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Diagnosis, Management, and Treatment of Alzheimer Disease
A Guide for the Internist
Stephanie S. Richards, MD;
Hugh C. Hendrie, MB, ChB
Arch Intern Med. 1999;159:789-798.
ABSTRACT
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Alzheimer disease (AD) is a diagnosis of inclusion based on patient history, physical examination, neuropsychological testing, and laboratory studies; however, there is no definitive diagnostic test for AD. Early recognition of AD allows time to plan for the future and to treat patients before marked deterioration occurs. Effective treatment requires monitoring of symptoms, functional impairment, and safety, and the use of multiple treatment modalities including pharmacotherapy, behavioral management, psychotherapies, psychosocial treatments, and support and education for families. Pharmacotherapeutic agents available for AD only provide symptomatic relief. The cholinesterase inhibitors, tacrine and donepezil, are effective in improving cognition, delaying nursing home placement, and improving behavioral complications in some patients. Other cholinesterase inhibitors are in development, as are other cholinomimetic agents such as muscarinic and nicotinic receptor agonists. Symptomatic treatments are available for the psychiatric manifestations of AD. Anti-inflammatories, antioxidants, neurotrophic factors, and other agents are promising new treatments for the future.
INTRODUCTION
Alzheimer disease (AD) is one of a group of neurodegenerative disorders that frequently cause dementia. Dementia is characterized by a progressive cognitive decline leading to social or occupational disability occurring in a state of clear consciousness.
Specifically, AD is characterized clinically not only by an impairment in cognition but also by a decline in global function, a deterioration in the ability to perform activities of daily living, and the appearance of behavioral disturbances. When AD was originally described by Alois Alzheimer in 1907,1 it was considered to be a relatively uncommon disorder. However, subsequent clinical and neuropathological studies identified the characteristic AD pathology of senile plaques and neurofibrillary tangles as the most common cause of dementia in the elderly. With the aging of our population, the management and treatment of AD is likely to become one of the major public health problems facing our society in the next century. Our knowledge of the pathophysiology and natural history of the disease has increased greatly over the past decade, yet the definitive cause remains unclear and a cure has been elusive. Nevertheless, we now have available effective pharmacological and psychosocial interventions to alleviate the symptoms and suffering of patients with AD and their families. The purpose of this article is to discuss the epidemiology, presentation, diagnosis, and pharmacological management of the disorder.
EPIDEMIOLOGY
The prevalence of dementia in the United States in individuals aged 65 years or older is about 8%, with these rates doubling if those with milder forms of dementia or cognitive impairment are included. Rates of dementia are very much age dependent, doubling every 5 years from 1% to 2% at ages 65 to 70 years, to 30% and higher after the age of 85 years. Alzheimer disease is by far the most common of the dementing disorders in the United States, accounting for 65% to 75% of cases.2-5
COST
The calculated economic cost of the management and treatment of AD is staggering. The combined direct costs, including medical and long-term care and lost productivity, and indirect costs, including resource loss and family care, approach $100 billion per year.6 In addition, there is also the immeasurable emotional cost to families who suffer tremendously watching their affected loved ones slowly lose their identity.
RISK FACTORS
Our knowledge of putative genetic risk factors for AD has increased dramatically over the past decade. There is now evidence that certain types of early-onset, autosomal dominant AD are associated with gene mutations on chromosome 21, chromosome 14, and chromosome 1.7-9 These findings are important for determining pathologic mechanisms but account for only a small proportion (about 2%) of all cases of AD.10
The presence of the APOE 4 allele on chromosome 19 has been associated with a considerably greater risk for developing the more common, late-onset form of AD.8, 11-12 The effect appears to be dose dependent. The presence of a single4 allele increases the risk of AD by 2- to 4-fold, whereas possessing the double4 allele increases the risk from 4- to 8-fold. It must be remembered that possessing the4 allele is neither necessary nor sufficient for the development of AD. Therefore, APOE genotyping is not recommended as a predictive test for AD in asymptomatic individuals.13 However, experts disagree on the utility of APOE genotyping as a diagnostic test. It may be useful for confirmation in some patients with dementia when a diagnosis of AD is unclear, although the presence of 1 or 2 copies of the APOE 4 allele still does not make the diagnosis certain and absence of the4 allele does not preclude a diagnosis of AD. APOE genotyping, when used in patients with a clinical diagnosis of AD, may increase the specificity of the diagnosis.14
Research on other risk factors for AD is relatively new. To date, only age, family history of dementia, and Down syndrome consistently have been shown to be associated with AD. However, high education and ingestion of estrogen, nonsteroidal anti-inflammatory drugs, and vitamin E may be protective. It is likely in the future that risk factor models involving genetic and environmental interactions will emerge.
DIAGNOSTIC PROCESSES AND DIFFERENTIAL DIAGNOSIS
As AD is both a clinical and a neuropathological entity, the definitive diagnosis of AD can be made only with a brain biopsy or an autopsy. One of the major clinical advances in the diagnosis of AD has been the promulgation of diagnostic criteria for possible and probable AD by a select group sponsored by the National Institute of Neurological and Related and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association (Table 1).15 Using these criteria, the clinical diagnosis of AD has been confirmed at autopsy in close to 90% of cases. It has been stated that AD is a diagnosis of exclusion. This is only partially correct. While it is essential for the physician to evaluate other possible causes of memory loss, a positive diagnosis of probable AD can be made based on a characteristic history from a spouse or a knowledgeable informant together with a physical and neurologic examination. The differential diagnosis for AD includes a broad range of other causes of dementia and nondementing metabolic or psychiatric illnesses.
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Criteria for Clinical Diagnosis of Probable Alzheimer Disease*
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Among the more important nondementing causes of dementia are delirium and depression. Delirium is common in elderly subjects, particularly in inpatient settings and in nursing homes. Unlike delirium in children, which is an acute disorder, delirium in the elderly can be subacute at onset, stretching over weeks or even months, characterized by apathy rather than agitation, and vague paranoid symptoms rather than vivid hallucinations. Thus, delirium in the elderly can often be misdiagnosed. Common causes of delirium include infection (particularly urinary tract infections), hypoglycemia, electrolyte abnormalities (such as those accompanying dehydration), hepatic dysfunction, renal insufficiency, endocrine dysfunction (particularly thyroid abnormalities), and medications (especially anticholinergic agents, benzodiazepines, histamine2 antagonists, and narcotics), all of which are eminently treatable. Delirium and dementia can coexist. In fact, dementia predisposes to the development of delirium with even modest metabolic insults.
Severe depression in the elderly is often accompanied by complaints of memory loss and the presence of mild cognitive deficits on neuropsychological testing. In depression, the subjective complaints of cognitive impairment often exceed the neuropsychological deficits, and the primary problem seems to be one of motivation or lack of effort. Depression and dementia can coexist, however.
Among the dementing disorders, vascular dementia follows AD as the second most common form.16 The vascular dementias usually, but not always (eg, Binswanger disease), have a relatively acute onset temporally related to a vascular event such as transient ischemic attack or stroke and have a more fluctuating course than AD. Focal neurologic signs or symptoms usually accompany them. Cerebrovascular changes can also coexist with AD pathology, and this combination can adversely affect the dementing process.17
Other neurodegenerative disorders that can cause dementia include Parkinson disease, Huntington disease, Pick disease, and dementia with Lewy bodies. Parkinson disease and Huntington disease are characterized by extrapyramidal signs, which usually predate the cognitive decline. Pick disease is one of the frontal lobe dementias and usually presents with behavioral disinhibition, poor insight, and language deficits early in the course of the illness. Memory and constructional praxis are relatively spared early on. Frontal and temporal lobe atrophy is usually evident on computed tomography. Dementia with Lewy bodies is a progressive dementia characterized by detailed recurrent visual hallucinations, parkinsonism, and fluctuations of alertness and attention.18 Other common features include frequent falls, syncope, systematized delusions, and neuroleptic sensitivity. Autopsy series findings demonstrate cortical Lewy bodies in 20% to 30% of dementia cases and there may be overlap with AD.18 A long history of heavy use of alcohol can also cause dementia.
Creutzfeld-Jakob disease is an example of an infectious cause of dementia caused by prions. Creutzfeld-Jakob disease is characterized by relatively sudden onset and rapid progression with myoclonic jerks, pyramidal frontal motor signs, visual agnosia, and death within months.
Other neurologic disorders less commonly associated with dementia include normal pressure hydrocephalus, subdural hematoma, brain tumor, posttraumatic brain injury, and posthypoxic damage.
DIAGNOSTIC EVALUATION
A diagnostic evaluation for dementia involves a complete history, neuropsychological examination (eg, the Mini-Mental State Examination [MMSE]),19 physical examination, and selected laboratory studies and neuroimaging.20 The history should be obtained from a reliable informant. In this regard, attention should be paid to change in cognition and functioning relative to previous performance, mode of onset of impairment (insidious onset is characteristic of AD), progression of illness (slow gradual decline is typical of AD), and duration of impairment (it is important to repeatedly ask if there were any earlier signs that may have indicated a change). One should ask about all cognitive domains and give examples of early signs. For example, when asking about memory impairment, one could ask if the patients have difficulty remembering what day it is, what they ate for the previous meal, or if they have trouble keeping appointments. Be aware that patients and families often make excuses for memory problems. For the language domain, one could ask if the patients have trouble finding the right word for things or call something by the wrong name, mispronounce words, or if they feel that they have more trouble expressing themselves verbally. For praxis, it would be appropriate to ask if they have trouble figuring out how to use machines that they knew how to use before (microwave, washing machine, or lawn mower) or if they have trouble with any skills (crafts or hobbies) in which they previously engaged. For agnosia, determine if they have trouble recognizing common objects such as a telephone, toaster, or broom. Difficulty with executive functioning manifests as trouble with complex tasks such as preparing a meal or managing finances. In addition to inquiring about cognitive function, it is critical to inquire about the use of prescription and over-the-counter medications, alcohol, and illicit drugs and their temporal relationship to any cognitive changes.
The instrument used most commonly for assessing cognitive function is the MMSE. This instrument is a nonspecific screen for cognitive function and has some limitations. The MMSE is not sensitive for detecting cognitive impairment in individuals with higher levels of education or high levels of premorbid functioning. Conversely, those with low levels of education or minority cultural backgrounds may score low on the test without having impairment. However, the MMSE is especially useful when repeated regularly to follow illness progression.
A complete physical and neurologic examination is indicated. Focal neurologic signs may suggest vascular dementia or some other neurologic disorder, and parkinsonism suggests Parkinson disease or dementia with Lewy bodies disease depending on the time course of symptoms relative to the cognitive impairment. Results of the neurologic examination are usually essentially normal in early AD.
Laboratory evaluation should include tests for complete blood cell counts, electrolytes, blood chemistries, liver functions, thyrotropin levels, vitamin B12 levels, and a serologic test for syphilis. Other tests should be obtained as indicated by the history such as erythrocyte sedimentation rate (autoimmune disease), heavy metal screen (industrial exposure), human immunodeficiency virus (with human immunodeficiency virus risk factors), and toxicology screen (suspected use of illicit drugs). An electroencephalogram reveals nonspecific changes and is rarely indicated except to diagnose Creutzfeld-Jakob disease, a disease associated with a characteristic periodicity on the electroencephalogram, or hepatic encephalopathy with characteristic triphasic waves.
A neuroimaging study may be obtained in a complete workup to rule out neurologic disease, which may contribute to cognitive decline, but is not required for diagnosis unless warranted by unusual findings. A computed tomographic scan of the head without contrast is usually sufficient to rule out cerebrovascular disease, subdural hematoma, normal pressure hydrocephalus, or brain tumor. Magnetic resonance imaging is more expensive but is better for visualizing small subcortical lacunae and mesial temporal lobe atrophy (in coronal slices). However, there is a tendency to overread vascular changes (periventricular and subcortical white matter hyperintensities) on magnetic resonance imaging. Single proton emission computed tomography may be helpful in atypical, difficult, or early cases. In AD, there is a characteristic hypoperfusion in the temporal and parietal lobes. In vascular dementia, there are more patchy changes. Pick disease is marked by frontal and temporal lobe perfusion defects. Single proton emission computed tomography may be most useful in distinguishing AD from vascular dementia and frontotemporal dementia, but should be used selectively and only as an adjunct to clinical evaluation and computed tomography.21 Positron emission tomography has the advantage of greater sensitivity and spatial resolution but at a much higher price, and while it is a better tool for research purposes, it has limited clinical application. Single proton emission computed tomography is simpler to perform, less expensive, and has greater potential in the clinical setting than positron emission tomography.22
Detailed neuropsychological testing is also helpful in characterizing the pattern of cognitive impairment. It is also more sensitive than a screening instrument such as the MMSE in detecting early impairment in highly educated individuals. It also provides a quantitative measure, which affords the ability to follow disease progression over time.
If the diagnosis remains unclear after a complete evaluation, there are several options. Repeating the cognitive testing in 6 months will determine if there is progressive cognitive decline during the intervening period. More complete neuropsychological testing may also be helpful. Consultation with a specialist, either a neurologist or geriatric psychiatrist, is warranted.
IMPORTANCE OF EARLY DIAGNOSIS
Early diagnosis of AD is important for many reasons. Patients may present with nonspecific physical complaints that may prompt extensive and costly diagnostic workups and unnecessary treatments. Early recognition allows the possibility of treating with agents that can slow the cognitive decline at a point where there is still minimal impairment. Early diagnosis also allows the patient and the family time to plan for the future such as developing advanced directives and appointing durable power of attorney while competence is not yet an issue. The practitioner can educate the patient and the family regarding disease progression and prognosis, provide support, and monitor judgment and safety issues so that the patient can continue independent or community dwelling as long as possible.
Unfortunately, AD is frequently not diagnosed at this early stage despite visits to the primary care physician. There are many reasons for this delay in diagnosis. Patients and families often underreport symptoms, families attribute symptoms to normal aging and compensate for functional impairment, and social skills are maintained, masking any impairment during a short, focused office visit. Even when cognitive testing is performed, individuals with dementia may score in the "normal" range on the MMSE. Results of laboratory tests are normal in AD so a diagnostic workup will not reveal any abnormalities.
There is a need to improve early recognition of AD in the primary care setting and to avoid delays in diagnosis. Practitioners should screen for functional and cognitive decline and any concerns should prompt a full dementia workup.
TREATMENT OF AD IN THE PRIMARY CARE SETTING
The successful treatment of AD involves multiple treatment modalities targeting various aspects of the illness and its consequences for the patient and the family. Again, it is important to stress the necessity for accurate diagnosis of AD and early recognition to provide the best possible treatment. While there is no cure for AD, there are approaches to improving cognition and possibly delaying the progression of the illness, and there are efficacious treatments for the psychiatric and behavioral manifestations. Another important aspect of treatment is helping the patient and the family with the legal aspects, supporting the family through caregiving, and assisting with decisions about long-term care placement. Providing regular appointments for maintenance and surveillance is necessary to meet the goals of minimizing excess disability and ensuring safety and security.
PHARMACOLOGICAL TREATMENT OF AD
There are several conceptual approaches to the treatment of AD. The first approach is to treat symptomatically. This includes treating the cognitive impairment, decline in global function, deterioration in the ability to perform activities of daily living, and behavioral disturbances. This approach reflects the current state of treatment. Another approach is to slow disease progression or delay onset of disease. Eventually, it may be possible to be able to prevent the development of AD or even repair neuronal damage after onset of disease. These latter approaches are currently being investigated at a basic science level. The only currently available therapeutic agents are targeted at specific symptoms of AD.
Cognitive Impairment
Cholinesterase Inhibitors
Alzheimer disease is in part a disorder of cholinergic functioning. Degeneration of basal forebrain cholinergic systems is a hallmark feature of AD and appears to be associated with cognitive deficits, functional impairment, and behavioral disturbances. One strategy for ameliorating the symptoms of AD is to enhance cholinergic neurotransmission. Acetylcholinesterase inhibitors are the best studied and the only currently available agents for the symptomatic treatment of AD. Acetylcholinesterase inhibitors delay the degradation of acetylcholine at the synaptic cleft, thus potentiating cholinergic neurotransmission.
The only 2 agents currently available for the treatment of AD are the cholinesterase inhibitors tacrine and donepezil. Both agents inhibit acetylcholinesterase in a dose-dependent manner. Both are effective in improving performance on a test of cognitive function and global performance in patients with mild to moderate AD.23-29 Cognitive improvements are, on average, modest and may not be clinically relevant in many patients. However, some patients demonstrate a dramatic improvement in cognitive scores that is readily observable in daily functioning. Some cholinesterase inhibitors are also associated with improvement in behavioral symptoms, including depression, psychosis, and agitation, even in the absence of profound cognitive change.30 However, this is based on an open-label study. Cholinesterase inhibitors are also associated with a delay in nursing home placement.31 Methodological limitations of this study include the open-label, nonrandomized, and nonblinded design.
Studies of acetylcholinesterase inhibitors have generally shown an initial improvement in cognitive scores beginning early in the treatment course with a subsequent decline at a rate similar to untreated patients with AD.32 When the medication is stopped, cognitive functioning declines to nontreatment levels. This is consistent with the hypothesis that cholinesterase inhibitors provide symptomatic relief without altering the disease course. The long-term effects or continued benefit of cholinesterase inhibitors will become clearer in clinical practice. One neuroimaging study33 demonstrated increased regional cerebral blood flow in the parietal lobe, which persisted up to 14 months with continued treatment.
Treatment with tacrine requires a lengthy dose titration beginning with 10 mg orally 4 times daily and increasing by 10 mg 4 times daily every 6 weeks as tolerated to a maximum of 160 mg/d. Only doses of 120 to 160 mg/d are significantly more efficacious than placebo. However, dose titration is frequently limited by adverse effects to the gastrointestinal tract or hepatic transaminase elevations. Transaminase activity (alanine and aspartate aminotransferase) must be monitored weekly until a steady dose has been achieved for 6 weeks, after which monitoring every 3 months is sufficient. If transaminase activity levels rise to more than 5 times the upper limit of normal, treatment with tacrine should be discontinued. Transaminase elevations are usually asymptomatic and reversible and patients may be rechallenged after transaminase normalization (see package insert for details).
Donepezil has replaced tacrine as the first choice "cognitive enhancer" owing to ease of administration, less titration, greater tolerability, relative lack of hepatotoxic side effects, and absence of monitoring requirements. Donepezil is selective for acetylcholinesterase and is longer acting than tacrine. It is metabolized via the hepatic cytochrome P450 system and is highly plasma protein bound. Donepezil is administered in once-daily dosing and requires less extensive titration. Dosing is initiated at 5 mg/d and may be increased to 10 mg/d in 1 month. It is well tolerated and the most common adverse effect is gastrointestinal tract distress (nausea, vomiting, and diarrhea).
Other cholinesterase inhibitors are in development and are expected to reach the market soon. Metrifonate is a prodrug for the long-acting cholinesterase inhibitor, 2,2-dichlorovinyl dimethyl phosphate. Its pharmacokinetic profile permits once-daily dosing. Early studies demonstrate improvement in cognitive scores and global function compared with placebo, with few adverse effects.34-36 Rivastigmine is a central nervous system–selective, pseudo-irreversible, carbonate-selective cholinesterase inhibitor.37 Dosing is 2 or 3 times daily and extensive titration is required. It is well tolerated at the lower doses with predominantly adverse effects on the gastrointestinal tract. Heptylphysostigmine is a derivative of physostigmine with a long duration of inhibition.38 Several other agents are also in development.
Other Cholinergic Agents
Another strategy targeting the cholinergic system is specific cholinergic receptor agonists. Muscarinic acetylcholine postsynaptic m1 receptors are relatively intact in AD, while the m2 presynaptic receptors are decreased. Agents that target the postsynaptic m1 receptors are being developed. There is some evidence suggesting that these agents may also slow disease progression, but most have not been well tolerated at therapeutic doses. Xanomeline is a selective m1 and m4 agonist that has demonstrated moderate efficacy in improving cognitive performance, but even greater efficacy in decreasing psychotic symptoms and agitation.39 However, adverse events to xanomeline were associated with high discontinuation rates primarily because of adverse effects on the gastrointestinal tract and syncope. Other cholinergic agonists in development include milameline, SB202026, AF 102B, and ENS-163. Stimulation of presynaptic nicotinic receptors increases the release of acetylcholine and may be associated with cognitive improvement in selected domains. Therefore, nicotinic acetylcholine receptor agonists also appear promising.
Disease-Altering Treatment Strategies
One target for disease-altering treatments is apoptosis or programmed cell death. Mechanisms that are implicated in neuronal degeneration are the inflammatory response and oxidative stress. The inflammatory response contributes to cell death in part by triggering release of free radicals. An accumulation of free radicals in turn damages cell membranes and triggers the neurodegenerative cascade. In addition, components of the inflammatory response are found in association with senile plaque formation. Anti-inflammatory agents may be protective against AD; in epidemiological studies, the use of anti-inflammatory drugs is associated with a decreased risk of AD. Prednisone is currently under investigation for the treatment of AD.40 Antioxidants may also be protective against cell death. In one clinical trial,41 alpha-tocopherol (vitamin E) and selegeline hydrochloride (L-deprenyl), a selective monoamine oxidase–type B inhibitor that acts as an antioxidant, demonstrated efficacy in delaying adverse events. Methodological limitations of this study include poor randomization whereby baseline scores on the MMSE were higher in the placebo group, requiring adjustment for this in the analysis. Chelating agents may also work via an antioxidant mechanism. Other monoamine oxidases are currently under investigation.
Neurotropic factors may have a modulating effect on neuronal structural integrity and neurotransmitter function. Estrogen acts as a neurotropic factor and may be protective in decreasing the incidence or delaying the onset of AD and enhancing response to cholinesterase inhi |
