
If the patient has evidence of multiple cognitive deficits manifested by memory impairment and aphasia and/or apraxia and/or agnosia, along with disturbances in executive functioning (DSM-IV-TR criteria for Alzheimer's disease), a targeted history and physical examination should be conducted. The history should focus on the following:
In addition to a thorough cardiovascular and pulmonary physical examination, the neurological examination should determine if there are any localizing findings or balance or gait abnormalities.
The presence of multiple cognitive deficits does not necessarily mean Alzheimer's disease. A number of neurodegenerative diseases other than Alzheimer's disease can produce cognitive deficits (vascular dementia, dementia with Lewy Bodies, fronto-temporal dementia), but they will not be addressed in this article. Cognitive deficits also can be associated with polypharmacy, mood disorders (especially depression), cerebrovascular disease, and a myriad of medical conditions.1,2,4,36 Therefore, a critical early step in the evaluation at the primary care level is to attempt to rule out the most common diseases and conditions that may mimic Alzheimer's disease with appropriate initial actions and tests. (See Table 2.)
The importance of a thorough review of medications (both prescription and non-prescription drugs) cannot be over-emphasized. Drugs with anticholinergic activity can have a profound effect on cognition.38-41 Since many of the older adults in the community are on multiple medications, cumulative anticholinergic effect is of increasing concern. Any single drug that the older patient is taking may have only a small anticholinergic effect, but in aggregate, the effect may be large. In a report on 201 community-dwelling older adults who were randomly selected to undergo testing for serum anticholinergic activity (SAA), 180 (90%) had detectable SAA, and there was a significant association between SAA and Mini-Mental State Examination scores.42 Logistic regression analysis indicated that subjects with SAA at or above the sample's 90th percentile (SAA 2.80 pmol/mL) were 13 times (odds ratio, 1.08-152.39) more likely than subjects with undetectable SAA to have a Mini-Mental State Examination score of 24 (the sample's 10th percentile) or below.42 The implications of these findings are that even low SAA may be associated with cognitive impairment.
Depressive symptoms or Major Depression Disorder may either mimic or accompany Alzheimer's disease; therefore, screening for depression and crafting a treatment plan for depression are important tasks for the primary care physician.2,36,43-45 Two screening tests that are easily administered in the office setting are the Short-Form Geriatric Depression Scale (GDS)46 and the Patient Health Questionnaire-2 (PHQ-2).47 The Short-Form GDS takes five to seven minutes and can be administered by a provider with minimal training in its use.46 The PHQ-2 asks about depressed mood and anhedonia over the past two weeks (score 0 to 3 for each with 0 = "not at all" and 3 = "nearly every day"). A PHQ-2 score > 3 has a sensitivity of 83% and a specificity of 92% for major depression in the primary care setting.47 However, this study involved a younger patient population.
With regard to laboratory testing, the AAN guideline recommends complete blood count, glucose, thyroid function tests, serum electrolytes, BUN, creatinine, liver function tests, and vitamin B12 level.36 Table 2 also includes a recommendation for lipid testing because the AAGP emphasizes the importance of addressing cardiovascular risk factors, including screening for and treating lipid disorders.2 Controlling cardiovascular risk factors, especially hypertension and hyperlipidemia, are probably important strategies for preventing or slowing the progression of mixed dementia (defined as the coexistence of Alzheimer disease and vascular dementia), which is likely to increase as the population ages.48 The AAN guideline does not recommend routine screening for syphilis, linear or volumetric magnetic resonance or computed tomography measurement strategies, SPECT, APOE genotyping, EEG, or lumbar puncture.36 However, lumbar puncture may be indicated in certain situations, including metastatic cancer, suspicion of CNS infection, reactive serum syphilis serology, hydrocephalus, age under 55, rapidly progressive or unusual dementia, immunosuppression, or suspicion of CNS vasculitis.36
According to the AAN guideline, "structural neuroimaging with either a noncontrast computed tomography or magnetic resonance scan in the initial evaluation of patients with dementia is appropriate."36 For the most part, the purpose of structural neuroimaging is to provide clues that a process other than Alzheimer's disease may be the cause of the dementia. But as imaging techniques improve and stronger clinical correlation studies emerge, things are beginning to change. For example, magnetic resonance imaging can detect predominantly left atrophic changes in the entorhinal cortex, amygdala, and anterior hippocampus several years before the onset of clinical symptoms of Alzheimer's disease in some cases.49 The future of neuroimaging, however, is likely to be influenced greatly by findings from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a public-private research partnership organized by the National Institutes of Health. The ADNI study follows normal individuals, people with mild cognitive impairment, and people with Alzheimer's disease. Researchers will use positron emission tomography and magnetic resonance imaging of the brain, biomarkers in blood and cerebrospinal fluid, and clinical interviews and neuropsychological testing to track cognitive performance over time.50
If the history, physical examination, and other diagnostic tests are consistent with Alzheimer's disease and if the patient and family are satisfied with the thoroughness of the assessment, a referral to a neurologist, geriatric psychiatrist, or a center specializing in dementia may not be necessary. However, referral for neuropsychological testing should be considered because findings may be helpful when developing the person-centered plan of care.4
At this stage, the primary care physician should open a discussion with the patient and family about the diagnosis of Alzheimer's disease. Providing information about the diagnosis, how it was made, and why other diagnoses appear unlikely may strengthen the doctor-patient and doctor-family bonds at this critical time.4 An offer to help the patient and family secure a second opinion if they wish and to provide contact information for local community resources is also appropriate at this time.4,51 Open a discussion about safety issues as soon as possible emphasizing the current living situation and driving. If depression is also suspected, suicide risk must be assessed.52 After these initial steps have been taken, the primary care physician can start to work with the patient and family to develop and implement a more detailed plan of care.
General Principles of Care. The AAGP position statement about the care of patients with Alzheimer's disease should resonate with primary care physicians. The statement contends that while evidence is limited, the existing literature, coupled with clinical experience and common sense, is adequate to produce a set of effective care principles aimed at:
The AAN guideline emphasizes pharmacotherapy for cognitive symptoms, agitation, psychosis, and depression as well as psychosocial support for the person with Alzheimer's disease and the caregiver.36
Primary care physicians often are best suited to help patients and family members understand Alzheimer's disease, its symptoms, and prognosis and to advise them about community resources. Family members of patients with Alzheimer's disease, especially those who are or will become caregivers, often are devastated when the diagnosis is presented.51 Therefore, spending time with both patient and caregiver at this point can strengthen the relationship between the physician and the patient-caregiver dyad and create a bond that will help all three make the best of the journey ahead. Tailoring disclosure of the diagnosis to the characteristics of the patient and family members is important and may be done best by the physician who has provided primary care prior to the diagnosis.51 Caregivers want physicians to listen and respond to their concerns and to include the patient in discussions even when they may not understand all that is being discussed.51
There are three resources that are generally available across the country. The Alzheimer's Association is available online at www.alz.org or at 800-337-3827 and provides information about local chapters, support groups, 24-hour support line services, education, and safe return programs. Area Agencies on Aging (www.aoa.dhhs.gov or 800-677-1116) offer information and assistance with finding a variety of services, such as care management, home-delivered meals, personal care, and respite or day care. The Family Caregiver Alliance (http://www.caregiver.org or 415-434-3388) is dedicated to working with caregivers and provides fact sheets, research updates, and an email-based support group.
Drugs for Alzheimer's Disease. The most obvious and consistent abnormality in the neurochemistry of Alzheimer's disease is a deficiency of acetylcholine. Injury and ultimately death of cholinergic neurons are associated with decreasing activity of acetylcholine in the brain, which in turn leads to some of the clinical manifestations of Alzheimer's disease.2 This cholinergic hypothesis has focused attention on the development of drugs that prolong activity of any acetylcholine in the brain as long as possible. Acetylcholinesterase inhibitors act by inhibiting acetylcholinesterase, the enzyme that degrades acetylcholine by hydrolysis.7
Four cholinesterase inhibitors are available for the treatment of mild to moderate Alzheimer's disease: tacrine (Cognex®), donepezil (Aricept®), galantamine (Razadyne®), and rivastigmine (Exelon®).7 Tacrine was licensed in 1993 and used widely in the U.S. However, it required T.I.D. or Q.I.D. dosing, was poorly tolerated, and caused a specific reversible hepatotoxicity.7 Donepezil, which became available in 1997, quickly replaced tacrine as the drug of choice because of its better tolerability and once-a-day dosing.7 Galantamine became available in 1998 and rivastigmine in 2000.7
Donepezil is a piperidine-based reversible acetylcholinesterase inhibitor that reaches steady state after about 15 days. Absorption is not affected by food or time of administration. Staring dose is 5 mg once a day for a minimum of 4 weeks with an increase to 10 mg daily if no problems with tolerability.7
Rivastigmine is a centrally selective carbamate inhibitor of both acetylcholinesterase and butyrylcholinesterase and is described as a pseudo-irreversible inhibitor because it inactivates the enzymes for about 10 hours. The oral form should be given with food starting at 1.5 mg BID with an increase at a minimum of every two weeks to reach a dosing range of 3 to 6 mg BID.7 The initial strength of the transdermal patch is 4.6 mg/24 hours. The dose can be increased to 9.5 mg/24 hours, the recommended effective dose, after a minimum of 4 weeks and if there are no problems with tolerability. Higher doses confer no appreciable additional benefit and are associated with significant increase in the incidence of adverse events.53
Galantamine, a phenanthrene alkaloid, is a reversible competitive inhibitor of acetylcholinesterase and an allosteric modulator of neuronal nicotinic receptors.7 One of its metabolites is also an active inhibitor of acetylcholinesterase. The immediate-acting form is administered at a starting dose of 4 mg BID followed in 4 weeks by 8 mg BID with another increase to 12 mg BID if tolerated. Galantamine is available as an extended-release capsule for once-a-day dosing. The recommended starting dose is 8 mg/day. The dose should be increased to the initial maintenance dose of 16 mg/day after a minimum of 4 weeks with further increase to 24 mg/day after a minimum of 4 weeks at 16 mg/day if there are no problems with tolerability of the previous dose.54
Memantine (Namenda®, Ebixa®) is a fifth drug that is available for the treatment of Alzheimer's disease. Approved for moderate to severe disease, memantine is a moderate affinity, uncompetitive glutamate antagonist at the N-methyl-D-aspartate (NMDA) receptor. The neurotransmitter glutamate activates several classes of receptors in the central nervous system, including the NMDA receptor. In Alzheimer's disease, glutamate mediates neurotoxicity by over-activating the NMDA receptor potentially leading to neuronal damage or death.2,8 Memantine comes as a tablet or solution and can be taken with or without food. The recommended target dose is 20 mg/day. The dose should be increased in 5 mg increments starting at 10 mg/day (5 mg twice a day), then 15 mg/day (5 mg and 10 mg as separate doses), and finally 20 mg/day (10 mg twice a day). The minimum recommended interval between dose increases is one week.55 A target dose of 5 mg BID is recommended for patients with severe renal impairment.55
The primary care physician is faced with a number of questions when working with patients and their families to make decisions about the drugs approved for Alzheimer's disease. Do any of these drugs offer meaningful clinical benefit? If they do, is one cholinesterase inhibitor preferred over another? When should memantine be used, and should it be added to a cholinesterase inhibitor? How long should pharmacotherapy for Alzheimer's disease be continued? What are the consequences of discontinuing pharmacotherapy, especially a cholinesterase inhibitor for Alzheimer's disease?
Do any of these drugs offer meaningful clinical benefit? Meta-analyses of randomized, controlled trials and systematic reviews of treatment with donepezil, rivastigmine, or galantamine suggest modest benefits on cognitive, behavioral, functional, or global measures and modest benefits with regard to slowing disease progression.56-71 In spite of these reports, most guidelines recommend treatment with cholinesterase inhibitors, and the number of prescriptions for these drugs continues to increase.72 A recent population-based study of cholinesterase inhibitor use among 28,961 patients in Canada found that on average patients had 26 physician visits in the year before cholinesterase inhibitor therapy was started but only 28% had seen a specialist during that time and over one-third were receiving potentially inappropriate drugs (e.g., benzodiazepines or drugs with anticholinergic effects).72 Average length of treatment with a cholinesterase inhibitor was about 2.4 years, 43% remained on the initial dose prescribed, 6% switched to another cholinesterase inhibitor, and 19% died while on cholinesterase inhibitor therapy.72 If these findings are generalizable, they are disturbing on at least two counts. First, primary care physicians may not be doing a very good job of eliminating drugs with anticholinergic effects in patients with Alzheimer's disease. Second, many patients may not be receiving an effective dose of a cholinesterase inhibitor despite being on one of the drugs for well over two years. For now, the consensus of expert opinion seems to be that Alzheimer's disease is fatal and that important benefits can be achieved for individual patients and their caregivers by prescribing a cholinesterase inhibitor.7
Is one cholinesterase inhibitor preferred over another? A number of head-to-head comparisons of cholinesterase inhibitors have been reported,73-77 but these studies are technically difficult because of the different dosing regimens for each of the cholinesterase inhibitors. In addition, most were sponsored by one or another of the manufacturers. At this point, it appears that all three of the cholinesterase inhibitors are efficacious, that donepezil had the advantage of once-a-day dosing (but now galantamine also is supplied in a once daily extended release form and there is a rivastigmine patch), and that rivastigmine may have more gastrointestinal side effects.7 For now, the consensus of expert opinion seems to be that the primary care physician should select a cholinesterase inhibitor that seems to fit the person's and caregiver's daily routine the best and titrate to the effective dose as recommended by the manufacturer.7
When should memantine be used, and should it be added to a cholinesterase inhibitor? Memantine is an important addition to current treatment because it may offer some neuroprotection by partially blocking the excitotoxicity of glutamate.2,8 Symptomatic improvement has been observed in patients with moderate to severe Alzheimer's disease and in patients with vascular dementia.7 However, there is insufficient evidence to guide physicians about the optimal approach to combining memantine and cholinesterase inhibitors. Further studies are needed and are in progress.7
How long should pharmacotherapy for Alzheimer's disease be continued? Guidelines are silent about the length of treatment that is optimal, but as seen earlier in the Canadian study,72 the average time on a cholinesterase inhibitor is well over two years. For now, the duration of therapy remains a case-by-case, shared decision between the primary care physician and the person with dementia or his or her decision maker.
What are the consequences of discontinuing pharmacotherapy for Alzheimer's disease? Guidelines are likewise silent about when to discontinue cholinesterase inhibitors. One cross-sectional study of outpatients with Alzheimer's disease found that termination of therapy with any cholinesterase inhibitor was associated with a cognitive decline during the following 6-7 weeks.78 However, in a study to evaluate the change in cognition (at week 26 vs baseline) observed in patients from 3 large clinical trials of Alzheimer's disease who prematurely discontinued treatment with placebo or rivastigmine, researchers found that rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients.79 For now, discontinuing a cholinesterase inhibitor should be a shared decision between the primary care physician and the person with dementia or his or her decision maker. In practice, by the time the discussion to consider discontinuation comes up, the patient's condition has deteriorated markedly.
Drugs for Accelerators. Several factors have been identified as potentially initiating the pathological changes of Alzheimer's disease and/or accelerating its progression.2 Consequently, these factors have been targeted for drug therapy.
Amyloid plaques and neurofibrillary tangles are the most familiar footprints left in the brains of patients with Alzheimer's disease, but inflammation has been suspected from the beginning. Alzheimer himself noted activated microglial cells around the plaques and tangles, and since then, evidence for inflammation has continued to accumulate.7 Epidemiologic and observational studies have linked non-steroidal anti-inflammatory drug (NSAID) use with a lowered risk for developing Alzheimer's disease.80-84 However, a number of subsequent clinical trials have not supported the use of prednisone, celecoxib, rofecoxib, naproxen, or hydroxychloroquine in either the prevention or treatment of Alzheimer's disease.85-89 At this point, then, NSAIDs are not recommended for either prevention or treatment. However, inflammation may turn out to be an important component that initiates and/or accelerates the pathological changes seen in the brains of patients with Alzheimer's disease.7 Some NSAIDs and related drugs not only decrease inflammation but slow amyloid production as well.90-92 More research in this area is needed and is in progress.
The potential effect of oxygen free radicals on initiation and progression of Alzheimer's disease has led to the recommendation for the use of anti-oxidants such as vitamin E.2,36 A number of observational studies support the notion that diets rich in vitamin E or supplements containing vitamin E reduce the risk of Alzheimer's disease and other forms of dementia or slow progression.93-97 However, the methodological limitations of these and similar studies preclude definitive conclusions.7 An article published more than 10 years ago supported the use of high doses of vitamin E (2000 IU/day).98 This study, which involved community-dwelling elders in a multicenter randomized trial, evaluated the use of vitamin E (alpha tocopherol), selegiline, or both compared to placebo. All treatment groups had improved outcomes in several areas (nursing home placement, progression to severe dementia, or death), and the vitamin E group also benefited in measures of activities of daily living.98 However, more recent work has raised concern about high doses of vitamin E and mortality.99-101 Therefore, current recommendations are to provide 400 IU of vitamin E daily.2,7,36 Ginkgo biloba is also a powerful anti-oxidant.2,7 In addition, it may interfere with platelet aggregation and act as a vasodilator. There are numerous and conflicting studies evaluating the effect of ginkgo biloba on Alzheimer's disease, but neither the AAGP position statement nor the AAN guideline recommends its use in the prevention or treatment of Alzheimer's disease.2,36
The potential role of postmenopausal estrogen depletion as either a risk factor for or an accelerator of Alzheimer's disease gained favor on the basis of epidemiologic studies and early clinical trials, but more recent studies have not supported the use of estrogen for Alzheimer's disease.2 For example, a population-based case-control study of postmenopausal women who developed Alzheimer's disease (264 cases and 264 controls without dementia) found similar frequencies of estrogen use (11.4% in cases and 10.6% in controls).102 Estrogen for either prevention or treatment of Alzheimer's disease is not supported by a Cochrane review and is not recommended in the AAGP position statement or the AAN guideline.2,36,103
Vascular disease in the brain appears to be involved in the progression of Alzheimer's disease in two ways.2 First, for any given extent of Alzheimer's disease brain pathology, vascular disease in the brain may be additive with regard to cognitive impairment.2 Second, vascular disease in the brain may accelerate amyloid deposition and make both neurons and synapses more susceptible to amyloid toxicity.2,104 Therefore, the AAGP position statement proposes that the management of vascular disease in the brain and vascular risk factors in general should be included in the treatment plan for people with Alzheimer's disease.2 Specifically, treatment of hypertension, hyperglycemia, and hypercholesterolemia are mentioned as is the prescription of low dose aspirin.2 The association between high levels of cholesterol, amyloid-precursor protein metabolism, and the risk of Alzheimer's disease is intriguing. The use of HMG-CoA reductase inhibitors (statins) was associated with a lower frequency of Alzheimer's disease in an epidemiologic study,105 but a 3-year randomized clinical trial of pravastatin failed to show a beneficial effect on cognition in older adults at risk for cardiovascular disease.106
In summary, epidemiologic studies have suggested that NSAIDs, estrogen, HMG-CoA reductase inhibitors (statins), or tocopherol (vitamin E) can prevent Alzheimer's disease. However, prospective, randomized studies do not support clinical efficacy at this time. Major progress in molecular medicine suggests other approaches. For example, the metabolism of the amyloid-precursor protein and the aggregation of its Abeta fragment are the focus of current studies.107 Peroxisome proliferator activated receptor-gamma agonists and selected NSAIDs may modulate both Abeta production and inflammatory activation. On the basis of autopsy reports, active immunization against Abeta in humans seems to clear amyloid deposits from the brain.107 However, clinical trials with active vaccination against the full length Abeta peptide have been halted because of adverse effects.107 Further trials with vaccination or passive transfer of antibodies are in progress.
Drugs for Depression. Both depressive symptoms or Major Depressive Disorder are common among patients with Alzheimer's disease.2,36,43-45 Individual counseling and support groups for the patient and the caregiver may be helpful.52 If medication is needed, a selective serotonin reuptake inhibitor (SSRI) with low anticholinergic effect is a good choice.52,108,109 If the patient is on multiple medications, choosing an SSRI with the fewest drug-drug interactions given the patient's medication list is important as well.109
Drugs for Behavioral Disturbance. Behavioral symptoms associated with Alzheimer's disease have a substantial negative effect on quality of life for patients and their caregivers.2,36,110 When behavioral problems arise, the caregiver should try to determine if there are triggers for the behaviors and eliminate or modify the triggers if possible. The AAN guideline lists nine strategies to reduce behavioral disturbances, but only the first two have good evidence to support their use: music, especially during meals and bathing; walking and other forms of light exercise; simulated presence therapy, e.g., videotapes of family; massage; comprehensive psychosocial care programs; pet therapy; commands delivered at the patient's level of comprehension; bright light and white noise; and cognitive remediation.36 Tips for the caregiver from the Alzheimer's Association for managing behavioral disturbances when they do occur include remaining calm and reassuring, being patient and flexible, not arguing or trying to convince the person, acknowledging requests and responding to them, trying not to take behaviors personally, and accepting the behavior as a reality of the disease and trying to work through it.111 When behavioral and environmental approaches do not reduce these disturbances, treatment with cholinesterase inhibitors, alone or in combination with memantine as appropriate for the stage of disease, may be considered as a first-line option in the early pharmacologic management of Alzheimer's disease-related behavioral symptoms.2,110
The use of atypical antipsychotics in patients with behavioral symptoms related to Alzheimer's disease is controversial.2,112 Atypical antipsychotics have been used extensively for treating psychotic symptoms and agitation in older adults, but have potential complications related to sedation, metabolic disturbances, and anticholinergic effects.112 The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) found that although these drugs have some efficacy, their adverse effects limit their use in this population.112 The FDA's "black box warning" further complicates the situation.2 Antidepressants, anxiolytics, mood stabilizers, and other classes of drugs have been used as well but a discussion of these agents is beyond the scope of this article.
Key Decision Points
Three situations that can be particularly difficult for the primary care physician when working with the patient with dementia and his or her family are driving, living arrangements, and end-of-life issues. Each of these situations may require a great deal of time, but anticipating them and addressing them prior to an urgent or crisis situation can be beneficial for the patient, caregiver, and physician.
Driving. Driving is a complex skill that requires sound judgment and the ability to assess a situation quickly and at times, make a series of rapid responses to changes in road conditions or traffic patterns. The Alzheimer's Association offers the following warning signs of unsafe driving:113
A diagnosis of Alzheimer's disease alone does not mean that a person should stop driving, but it is often difficult to determine when the person's cognitive impairment reaches the point that he or she should no longer drive. Office-based cognitive tests recommended in various guidelines do not have validated cutoff scores and are, therefore, not very useful.114 Clinical judgment or testing by the Department of Motor Vehicles (or the equivalent state agency) is generally used to determine fitness to drive. Primary care physicians who attend patients with Alzheimer's disease should be familiar with their state's rules, regulations, and reporting mechanisms concerning potentially impaired drivers. Once it has been determined that the person with Alzheimer's disease can no longer drive safely, the Alzheimer's Association suggests that the physician write the person a "do not drive" prescription and that the family or caregiver use some of the following approaches to address driving:113
Living Arrangements. Most older adults, including those with Alzheimer's disease, want to live in their own homes. As Alzheimer's disease progresses, home safety and wandering can become areas of concern for the caregiver and the primary care physician. Just as for driving, determining where along the continuum of cognitive decline that a person can no longer live alone or be left alone is difficult and requires open and frank discussions in the office. Sometimes, a referral to a geriatrician, neurologist, psychiatrist, or neuropsychologist or a referral to a center that specializes in dementia is the best way to gauge the person's need for supervision. The Alzheimer's Association provides some useful safety tips about protecting the person with Alzheimer's disease from potentially dangerous situations:115
Likewise, tips to reduce wandering behavior may also be helpful:116
Tips to protect the person who may wander and get lost are also provided at the Alzheimer's Association Web site:
The Safe Return® is a nationwide identification and support program that is administered by the Alzheimer's Association and provides assistance if a person with Alzheimer's disease wanders and becomes lost. The enrollment fee is $40, and assistance is available 24 hours a day, 365 days a year. If an enrollee is missing, one call immediately activates a community support network to help find the lost person.
End-of-life Issues. Soon after the diagnosis is made, the physician should open a discussion about advance care directives to ascertain from the patient what interventions he or she wants and does not want as the disease progresses. This discussion should take place early in the course of the disease, thus allowing direct input from the patient. In order to have an informed discussion, however, some estimate of life expectancy is helpful. Life expectancy following the diagnosis of Alzheimer's disease is important not only for meaningful dialogue among patients, their families and caregivers, and clinicians but also for health planners and policy makers.117,118 A study of participants in the Baltimore Longitudinal Study of Aging found that median survival time ranged from 8.3 years for persons diagnosed with Alzheimer's disease at age 65 to 3.4 years for persons diagnosed at age 90 with no significant differences in survival noted between men and women.117 Having a diagnosis of Alzheimer's disease reduced median survival by 67% for 65-year-olds and 39% for 90-year-olds.117 A prospective observational study using an Alzheimer's disease registry from a base population of 23,000 community-dwelling elders age 60 and older in the Seattle area reported a median survival of 4.2 years for men and 5.7 years for women following the diagnosis of Alzheimer's disease.118 Features associated with reduced survival at diagnosis were increased severity of cognitive impairment, decreased functional level, history of falls, the presence of frontal release signs, and abnormal gait.118 Both of these studies report a longer median survival than the finding of 3.3 years reported in a 2001 New England Journal of Medicine article119 and emphasize the importance of age and severity of symptoms at the time of diagnosis.
The message from the Baltimore and Seattle studies for patients and their families is that the median survival may be as long as 7-10 years for patients who are diagnosed in their 60s and early 70s.117,118 Given such a prediction, the treatment recommendations outlined above should be discussed in detail with the patient and the family and a care plan outlined taking the person's advance care directive into account. The care plan should be reviewed and revised periodically with the frequency of review and revision determined in a shared way among the primary care physician and the patient and caregiver. In addition, the care plan should also be reviewed and possibly revised whenever there is a change in the patient's condition. A change in condition for a person with Alzheimer's disease may be manifested by a decline in physical function, cognition, or mood or a change in behavior. When such a change occurs, it may be helpful for the primary care physician and the caregiver to use the mnemonic shown in Table 3 to work through potential causes of the change in the person's condition. KISSES is easy to remember and provides a systematic approach that can allow the caregiver to provide useful information to the physician and can give the physician and the caregiver a mechanism for reviewing and revising the care plan.
At some point in the course of Alzheimer's disease, the patient's condition will decline to the point that the caregiver and other people who are important in the person's life conclude that treatment targeted at Alzheimer's disease is no longer warranted. Ideally, discussions about this eventuality should have taken place all along, and the care plan should have focused on function and quality of life as well as disease-driven processes of care. New goals of care should be set and a new care plan established. Depending on the patient's medication list, most of them can either be stopped right away or tapered and stopped. The plan and rationale for removing medications should be clear to the caregiver. Patients with Alzheimer's disease and their caregivers and family can benefit from hospice care.120
The recognition, assessment, and management of Alzheimer's disease necessarily will become the purview of the primary care physician because of the dramatic aging of the U.S. population and the prevalence of Alzheimer's disease among older adults. Knowledge about risk factors, warning signs, and triggers will help the primary care physician recognize that an older adult may have the disease. An accurate history and physical examination along with blood tests, a test to measure cognition, a screen for depression, and a brain imaging study along with application of DSM-IV-TR criteria will establish the diagnosis. Eliminating or reducing the number of drugs with anticholinergic activity is crucial. Treatment with a cholinesterase inhibitor with the addition of memantine at the appropriate time is indicated as is treatment of depression. Care for the caregiver in the form of information about available resources is a fundamental part of the care plan, which needs to be crafted in a shared manner and reviewed and revised as needed. Hospice can be useful for the patient with Alzheimer's disease and the patient's caregiver and family and friends when the disease enters its final stages.
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