Authors: Daniel J. Tambunan, MD, Florida Hospital, Orlando, FL; Ariel F Cole, MD, Director, Geriatric Fellowship, Assistant Director, Florida Hospital Family Medicine Residency; Rhonda L. Randall, DO, Evercase-Florida, State Medical Director Community Programs, Hospice of the Comforter, Altamonte Springs, FL, Team Physician.
Peer Reviewer: Alan Z. Segal, MD, Assistant Professor, Department of Neurology, Weill-Cornell Medical College, New York Presbyterian Hospital.
Epidemiology
The first case of pre-senile dementia with pathologic features of plaque formation and neurofibrillary degeneration was described in 1907 by Alois Alzheimer. Today, approximately 4 million Americans have Alzheimer’s disease (AD). It is estimated to rise to 7 million by 2010 and that number is expected to reach 14 million by the year 2050.1 The prevalence of Alzheimer’s doubles every 5 years after the age of 65 years.1 Ten percent of people older than 65 years and 50% of those older than 85 years have the disease. Rarely, patients in their thirties and forties are diagnosed with early-onset AD.2 Alzheimer’s is the most common form of dementia.1 Both Alzheimer’s and vascular dementia account to 90% of dementia. Average life expectancy for a patient with AD is 8 to 20 years from the onset of symptoms.3 As of the year 2000, the annual deaths from Alzheimer’s were 49,558 making it the eighth leading cause of death among Americans.3 An interesting finding is that 70% of Alzheimer’s patients live at home. And of those, 75% are cared for by a family member. One half of all nursing home residents have AD or a related disorder.3 Dementia is the number one precipitator of nursing home placement.
The United States spends $100 billion a year on AD. American businesses lose approximately $36.5 billion annually because of the absenteeism of caregivers for Alzheimer’s patients. Families pay about $12,500 per year for paid caregiver assistance. The average annual cost for nursing home care is $42,000.The lifetime healthcare cost per AD patient is $174,000.2 With all these staggering statistics, Alzheimer’s disease is truly a disease that one cannot ignore.
Pathophysiology
The pathophysiology of Alzheimer’s dementia is the subject of significant research and debate. The two hallmark pathologic changes noted in the brains of Alzheimer’s victims are senile plaques and neurofibrillary tangles. The plaques are composed of beta-amyloid peptides and may form due to a condition of excess beta-amyloid and/or its precursor protein.4 Inflammation around these plaques may destroy neighboring neurons causing the general cerebral atrophy found in AD.4, 5
Neurofibrillary tangles are composed partly of the tau protein, which links together to form filaments and eventually, tangles.4 The tangles compromise neuronal function and cause neuronal death.4 Genetics influence the formation of forms of tau that are more likely to tangle.6
There is evidence that multiple mechanisms are responsible for the development of AD. Apolipoprotein E type 4 (ApoE-4) located on chromosome 19 increases the lifetime risk of developing AD from 9% to 29%.7 ApoE-4 is a protein that is present in plaques in the brains of patients with AD and may trap amyloid in the brain parenchyma.5 Another possible reason is reduction or deficiencies in the neurotransmitters like acetylcholine or adrenaline and glutamate. Acetylcholine plays a role in learning and short-term memory and in AD is markedly decreased in the cerebral cortex and hippocampus. Other neurotransmitters have been implicated in neurodegenerative disorders, including glutamate. Glutamate is the principle excitatory transmitter in the brain. Glutamate overstimulation of the N-methyl-D-aspartate receptor (NMDA) can lead to calcium overload and excitotoxicity.8
Risk Factors
One percent of the population older than 65 years has AD. The prevalence rates double every five years thereafter, to the point that 50% of the population older than 85 years may have AD.1, 2 Therefore, the most significant risk factor for cognitive impairment is advanced age. Other risk factors include family history, head trauma, history of stroke, and Down syndrome.
Diagnosis
Dementia is defined as a progressive loss of nerve cells that are responsible for normal thought, memory, and daily functioning. The establishment of an AD diagnosis is accomplished by a detailed history and physical, neuropsychiatric testing and laboratory studies. Together, these methods accurately diagnose 90% of dementias. Unfortunately, the only definitive diagnosis of Alzheimer’s disease can be accomplished antemortem by brain biopsy or postmortem by autopsy.
There are two established criteria for diagnosis of Alzheimer’s disease that have been standardized. Both the DSM IV criteria (Table 1) and NINCDS – ARDA (Table 2) probable AD definitions have good sensitivity (81%) and a fair specificity (70%) for the diagnosis of AD.9, 10
Table 1. DSM-IV Criteria
Table 2. NINCDS-ARDA Criteria
Of the known cases of AD, approximately half are diagnosed with history and physicals completed by their primary care physician. First, reversible causes must be ruled out. Reversible causes include metabolic abnormalities, nutritional deficiencies, vasculitis, infection, intoxication, and anatomical causes (e.g., intracranial masses, bleeding and hydrocephalus). This exclusionary work-up is important, because approximately 10-15% of dementia diagnoses are due to a reversible cause. See Table 3 for suggested laboratory workup for potentially reversible causes of dementia.11
Table 3. Dementia Lab Work-up
The best diagnostic tool for diagnosing Alzheimer’s disease is a thorough history. In addition, several geriatric assessment tools are helpful. These include: a Mini Mental Status Exam (MMSE), Geriatric Depression Scale (GDS), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) inventories, a medication review, as well as hearing, vision, and nutrition screenings.
A widely accepted and standardized test for dementia is the MMSE.12 Two U.S. studies show that the sensitivity is 49% with a specificity of 92% in detecting dementia.13, 14 The MMSE is scored on a possible 30. A score of more than 24 is considered normal, 20-24 is mild, 10-19 moderate, and less than 10 indicates severe dementia. The clock drawing test (CDT) and Memory Impairment Screen are other useful screening tools.15, 16 These tests need a baseline to which comparison can be made to establish the presence of a decline. (See staging table, below.)
Table 4. Staging of Alzheimer’s Disease
ADL and IADL are geriatric assessment tools that evaluate the degree of function for activities of daily living. (See insert.) A total score of less than 9 of 25 indicates dependency in either inventory. Therefore, the lower the score the greater degree of dependence. The usual decline in AD patients starts with loss of IADL prior to loss of basic ADLs as more complex skills are needed to do IADLs.17 - 21
Depression is known to be a leading cause of pseudodementia. One study by Forsell showed that as much as 12% of patients with dementia also were depressed.22 There are several accepted GDSs: the Yesavage 30-point and Yesavage 15-point scales are the most widely accepted. On the 15-point scale, a score of more than 2 suggests depression. Additionally, the single question: Do you often feel sad or depressed? is statistically significant for the diagnosis of depression.23-25 It is important to note that all these tests may be administered by any trained health professional, not necessarily a physician only.
The diagnosis of Alzheimer’s disease is best accomplished with a thorough history and physical examination, and elimination of reversible causes. In certain cases, if the diagnosis is unclear, or the patient and/or family insists on further testing, there are several studies that can be performed that may help to support the clinical diagnosis. Presently, no laboratory test is appropriate for routine use in patients with suspected AD. The field of genetic testing is in infancy; therefore, centers with experience/expertise would be more apt to handle it. A cohort study shows that APO E4 allele has been shown to slightly increase the positive predictive value in Alzheimer’s patients from 90% to 94%.26
In recent years, examination of cerebrospinal fluid (CSF) markers has drawn a lot of interest and research. CSF ß amyloid 1-42 has been shown to be significantly decreased and CSF tau increased in patients with clinical AD.27 The sensitivities and specificities of these results are reported to be 85% and 87%, respectively.28-30 Kahle and associates showed that CSF AD7C had a specificity of 87% and a sensitivity of 70%.31
Radiological studies are another avenue in the array of options in diagnosing AD. A noncontrast computed tomography (CT) or magnetic resonance imaging (MRI) are useful to identify vascular dementia, neoplasms, subdural hematomas, or normal pressure hydrocephalus. MRI showing medial temporal atrophy has a sensitivity range from 77-92% and specificity range from 49% - 95%.32, 33 Functional neuroimaging (e.g., single photon emission computed tomography [SPECT] scan) was noted to be of greatest value for a positive test in patients with mild dementia and low index of suspicion for the diagnosis of AD. In this setting, a positive SPECT scan would increase the posttest probability by 30%.34, 35
The positron emission tomography (PET) scan is the newest form of radiological imaging in the field of AD. It can detect early changes in the brain and may show decreased temporal/ parietal activity. Two studies regarding comparison of PET vs SPECT show a higher sensitivity for the former.36, 37 Additionally, combining a PET scan and MRI can create a three-dimensional brain image that may detect subtle brain abnormalities. Due to the high cost of functional imaging, further studies are needed to establish its role in the diagnosis of AD in light of a competent clinical diagnosis.
Although AD is the most common form of dementia, other causes of dementia may coexist with AD. Vascular dementia (VAD) is the second most common form of dementia. Currently, the four criteria that are used include the DSM-IV,38 the California criteria,39 the Haschinski Ischemic Score (HIS),40 and the National Institute of Neurological Disorders and Stroke and the Association Internationale por la Recherche et l’Enseignement en Neurosciences (NINDS-AIREN).41 Comparison studies of the criteria and neuropathologic findings show a low sensitivity (43%) and high specificity.42
Dementia with Lewy bodies is another form of dementia. It is clinically defined as the presence of dementia, gait disorder, prominent hallucinations/delusions, fluctuation in alertness, and sensitivity to traditional antipsychotics.43 However, all these features may occur in patients with AD, therefore these criteria give low sensitivity and high specificity when comparing with neuropathologic findings. 42
Frontotemporal dementia (FTD) is less common than the above dementias.44 Patients with FTD typically have deficits in frontal lobe tasks that include verbal fluency and executive function.45 Early loss of personal and social awareness and perseverative behaviors are clinical criteria that are highly specific for FTD.46
Lastly, Creutzfeldt-Jakob disease is a disease that causes a rapidly progressive dementia. Until recently, diagnosis is mainly through pathologic examination of brain tissue. Master has developed clinical criteria that are high in specificity (81%).47, 48
Clinical Course
The staging of AD can be quantified as mild, moderate, or severe. (See insert.)
Although death is usually a result of co-morbid conditions, end stage AD qualifies a patient for hospice services.51, 52 The patient must score at or beyond stage seven of the Functional Assessment Staging (FAST) score. This includes: A) ability to speak limited to approximately a half a dozen intelligible different words or fewer in the course of an average day or in the course of an intensive interview, B) ability to speak is limited to the use of a single intelligible word in an average day or in the course of an intensive interview (the person may repeat the word over and over), C) ambulatory ability is lost (e.g., cannot walk without personal assistance), D) cannot sit up without assistance (e.g. the individual will fall over if there are not lateral rests [arms] on the chair), E) loss of ability to smile, and F) loss of ability to hold up head independently.53
Mild Cognitive Impairment
Mild cognitive impairment (MCI) describes a transitional stage between normal aging and clinical dementia. Patients with MCI have a measurable cognitive deficit—often strictly amnesia — but do not meet criteria for AD. Patients with MCI develop clinical AD at a rate of approximately 10% per year.54 It is difficult to clinically separate MCI from normal aging without extensive neuropsychological testing. The Montreal Cognitive Assessment recently was developed as a brief screening tool for MCI and validated having a 90% sensitivity and 87% specificity.55
Prevention
Several options are available to reduce the likelihood of Alzheimer’s: blood pressure control and avoidance of anticholinergic drugs are starting points for prevention. There is also evidence supporting Vitamin E supplementation, although one has to be careful in patients on anticoagulation medication due to its drug interaction properties with warfarin. Currently, there is no conclusive evidence that estrogen in women or nonsteroidals prevent AD.56 Elevated levels of beta amyloid and tau have been observed in severe traumatic brain injury patients.57 And, severe head trauma is known to double the risk for the development of AD.58 Therefore, prevention of head trauma is important in decreasing the risk of developing AD.
Stimulating activities may reduce Alzheimer’s risk. This is the “use it or lose it” concept. A recent study by the Rush Alzheimer’s Disease Center found that more frequent participation in cognitively stimulating activities is associated with a reduced risk of AD.59
Treatment of Alzheimer’s Disease
Cholinesterase inhibitors are the cornerstone of pharmacotherapy for Alzheimer’s disease. These medications inhibit the action of the enzyme acetylcholinesterase, thereby increasing cholinergic activity in the central nervous system (CNS). This appears to improve cognition in some patients with AD. Elevated peripheral acetylcholine levels also results, which produces primarily gastrointestinal side effects.60 These four agents have been shown to maintain cognitive function at or above baseline in six-month treatment studies.61 Longer studies reveal a slowed decline compared with patients on placebo, delaying nursing home placement a year or more.62
In 1993, tacrine (Cognex) was the first cholinesterase inhibitor approved for treatment of AD. Tacrine causes liver enzyme level elevation in 40% of patients, therefore liver function assays are recommended every two weeks during dose titration and then every three months.63 Due to the potential for liver toxicity and the short half-life requiring four times daily dosing, tacrine is now a second-line agent.
No large head-to-head studies have been completed comparing the remaining three cholinesterase inhibitors currently FDA approved in the United States. The three agents that are firstline in the treatment of AD and their characteristics are listed in the insert.60, 63
The newest pharmacologic agent for the treatment of AD, memantine, is in a new therapeutic class: NMDA receptor antagonist.64 Memantine has been shown effective as monotherapy as well as an add-on to cholinesterase inhibitor.65-67
Randomized controlled trials have shown reliably that cholinesterase inhibitors produce small improvements on cognitive tests over 3-12 months in patients with mild to moderate AD. However, cholinesterase inhibitors are expensive, and the degree of clinical significance of these modest improvements in cognition is debatable. Physicians and families are left struggling to decide when (or if) to start these medicines in a patient with probable AD. The recent AD2000 randomized trial added weight to the therapeutic nihilists among us. While some have argued that the trial design deviated from usual use, the AD2000 trial is one of the largest nonpharmaceutical funded studies to date.68 The authors of the AD2000 study concluded that donepezil is not cost effective, with benefits below minimally relevant thresholds, based primarily on a lack of difference in time to institutionalization between treatment and placebo groups.68
The decision to start a cholinesterase inhibitor in a patient with mild AD is an individual choice. Some physicians recommend explaining cost, side effects, and potential benefit with patients and their caregivers. Some physicians believe that a cholinesterase inhibitor and/or memantine are useful particularly in patients who are cared for in the home by family members. This belief is supported by those trials that found a significant reduction in caregiver burden, reducing time spent caregiving as much as 46 hours per month.64, 69 A second niche may be the demented patient, usually in moderate to severe stage, who has agitated or psychotic behaviors, as these medications may help control these behaviors with a safer side effect profile than an antipsychotic.
Memantine is only approved for patients with moderate-severe AD because it has failed to show efficacy in the mild AD group. Patients already on a cholinesterase inhibitor or those who could not tolerate a cholinesterase inhibitor are both candidates once they decline into the moderate stage (i.e., generally a MMSE score below 15). Similar to the cholinesterase inhibitors, memantine offers only a modest improvement in cognitive function. While it has very few side effects, it is also expensive, and therefore the potential benefits must be weighed against the significant cost. Treatment decisions are not easy, and it is worth keeping in mind that the most effective treatment for the AD patient may be caregiver support and education.
Recently, researchers have been exploring the use of cholinesterase inhibitors in MCI. One study investigated the efficacy of donepezil in MCI and failed to find a statistically significant difference in primary outcomes between treatment and placebo groups, however trends favored the donepezil-treated group.70 Studies investigating galantamine in patients with MCI had a higher all-cause mortality in the treatment groups and a recent bulletin from the manufacturer cautions physicians against use of galantamine in MCI patients.
Other Pharmacologic Agents
Vitamin E at the dose of 1000 mg twice daily was found to be beneficial in slowing the progression of symptoms of Alzheimer’s disease in the Alzheimer’s Disease Cooperative Study. The same study also found that selegiline (Eldepryl) at a dose of 5 mg bid may slow cognitive decline, however current guidelines recommend vitamin E only as selegiline has a less favorable risk-benefit ratio.71-73
The over-the-counter herbal preparation ginkgo biloba is commonly used for dementia, however evidence of efficacy is lacking.72 Epidemiologic studies previously showed a preventive benefit of estrogen, however multiple studies using estrogen to treat dementia have shown no benefit.72, 74, 75 In addition, the Women’s Health Initiative study showed in a randomized, placebo controlled fashion that estrogen increases the risk of cognitive impairment. Nicotine produced some improvement in patients with AD in one small study, but it also increased anxiety.76
Nonsteroidal anti-inflammatory medications have been proposed as a possible protective agent against cognitive decline in AD. Cyclooxegenase is an important mediator of signal transduction for excitotoxic cell death. However, while epidemiologic studies have shown a protective benefit,77 treatment trials show little benefit and high dropout rates due to adverse events.78, 79
Treatment of Behaviors Associated with Alzheimer’s Disease
Behaviors such as paranoia, agitation, aggression, and wandering are common features of AD and increase as the disease progresses.63 Nonpharmacologic interventions are the firstline treatment. Examples of environmental modifications to control behavior include utilizing clocks and calendars to orient the patient, avoiding overstimulation, placing safety latches on doors, and having a daily routine.63,80 Behavioral modifications such as simplifying complex tasks with a step-wise approach, communicating with simple phrases, maintaining eye contact, and distracting or redirecting an agitated or confused patient are all important skills for caregivers.63,80
When nonpharmacologic interventions are inadequate, multiple medications are currently available to control behaviors associated with AD. Cholinesterase inhibitors produce some improvements in neuropsychiatric and functional outcomes in patients with AD and are sometimes started even in severe dementia to aid with these symptoms.81 Analyses of multiple studies showed improvement in cooperation, delusions, pacing, and various other behaviors in patients treated with cholinesterase inhibitors compared with those on placebo.80
While the evidence is limited, the atypical antipsychotics have been used and found to be effective particularly for agitation with combativeness, delusions, and hallucinations.82 The typical antipsychotics, while effective, are used for acute management of psychotic symptoms but are second-line agents for long-term use due to the side-effect profile and risk of tardive dyskinesia. The characteristics of the atypical antipsychotics and suggested dosages are listed on the insert.
Mood-stabilizers are also used to treat agitation, delusions, hallucinations, and combative behaviors in AD patients.63 These agents can be used as firstline treatment or in addition to the atypical antipsychotics for long-term treatment of the behaviors.
The selective serotonin reuptake inhibitors (SSRIs) are generally safe and effective for depressive symptoms. Those with sedating effects can be helpful for aggression, confusion, irritability, and anxiety. Mirtazapine (Remeron) is an antidepressant that promotes sleep, appetite, and weight gain. Bupropion (Wellbutrin) and some of the activating SSRIs can be useful in patients with sedation associated with depression. Some antidepressant drugs and their characteristics are listed in the insert.
Education
Nonpharmacologic measures are often the most effective in changing or controlling behaviors in patients with AD. Care for 80% of AD patients is provided in the community by family members, and the median length of in-home caregiving before nursing-home placement is 6.5 years.83 Therefore, caregiver education and support is critical. Some nationwide resources for those caring for AD patients are listed on the insert. Local organizations often provide the most immediate support.
Acknowledgment: The authors greatly appreciate Ms. Christine Joseph for her tireless work and patience.)
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Today, approximately 4 million Americans have Alzheimer’s disease. It is estimated to rise to 7 million by 2010, and that number is expected to reach 14 million by the year 2050.
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