Alzheimer Disease

Background
In 1901, a German psychiatrist named Alois Alzheimer observed a patient at the Frankfurt Asylum named Mrs. Auguste D. This 51-year-old woman suffered from a loss of short-term memory, among other behavioral symptoms that puzzled Dr. Alzheimer. Five years later, in April 1906, the patient died, and Dr. Alzheimer sent her brain and her medical records to Munich, where he was working in the lab of Dr. Emil Kraeplin. By staining sections of her brain in the laboratory, he was able to identify amyloid plaques and neurofibrillary tangles. A speech given by Dr. Alzheimer on November 3, 1906 was the first time the pathology and the clinical symptoms of presenile dementia (later to be renamed Alzheimer disease [AD]) were presented together. Alzheimer published his findings in 1907. AD is an acquired cognitive and behavioral impairment of sufficient severity that markedly interferes with social and occupational functioning. It is an incurable disease with a long and progressive course. AD not only has detrimental effects on the patient but tends to take a significant toll on patients families and caretakers as well. The most common form of dementia, AD affects about 4.5 million people in the United States alone, and that number is projected to exceed 13 million by the year 2050. Economically, it is a major public health problem. In the United States, the cost of caring for patients with dementia was $144 billion per year in 2009. The most recent data available on the cost for healthcare and long-term care services per patient, from 2004, show that the average yearly cost was about $33,007. In the past 15-20 years, dramatic progress has been made in understanding the neurogenetics and pathophysiology of AD (see Pathophysiology). Four different genes have been associated with AD, and others are likely to be discovered. The mechanisms by which altered amyloid and tau protein metabolism, inflammation, oxidative stress, and hormonal changes may produce neuronal degeneration in AD are being
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identified, and rational pharmacological interventions based on these discoveries are being developed. Currently, an autopsy or a brain biopsy is the only ways to make a definitive diagnosis of AD, although the diagnosis is usually made clinically from the history and findings on Mental Status Examination (see Workup). Symptomatic therapies are the only treatments available for AD. The standard medical treatments include cholinesterase inhibitors and partial N -methyl-D-aspartate (NMDA) antagonists. Psychotropic medications are often used to treat secondary symptoms of AD, such as depression, agitation, and sleep disorders

Healthy neurons have an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A special kind of protein, tau, makes the microtubules stable. In AD, tau is changed chemically. It begins to pair with other threads of tau, and they become tangled together. When this happens, the microtubules disintegrate, collapsing the neurons transport system (see the image below). This may result first in malfunctions in communication between neurons and later in the death of the cells.

Pathophysiology
AD affects the 3 processes that keep neurons healthy: communication, metabolism, and repair. This disruption causes certain nerve cells in the brain to stop working, lose connections with other nerve cells, and finally die. The destruction and death of these nerve cells causes the memory failure, personality changes, problems in carrying out daily activities, and other features of the disease. The anatomic pathology of Alzheimer disease includes neurofibrillary tangles (NFTs); senile plaques (SPs; also known as beta-amyloid plaques) at the microscopic level; and cerebrocortical atrophy, which predominantly involves the association regions and particularly the medial aspect of the
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temporal lobe. NFTs and SPs, which were described by Alois Alzheimer in his original report on the disorder in 1907, are now universally accepted as a hallmark of the disease. Considerable attention has been devoted to elucidating the composition of NFTs and SPs to find clues about the molecular pathogenesis and biochemistry of AD. The main constituent of NFTs is the microtubuleassociated protein tau (see Anatomy). In AD, hyperphosphorylated tau accumulates in the perikarya of large and medium pyramidal neurons. Somewhat surprisingly, mutations of the tau gene result not in AD but in some familial cases of frontotemporal dementia. Since the time of Alois Alzheimer, SPs have been known to include a starch like (or amyloid) substance, usually in the center of these lesions, which is surrounded by a halo or layer of degenerating (dystrophic) neurites and reactive glia (both astrocytes and microglia). One of the most important advances in recent decades has been the chemical characterization of this amyloid protein, the sequencing of its amino acid chain, and the cloning of the gene encoding its precursor protein (on chromosome 21). These advances have provided a wealth of information about the mechanisms underlying amyloid deposition in the brain, including information about the familial forms of AD. (See Amyloid hypothesis versus tau hypothesis.) Although the amyloid cascade hypothesis has gathered the most research dollars, other interesting hypotheses have been proposed, including the mitochondrial cascade hypothesis. In addition to NFTs and SPs, many other lesions of AD have been recognized since Alzheimers original papers were published. These include the granulovacuolar degeneration of Shimkowicz; the neuropil threads of Braak et al ; and neuronal loss and synaptic degeneration, which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder.

Neurofibrillary tangles and senile plaques Plaques are dense, mostly insoluble deposits of protein and cellular material outside and around the neurons. Plaques are made of betaamyloid (AB), a protein fragment snipped from a larger protein called
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amyloid precursor protein (APP). These fragments clump together and are mixed with other molecules, neurons, and non-nerve cells (see the images below).

The cause of AD is unknown. Several investigators now believe that converging risk factors trigger a pathophysiologic cascade that, over decades, leads to Alzheimer pathology and dementia. The following risk factors for Alzheimer-type dementia have been identified :

Advancing age Family history Apolipoprotein E epsilon 4 genotype Obesity Insulin resistance Vascular factors Dyslipidemia Hypertension Inflammatory markers Down syndrome In addition, epidemiology studies have suggested some possible risk factors (such as aluminum and previous depression) and some protective factors (education, , anti-inflammatory drugs). Moderate-to-severe head trauma appears to be linked to the development of AD as well as other forms of dementia later in life. A study that followed over 7,000 US veterans from World War II showed that those who had sustained head injuries had twice the risk of developing dementia later in life, with veterans who suffered more severe head trauma being at an even higher risk. The study also found that the presence of the apolipoprotein E gene and sustaining head trauma seemed to act additively to increase the risk of developing AD, although there was no direct correlation.

Insulin resistance

A small study by Baker et al implies that insulin resistance as evidenced by decreased cerebral glucose metabolic rate measured by a specific type of positron emission tomography (PET) scan may be useful as an early marker of AD risk, even before the onset of MCI. The PET scan revealed a qualitatively different activation pattern in patients with prediabetes or type 2 diabetes mellitus during a memory encoding task compared with healthy individuals who were not insulin resistant. Although their results were not statistically significant due to the small number of subjects (n=23) in the study, this certainly warrants further study because it may lead to a noninvasive test that could help to quantify risk for development of AD in presymptomatic patients. A similar study was performed in a much larger population of 3,139 participants to investigate the association of diabetes mellitus with an increased risk of AD and to assess whether the risk is constant over time.A different measure of insulin resistance was calculated, using the homeostasis model assessment. They found a similar association between insulin resistance and AD over 3 years, which then disappeared after that time. Disturbances in insulin metabolism may not cause neurological changes but may influence and accelerate these changes, leading to an earlier onset of AD.

Genetic causes

Although most cases of AD are sporadic (ie, not inherited), familial forms of AD do exist; however, they account for less than 7% of all cases. Mutations in genes coding for 3 proteins unequivocally cause AD. These genes (which code for amyloid precursor protein [APP, on chromosome 21], for PS1 [on chromosome 14], and for PS2 [on chromosome 1]) all lead to a relative excess in the production of the stickier 42-amino acid form of the AB peptide over the less sticky 40-amino acid form.
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This beta-pleated peptide is postulated to have neurotoxic properties and to lead to a cascade of events (as yet incompletely understood) that results in neuronal death, synapse loss, and the formation of NFTs and SPs, among other lesions. Nonetheless, the mutations that have been found to date account for less than half of all cases of early-onset AD. Other than the apolipoprotein E epsilon 4 (APOE E4) genotype, no polymorphisms in other genes have been consistently found to be associated with late-onset AD. Genetic factors associated or potentially associated with AD are summarized in Tables 1 and 2.

Table 1. Genetic Factors Associated With Alzheimer Disease Chromosome 21 19 Gene Defect APP Onset Putative Mechanisms Early Increased production of AB 42 Tau hyperphosphosphorylation Impaired production/

APOE E4 Late

-polymerzation/ clearance of AB

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PS-1 PS-2

Early Early increased production of AB 42 Early Early altered AB metabolism

Table 2. Other Locus or Susceptibility Genes Potentially Associated with Alzheimer Disease Chromosome Gene 12 6 Unidentified HLA A2 Onset Putative Mechanisms Late Late Unknown Possible relationship with immune system and inflammatory response AB aggregation

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Late a1antichymotrypsin A allele LRP Late

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Endocytosis of APOE/APP

APP mutations The observation that patients with Down syndrome (trisomy 21) develop cognitive deterioration and typical pathological features of AD by middle age led to the discovery of the APP gene on chromosome 21. Simultaneously, a locus segregating with a minority of early-onset familial AD kindreds was mapped to this chromosome in the same region as the APP gene. Subsequently, several missense mutations within the APP gene that resulted in amino acid substitutions in APP were identified in these FAD kindreds. Such mutations appear to alter the previously described proteolytic processing of APP, generating amyloidogenic forms of AB. Skin fibroblasts from subjects carrying APP mutations produce increased AB 42/43. Increased plasma concentration of AB 42/43 is also seen in these patients regardless of age, sex, or clinical status. Interestingly, some patients with sporadic AD may exhibit similar elevations of plasma AB 42/43.

PS1 and PS2 mutations In cases of early-onset autosomal-dominant AD cases, 50-70% appear to be associated with a locus (AD3) mapped by genetic linkage to the long arm of chromosome 14 (14q24.3). Numerous missense mutations have been identified on a strong candidate gene, called PS1. At the same time, another autosomal dominant locus responsible for early-onset AD was localized to chromosome 1. Two mutations were identified on the candidate gene, designated PS2. The physiological role of presenilins and the pathogenic effects of their mutations are not yet well understood. APOE E4 allele The gene encoding the cholesterol-carrying apolipoprotein E (APOE) on chromosome 19 has been linked to early-onset familial and sporadic AD. The gene is inherited as an autosomal codominant trait with 3 alleles. This article focuses on the allele that may have a direct correlation to AD. APOE E4 gene dose is correlated with increased risk and earlier onset of AD. Persons with 2 copies of the APOE E4 allele (4/4 genotype) have significantly greater risk of developing AD than persons with other APOE subtypes. Mean age at onset is significantly lower in the presence of 2 APOE E4 copies. A collaborative study has suggested that APOE E4 exerts its maximal effect before the age of 70. Many APOE E4 carriers do not develop AD, and many patients with AD do not have this allele. Therefore, the presence of an APOE E4 allele does not secure the diagnosis of AD, but instead, the APOE E4 allele acts as a biological risk factor for the disease, especially in those younger than 70 years.

Epidemiology
United States statistics Using 2000 US Census results, Hebert et al estimated that about 4.5 million people in the United States had AD. These researchers calculated

that by 2030, an estimated 7.7 million Americans aged 65 and older will have AD and that by 2050, that number will rise to more than 13 million. According to a 2010 report, AD affects approximately 5.3 million people in the United States. A larger number of individuals have decreased cognitive function (eg, mild cognitive impairment); this condition frequently evolve into a full-blown dementia, thereby increasing the number of affected persons. The statistical projections cited in this report indicate that the number of persons affected by the disorder in the United States could range from 11 to 16 million by the year 2050. The lifetime risk of AD is estimated to be 1:4-1:2. More than 14% of individuals older than 65 years have AD, and the prevalence increases to at least 40% in individuals older than 80 years. International statistics Prevalence rates of AD similar to those in the United States have been reported in industrialized nations. The prevalence of dementia in subjects 65 years and older in North America is approximately 6-10%, with AD accounting for two-thirds of these cases. If milder cases are included, the prevalence rates double. Countries experiencing rapid increases in the elderly segments of their population have rates approaching those in the United States. The World Health Organizations review in 2000 on the Global Burden of Dementia reported that an integrative analysis of 47 surveys across 17 countries suggested that approximate rates for dementia from any cause are under 1% in persons aged 60-69 years, rising to about 39% in persons 90-95 years old. The prevalence doubles with every 5 years of age within that range, with few differences taking into account secular changes, age, gender, or place of living. AD has become nearly twice as prevalent as vascular dementia (VaD) in Korea, Japan, and China since transition in the early 1990s. American and European studies consistently reported AD to be more prevalent than VaD. They found a dementia prevalence rate among Chinese aged 50 years and older on the islet of Kinmen for this age group of 11.2 per 1,000. AD accounted for 64.6% and VaD for 29.3%. These results, together with previous studies in Chinese populations, suggest that the rates of AD in the Chinese are low compared with those in whites.
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In Nigeria, the prevalence of dementia was low. Indian studies were contradictory, with both AD and VaD being more prevalent in different studies. Age distribution for Alzheimer disease The prevalence of AD increases with age. AD is most prevalent in individuals older than 60 years. Some forms of familial early-onset AD can appear as early as the third decade, but this represents a subgroup of the less than 10% of all familial cases of the disease. More than 90% of cases of AD are sporadic and occur in individuals older than 60 years. However, of interest, results of some studies of nonagenarians and centenarians suggest that the risk may decrease in individuals older than 90 years. If so, age is not an unqualified risk factor for the disease, but further study of this matter is needed. Savva et al found that the association between dementia and the pathological features of AD (eg, neuritic plaques, diffuse plaques, tangles) is stronger in younger old persons (ie, age 75 years) than in older old persons (ie, 95 years). These results were achieved by assessing 456 brains donated to the population-based Medical Research Council Cognitive Function and Ageing Study from persons 69-103 years of age at death. These results demonstrate that the relationship between cerebral atrophy and dementia persist into the oldest ages, but the strength of association between pathological features of AD and clinical dementia diminished. It is important to take age into account when assessing the likely effect of interventions against dementia on the population. Sex distribution for Alzheimer disease AD affects both men and women; however, Plassman et al found the risk of developing AD to be significantly higher in women than in men, primarily due to womens higher life expectancy. Prevalence of Alzheimer disease by race AD and other dementias are more common in African Americans than in whites. According to the Alzheimers Association, in the population aged 71 and older, African Americans are almost 2 times as likely to have AD and
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other dementias as whites (21.3% of African Americans vs 11.2% of whites). The number of Hispanic patients studied in this age group was too small to determine the prevalence of dementia in this population. In individuals age 65 and older, 7.8% of whites, 18.8% of AfricanAmericans, and 20.8% of Hispanics have AD or other dementias, and the prevalence of AD and other dementias is higher in older versus younger age groups

Prognosis

AD is initially associated with memory impairment that progressively worsens. Over time, patients with AD can display anxiety, depression, insomnia, agitation, and may become violent and paranoid. Eventually the patient with AD loses all bodily function, including the ability to walk and swallow; feeding is possible only by gastrointestinal tube. Difficulty swallowing may lead to aspiration pneumonia. The time from diagnosis to death varies from as little as 3 years if the patient is older than 80 years when diagnosed to as long as 10 or more years if the patient is younger. The primary cause of death is intercurrent illness, such as pneumonia. In the United States, AD is frequently considered a leading cause of death. In 2006, AD was the seventh leading cause of death ; however, AD as an underlying cause of death is frequently underreported.

Patient Education

When counseling patients following a diagnosis of AD, it is essential to involve the patients family and others who will play a supporting role in the discussion. It is important to emphasize that not only the patient, but also those who support him or her, will likely experience reactions of sadness
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and anger, and that these are normal reactions to such a catastrophic diagnosis. As the patients symptoms become more pronounced, a dialogue must be opened regarding the patients wishes for care when he or she is no longer able to make the necessary choices. Durable power of attorney should be discussed, with particular attention to who will make decisions for both medical and financial issues. Medical advance directives should be considered while the patient is still able to participate in the decisionmaking process. As the patient continues to decline, family members should be careful to select qualified and trustworthy individuals to be involved in the day-to-day management of the patient. Any suspicions of elder abuse should be immediately addressed. Throughout the course of the illness, it is important that the family be counseled to continue to treat the patient as a competent adult as much as possible, despite the patients decreasing ability to care for himself or herself.

Diagnostic Considerations

Clinical guidelines for the diagnosis of Alzheimer disease (AD) have been formulated by the National Institutes of Health-Alzheimers Disease and Related Disorders Association (NIH-ADRDA); the American Psychiatric Association, in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision, Text Revision (DSM-IV-TR); and the Consortium to Establish a Registry in Alzheimers Disease (CERAD). In 2011, the National Institute on Aging (NIA) and the Alzheimers Association (AA) workgroup released new research and clinical diagnostic criteria for AD. The NIH-ADRDA criteria for the diagnosis of AD require the finding of a slowly progressive memory loss of insidious onset in a fully conscious patient. AD cannot be diagnosed in patients with clouded consciousness or
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delirium. Toxic metabolic conditions and brain neoplasms must also be excluded as potential causes of the patients dementia. The focus of the 2011 NIA-AA criteria is the need to create a more accurate diagnosis of preclinical disease so that treatment can begin before neurons are significantly damaged, while they are more likely to respond. Therefore the report includes criteria for identification of asymptomatic, preclinical AD (for purposes of research, not clinical diagnosis); for diagnosis of mild cognitive impairment (MCI), an early symptomatic but predementia phase of AD ; and for diagnosis of AD dementia. The DSM-IV-TR lists 6 diagnostic criteria, labeled A-F, for dementia of the Alzheimer type: A. The development of multiple cognitive deficits manifested by both of the following:

Memory impairment (impaired ability to learn new information or to recall previously learned information) One or more other cognitive disturbances Other cognitive disturbances consist of the following: Aphasia (language disturbance) Apraxia (impaired ability to carry out motor activities despite intact motor function) Agnosia (failure to recognize or identify objects despite intact sensory function) Disturbance of executive functioning B. The cognitive deficits must each cause significant impairment in social or occupational function and represent a significant decline from a previous level of functioning. C. The course of disease is characterized by gradual onset and continuing decline. D. The cognitive deficits are not due to any of the following:

Other central nervous system conditions that cause progressive deficits in memory and cognition Systemic conditions that are known to cause dementia Substance-induced conditions E. The deficits do not occur exclusively during the course of a delirium.
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F. The disturbance is not better accounted for by another DSM-IV Axis I disorder (ie, a clinical disorder). These guidelines are widely believed to be 90-95% accurate (as histopathologically verified) when followed carefully. They are important not only for routine management but also for selecting and enrolling patients in therapeutic trials. Depression and AD and other dementias have an association that is likely to be complex and depression may be misdiagnosed in the realm of dementia. Recent Framingham data have helped bolster the epidemiological association. The study showed a 50% increase in AD and dementia in those who were depressed at baseline. During a 17-year follow-up period, a total of 21.6% of participants who were depressed at baseline developed dementia compared with 16.6% of those who were not depressed. In another related study, recurrent depression was noted to be particularly pernicious. One episode of depression conferred an 8792% increase in dementia risk, while having 2 or more episodes nearly doubled the risk. Other disorders to consider include the following:

Age-associated memory impairment Alcohol and drug abuse Chronic obstructive pulmonary disease Depression Fecal impaction Hearing or visual problems Hypernatremia Hypoglycemia Hypothyroidism Polypharmacy Volume depletion

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Differentials

Aphasia Carotid Artery, Stenosis Cortical Basal Ganglionic Degeneration Dementia in Motor Neuron Disease Dementia With Lewy Bodies Frontotemporal Lobe Dementia Huntington Disease Dementia Imaging in Normal Pressure Hydrocephalus Neurosyphilis Parkinson Disease Parkinson-Plus Syndromes Pediatric Lyme Disease Prion-Related Diseases Thyroid Disease Vascular Dementia Wilson Disease

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Approach Considerations

Clinical guidelines such as those described earlier are used. (See Diagnosis.) The main focus of these diagnostic guidelines consists of verifying the initial finding of mild, slowly progressive memory loss, confirming that additional spheres of cognition are also compromised, and ruling out other possible causes for dementia (eg, cerebrovascular disease, cobalamin [vitamin B-12] deficiency, syphilis, thyroid disease). A combination of clinical examination and ancillary imaging studies (eg, computed tomography [CT], magnetic resonance imaging [MRI], and, in selected cases, single-photon emission CT [SPECT] or positron emission tomography [PET]) and laboratory tests may be used. At the Alzheimers Association International Conference on Alzheimers Disease (AAICAD) in July 2010, operational research criteria were presented to define preclinical AD, mild cognitive impairment due to AD, probable AD, and possible AD, involving PET imaging, cerebrospinal fluid (CSF) A42 and tau levels, and genetic analysis in order to facilitate future studies. These criteria were not intended to serve as diagnostic criteria for clinical purposes. However, the final version of the NIA-AA criteria, published in April (online) and May 2011, also includes core clinical criteria for diagnosis of mild cognitive impairment by health care providers without access to CSF testing or advanced imaging. TheNIA-AA criteria for diagnosis of dementia due to AD are clinical, with biomarkers in an assisting, nonessential role.

Lab Studies Laboratory workup can be performed to rule out other conditions that may cause cognitive impairment. Current recommendations from the American Academy of Neurology (AAN) include measurement of the cobalamin (vitamin B-12) level and a thyroid function screening test. Additional investigations are left to the physician, to be tailored to the particular needs of each patient. Initial test results that require further investigation include the following:

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Abnormalities in complete blood cell count and cobalamin (vitamin B-12) levels require further workup to rule out hematologic disease Abnormalities found in screening of liver enzyme levels require further workup to rule out hepatic disease Abnormalities in thyroid-stimulating hormone (TSH) levels require further workup to rule out thyroid disease Abnormalities in rapid plasma reagent (RPR) require further workup to rule out syphilis There is a possible link between vitamin D deficiency and cognitive impairment.However, vitamin D deficiency has not been identified as a reversible cause of dementia.

Brain MRI or CT Scanning AAN recommendations indicate that structural neuroimaging with either a noncontrast CT or MRI scan is appropriate in the initial evaluation of patients with dementia, in order to detect lesions that may result in cognitive impairment (eg, stroke, small vessel disease, tumor). In patients with Alzheimer disease (AD), brain MRIs or CT scans can show diffuse cortical and/or cerebral atrophy, but these findings are not diagnostic of AD. In clinical research studies, atrophy of the hippocampi (structures important in mediating memory processes) on coronal MRI is considered a valid biomarker of AD neuropathology. Nonetheless, measurement of hippocampal volume is not used in routine clinical care in the diagnosis of AD. SPECT or PET scanning Brain scanning with SPECT or PET is not recommended for the routine workup of patients with typical presentations of AD. These modalities may be useful in atypical cases or when some form of frontotemporal dementia is a more likely diagnosis. Electroencephalography Electroencephalography (EEG) is valuable when Creutzfeldt-Jakob disease or other prion-related disease is a likely diagnosis . Periodic high-amplitude
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sharp waves can eventually be detected in most cases of Creutzfeldt-Jakob disease. EEG is also useful if pseudodementia is a realistic consideration when a normal EEG in a patient who appears profoundly demented would support that diagnosis. Multiple unwitnessed seizures rarely can present as dementia and an EEG would be valuable for evaluating that possibility. Lumbar Puncture Perform lumbar puncture in select cases to rule out conditions such as normal-pressure hydrocephalus, neurosyphilis, neuroborreliosis, and cryptococcosis. Cerebrospinal fluid (CSF) levels of tau and phosphorylated tau are often elevated in AD, whereas amyloid levels are usually low. The reason for this is not known, but perhaps amyloid levels are low because the amyloid is deposited in the brain rather than the CSF. By measuring both proteins, sensitivity and specificity of at least 80% and more often 90% can be achieved. At present, however, routine measurement of CSF tau and amyloid is not recommended except in research settings. Lumbar puncture for measurement of tau and amyloid may become part of the diagnostic workup when effective therapies that slow the rate of progression of AD are developed, particularly if the therapies are specific for AD and carry significant morbidity. Genotyping Genotyping for apolipoprotein E (APOE) alleles is a research tool that is helpful in determining the risk of AD in populations, but it is of little, if any, value in making a clinical diagnosis and developing a management plan in individual patients. In a prospective, randomized, controlled trial of the effect of disclosing APOE genotyping results to 162 asymptomatic adults who had a parent with AD, Green et al found that follow-up testing over the course of a year showed no significant differences with disclosure versus nondisclosure on time-averaged measures of anxiety, depression, or test-related distress.
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Test-related distress was reduced among those who learned that they did not carry the APOE epsilon 4 (APOE E4) allele. Persons who had high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure. Genetic Testing for APP and Presenilin Mutations After appropriate counseling, genetic testing for APP and presenilin mutations is appropriate in early-onset cases.

Approach Considerations

Therapeutic approaches to Alzheimer disease (AD) will someday include both symptomatic therapy and disease-modifying therapies. To date, only symptomatic therapies are available. All drugs approved by the US Food and Drug Administration (FDA) for the treatment of AD modulate neurotransmitters, either acetylcholine or glutamate. The standard medical treatment for AD includes cholinesterase inhibitors (ChEIs) and partial N methyl-D-aspartate (NMDA) antagonists. Psychotropic medications are often used to treat secondary symptoms of AD, such as depression, agitation, and sleep disorders. These include antidepressants, anxiolytics, antiparkinsonian agents, beta-blockers, antiepileptic drugs used for their effects on behavior, and neuroleptics. Several studies have examined the efficacy of psychotropic drugs; most have demonstrated no or limited efficacy, but many issues make interpretation of data from these studies difficult. Other medications that have been used to treat AD include antioxidants (vitamin E [-tocopherol]), hormones (conjugated estrogens), nonsteroidal anti-inflammatory drugs (NSAIDs), and Ginkgo biloba. Hospitalization should be considered for any unstable medical condition that may complicate the patients treatment. If a patient becomes a danger to him/herself or others, admission to a long-term care facility due to grave disability should be considered for everyones safety.

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Treatment of Mild to Moderate Disease

ChEIs and mental exercises are used in an attempt to prevent or delay the deterioration of cognition in patients with AD. Cholinesterase inhibition Numerous lines of evidence suggest that cholinergic systems that modulate information processing in the hippocampus and neocortex are impaired early in the course of AD. These observations have suggested that some of the clinical manifestations of AD are due to loss of cholinergic innervation to the cerebral cortex. Centrally acting ChEIs prevent the breakdown of acetylcholine. Four such agents have been approved by the FDA for the treatment of AD: tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne, formerly Reminyl). All ChEIs have shown modest benefit compared with placebo on measures of cognitive function and activities of daily living. Patients on ChEIs decline more slowly on cognitive and functional measures than patients on placebo. In general, the benefits are temporary because ChEIs do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. The ChEIs may also alleviate the noncognitive manifestations of AD, such as agitation, wandering, and socially inappropriate behavior. Although the ChEIs were originally expected to be efficacious in only the early and intermediate stages of AD (because the cholinergic deficit becomes more severe later in disease and fewer intact cholinergic synapses are present), they are also helpful in advanced disease. ChEIs are also helpful in patients with AD with concomitant infarcts and in patients with dementia with Lewy bodies. (Frequently, AD and dementia with Lewy bodies occur in the same patient; this is sometimes called the Lewy body variant of AD.) The ChEIs share a common profile of adverse effects, the most frequent of which are nausea, vomiting, diarrhea, and dizziness. These are typically dose related and can be mitigated with slow up-titration to the desired
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maintenance dose. As antimuscarinic drugs are used for the treatment of incontinence, logically, ChEIs might exacerbate incontinence. One brief report has supported this hypothesis. ChEIs prescribed to treat dementia can provoke symptomatic bradycardia and syncope and precipitate fall-related injuries, including hip fracture. A population-based cohort study that identified community-dwelling older adults with dementia who were taking cholinesterase inhibitors (n=19,803) and controls who were not (n=61,499) found hospital visits for syncope were more frequent in people receiving ChEIs than in controls (31.5 vs 18.6 events per 1000 person-years). Other syncope-related events, including hospital visits for bradycardia, permanent pacemaker insertion, and hip fracture, were also more common among people receiving cholinesterase inhibitors compared with controls. ChEI use in older adults with dementia is associated with increased risk of syncope-related events; these risks must be weighed against the benefits of taking ChEIs. Anecdotal reports exist of acute cognitive and behavioral decline associated with the abrupt termination of ChEIs. In several of these cases, restarting the ChEI was not associated with substantial improvement. These reports have implications concerning the best practice when switching a patient from one ChEI to another in this class. Reasons for switching might include undesirable side effects or seeming lack of efficacy. Nonetheless, no published data help clinicians know when switching to another ChEI would be helpful. The common practice of tapering a patient off one central nervous system (CNS)-active medication before starting a new one should not be followed when changing ChEIs. For example, a patient who had been taking 10 mg of donepezil should be started the next day on galantamine, at least 8 mg/d and possibly 16 mg/d. No current evidence supports the use of more than 1 ChEI at a time. Of note, tacrine has potential liver toxicity, requires frequent blood monitoring, and has been rarely prescribed since the other agents have become available. Centrally acting anticholinergic medications should be avoided. Patients not uncommonly receive both ChEIs and anticholinergic agents, which counteract each other. Medications with anticholinergic effects, such as
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diphenhydramine (Benadryl) and tricyclic antidepressants (eg, amitriptyline, nortriptyline) can cause cognitive dysfunction. Therefore, a careful listing of the patients medications is important so that the physician can reduce the doses of, or ideally eliminate, all centrally acting anticholinergic agents. Mental activity to support cognition Many patients with normal cognition or those with mild impairment are concerned that they may develop AD. Many experts believe that mentally challenging activities, such as doing crossword puzzles and brainteasers, may reduce the risk in such patients. Whether such activities might slow the rate of disease progression in patients who already have AD is not known. Clinical trials are underway to determine the effect these cognitive activities have on AD progression. The mental activities should be kept within a reasonable level of difficulty for the patient. They should preferably be interactive, and they should be designed to allow the patient to recognize and correct mistakes. Most important, these activities should be administered in a manner that does not cause excessive frustration and that ideally motivates the patient to engage in them frequently. Unfortunately, little standardization or rigorous testing has been done to validate this treatment modality. Some investigators have attempted various forms of cognitive retraining, also known as cognitive rehabilitation. The results of this approach remain controversial, and a substantial experimental study must still be performed to determine if it is useful in Alzheimer disease.

Treatment of Moderate to Severe Disease

The partial NMDA antagonist memantine (Namenda) is believed to work by improving the signal-to-noise ratio of glutamatergic transmission at the NMDA receptor. This agent is approved by the FDA for treating moderate and severe AD. Several studies have demonstrated that memantine can be safely used in combination with ChEIs. Studies suggest that the use of memantine with donepezil affects cognition in moderate to severe AD but not in mild to moderate AD.

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Treatment of Secondary Symptoms

A variety of behavioral and pharmacologic interventions can temporarily alleviate clinical manifestations of AD, such as anxiety, agitation, depression, and psychotic behavior. The effectiveness of such interventions is often modest and temporary, and they do not prevent the eventual deterioration of the patients condition. No specific agent or dose of individual agents is unanimously accepted for the wide array of clinical manifestations. At present, the FDA has not approved any psychotropic agent for the treatment of AD. Behavioral interventions Behavioral interventions range from patient-centered approaches to caregiver training to help manage cognitive and behavioral manifestations of AD. These interventions are often combined with the more widely used pharmacologic interventions, such as anxiolytics for anxiety and agitation, neuroleptics for aberrant and/or socially disruptive behavior, and antidepressants or mood stabilizers for mood disorders and specific manifestations (eg, episodes of anger or rage). Neuroleptic agents In 2005, the FDA added a black box warning on the use of atypical neuroleptics in the treatment of secondary symptoms of AD such as agitation. Analyses suggested that patients on atypical neuroleptics had increased risk of death or stroke compared with patients on placebo. In 2008, a black box warning was included on haloperidol, prochlorperazine, thioridazine, and chlorpromazine for the same reason. The general recommendation is to use such agents as infrequently as possible and at the lowest doses possible to minimize adverse effects, particularly in frail, elderly patients. Particular concern has been raised about the potential for dopamine-depleting agents to aggravate the motor manifestations of dementia with Lewy bodies (DLB), because patients with DLB may be extremely sensitive to these agents.

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Antidepressants and mood modulators Antidepressants have an important role in the treatment of mood disorders in patients with AD. Depression is observed in more than 30% of patients with AD, and it frequently begins before AD is clinically diagnosed. Therefore, palliation of this frequent comorbid condition may improve cognitive and noncognitive performance. Nyth found citalopram to be beneficial in mood and other neuropsychiatric symptoms in patients in the moderate stage of AD. However, Weintraub et al and Petracca found sertraline and fluoxetine to have no short- or longterm benefit in mood over placebo. Other mood modulators, such as valproic acid, can be helpful for the treatment of disruptive behaviors and outbursts of anger, which patients with moderately advanced or advanced stages of AD may have. Results of several studies indicate that anticonvulsants (eg, gabapentin, valproic acid) may have a role in the treatment of behavioral problems in patients with Alzheimer disease. Suppression of Brain Inflammation Many studies have suggested that intense inflammation occurs in the brains of patients with AD. Epidemiologic studies suggest that some patients on long-term anti-inflammatory therapy have a decreased risk of developing AD. Nonetheless, no randomized clinical trial of greater than 6months duration has demonstrated efficacy of anti-inflammatory drugs in slowing the rate of progression of AD. Although previous reports reflect delayed onset of AD in individuals who used nonsteroidal anti-inflammatory drugs (NSAIDs), a study by Breitner et al showed that NSAIDs do not protect against AD, at least in very old people. Relying on computerized pharmacy dispensing records and biennial dementia screening, investigators found AD incidence was increased in heavy NSAID users. These findings may represent deferral of AD symptoms from earlier to later old age. Experimental Therapies A variety of experimental therapies have been proposed for AD. These include antiamyloid therapy, reversal of excess tau phosphorylation,
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estrogen therapy, and vitamin E therapy free-radical scavenger therapy. Studies of these therapies have yielded mostly disappointing results. Antiamyloid therapy

In the past 10 years, numerous studies have been conducted, and many are still ongoing, that test therapies designed to decrease toxic amyloid fragments in the brain. A wide variety of approaches have been tried, including the following:

Vaccination with amyloid species Administration of monoclonal antiamyloid antibodies Administration of intravenous immune globulin that may contain amyloidbinding antibodies Selective amyloid-lowering agents Chelating agents to prevent amyloid polymerization Brain shunting to improve removal of amyloid Beta-secretase inhibitors to prevent generation of the A-beta amyloid fragment To date, no phase III study of these approaches has shown an acceptable combination of efficacy and acceptable side effects. Tau-directed therapies Studies are also ongoing with agents that may prevent or reverse excess tau phosphorylation and thereby diminish formation of neurofibrillary tangles. Free-radical scavenger therapy Excess levels of free radicals in the brain are neurotoxic. Nonetheless, no study has demonstrated efficacy of free-radical scavengers in the treatment of the cognitive symptoms of AD. Vitamin E therapy A report by Sano et al in 1997 suggested that high-dose vitamin E (2000 units per day of alpha-tocopherol) might decrease the risk of death or the rate of conversion to severe dementia. This benefit presumably resulted from the antioxidant effects of vitamin E. Nonetheless, subsequent studies
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suggested that vitamin E supplementation may increase risk of adverse cardiovascular outcomes. Therefore, use of these agents is not currently recommended, and most practitioners have abandoned their use. Estrogen therapy No data show that women with AD who are placed on estrogen therapy (ET) have fewer symptoms or progress more slowly than women treated with a placebo. Furthermore, a randomized clinical trial of estrogen in cognitively normal women aged 65 years and older with a first-degree relative with AD showed that ET might actually increase the risk of stroke and dementia. Whether ET might decrease risk if started well before age 65 years is not known. Presymptomatic disease-modifying therapy Disease-modifying therapies would delay the onset of AD and/or slow the rate of progression. Since brain changes associated with AD probably start decades before dementia becomes clinically apparent, many investigators believe that disease-modifying therapies are much more likely to be effective if they are started in a presymptomatic stage. Studies are identifying patients at increased risk with neuropsychological, neuroimaging, and genetic methods. Although phase III trials for several potential disease-modifying therapies have been completed, to date none of these agents have shown clear efficacy and hence none have been approved by the FDA. Surgical Treatment No accepted surgical treatments exist for AD. Potential surgical treatments in the future may include the use of devices to infuse neurotrophic factors, such as growth factors, to palliate AD. Dietary Measures No special dietary considerations exist for Alzheimer disease. Caprylidene is a prescription medical food that is metabolized into ketone bodies. The brain can use these ketone bodies for energy when its ability to process glucose is impaired. Brain-imaging scans of older adults and persons with AD reveal dramatically decreased uptake of glucose.
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The approval of caprylidene was based on a double-blind, randomized, placebo-controlled, 90-day study that enrolled 152 patients with mild-tomoderate AD. At day 45, Alzheimers Disease Assessment Scalecognitive subscale (ADAS-Cog) scores stabilized in the caprylidene group, whereas these scores declined in the placebo group. The ADAS-Cog change from baseline score was also analyzed based on APOE E4 genotype. The APOE E4(-) patients receiving caprylidene showed improved cognitive function when compared with APOE E4(-) patients receiving placebo. In APOE E4(+) patients, the mean change in ADAS-Cog total scores for the 2 groups was essentially identical at all time points, with more patients showing decline rather than improvement at days 45 and 90. Physical Activity Routine physical activity and exercise may have an impact on AD progression, and perhaps has a protective effect on brain health. Increased cardiorespiratory fitness levels are associated with higher hippocampal volumes in patients with mild AD, suggesting that cardiorespiratory fitness may modify AD-related brain atrophy. The activity of each patient should be individualized. The patients surroundings should be safe and familiar. If the patients activity is optimized too much, it can cause agitation, but too little can cause the patient to withdraw and maybe become depressed. The patient needs contact with the outside environment. Television can be helpful for this task. Maintaining structured routines may be helpful to decrease patient stress in regard to meals, medication, and other therapeutic activities aimed at maintaining cognitive functioning. Long Term Monitoring Patients should receive regular follow-up care by their outpatient physician to closely monitor the illness and maximize the patients functioning as long as possible.

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Medication Summary The mainstay of therapy for patients with Alzheimer disease (AD) is the use of centrally acting cholinesterase inhibitors to attempt to compensate for the depletion of acetylcholine (ACh) in the cerebral cortex and hippocampus. A partial N -methyl-D-aspartate (NMDA) antagonist is approved for treatment of moderate and severe AD. Various medications are used for treatment of secondary symptoms of AD, including antidepressants, anti-anxiety agents, and antipsychotic agents. Cholinesterase Inhibitors Class Summary Cholinesterase inhibitors (ChEIs) are used to palliate cholinergic deficiency. All 4 currently approved ChEIs (ie, tacrine, donepezil, rivastigmine, galantamine) inhibit acetylcholinesterase (AChE) at the synapse (specific cholinesterase). Tacrine and rivastigmine also inhibit butyrylcholinesterase (BuChE). Although BuChE levels may be increased in AD, it is not clear that rivastigmine or tacrine have greater clinical efficacy than donepezil and galantamine. Galantamine has a different second mechanism of action; it is also a presynpatic nicotinic modulator. No data exist that this second mechanism is of clinical importance.

Donepezil (Aricept, Aricept ODT)

Donepezil is a centrally acting AChE inhibitor, but it does not inhibit BuChE.

Rivastigmine (Exelon) Rivastigmine is a centrally acting inhibitor of both AChE and BuChE.
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Rivastigmine transdermal patch (Exelon patch)

The rivastigmine transdermal patch is a competitive and reversible AChE inhibitor. While its mechanism of action is unknown, it may reversibly inhibit cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in the central nervous system (CNS) and thereby enhance cholinergic function. The effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. It is available as a 5-cm2 patch containing 9 mg (releases 4.6 mg/24 h) and 10-cm2 patch containing 18 mg (releases 9.5 mg/24 h). It is indicated for the treatment of dementia associated with Alzheimer disease and for dementia associated with Parkinson disease.

Galantamine (Razadyne, Razadyne ER)

Galantamine is indicated for the treatment of mild-to-moderate dementia of the Alzheimer type. It enhances central cholinergic function and likely inhibits AChE.

N-Methyl-D-Aspartate (NMDA) Antagonists Class Summary

NMDA antagonists are the newest class of agents indicated for the treatment of AD. The only FDA-approved drug in this class is memantine. This agent may be used alone or in combination with AChE inhibitors.

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Memantine (Namenda, Axura)

Memantine is an NMDA antagonist indicated for all stages of AD. NMDAreceptor overstimulation in the CNS by glutamate (excitatory amino acid) may contribute to symptoms; no evidence confirms a glutamatergic deficit in AD.

Nutritional Supplement Class Summary

Caprylidene is a prescription medical food that is metabolized into ketone bodies. The brain can use these ketone bodies for energy when its ability to process glucose is impaired, which brain-imaging scans suggest is the case in AD. Vitamin E has antioxidant properties.

Caprylidene (Axona)

Caprylidene is indicated for clinical dietary management of metabolic processes associated with mild-to-moderate AD. It is available in oral powder form (40 g/packet; contains 20 g medium-chain triglycerides).

Vitamin E (Aquasol E, Natural Vitamin E)

Vitamin E is a nutritional supplement with antioxidant properties. It is used to palliate postulated oxidative damage as a cause or contributing factor of AD.

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Anticonvulsants

Class Summary
The activity of anticonvulsants may be related to increased brain levels of gamma-aminobutyric acid (GABA) or enhanced GABA action. Results from several studies indicate that anticonvulsants (eg, gabapentin, valproic acid) may have a role in the treatment of behavioral problems in patients with Alzheimer disease (AD).

Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Tegretol XR)

The anticonvulsant action of carbamazepine may involve depressing activity in the nucleus ventralis anterior of the thalamus, resulting in reduction of polysynaptic responses and blocking posttetanic potentiation. It reduces sustained high-frequency repetitive neural firing. Carbamazepine is a potent enzyme inducer that can induce its own metabolism. Due to potentially serious blood dyscrasias, undertake benefit-to-risk evaluation before carbamazepine is instituted. Therapeutic plasma levels are between 4-12 mcg/mL for analgesic and antiseizure response. Peak serum levels occur in 4-5 h. Half-life (serum) occurs in 12-17 h with repeated doses. It is metabolized in liver to active metabolite (ie, epoxide derivative) with half-life of 5-8 h. Metabolites are excreted through feces and urine. Carbamazepine is effective in patients who have not responded to lithium therapy. It has been effective in treating patients who have rapid-cycling bipolar disorder or those who have not been responsive to lithium therapy.

Valproic acid (Depacon, Depakene, Depakote, Depakote ER, Depakote Sprinkles)

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Although the mechanism of action of valproic acid is not established, its activity may be related to increased brain levels of GABA or enhanced GABA action. Valproate may also potentiate postsynaptic GABA responses, affect potassium channel, or have a direct membranestabilizing effect. Valproic acid has proven effectiveness in treating and preventing mania. It is classified as a mood stabilizer and can be used alone or in combination with lithium. It is useful in treating patients with rapid-cycling bipolar disorders and has been used to treat aggressive or behavioral disorders.

Gabapentin (Neurontin)

Gabapentin is a membrane stabilizer and structural analogue of inhibitory neurotransmitter GABA, which paradoxically is thought not to exert effect on GABA receptors. It appears to exert action via the alpha(2)delta1 and alpha(2)delta2 auxiliary subunits of voltage-gaited calcium channels Antidepressants, Selective Serotonin Reuptake Inhibitors

Class Summary This class of drug enhances serotonin activity due to selective reuptake inhibition at neuronal membrane. Antidepressants have an important role in the treatment of mood disorders in patients with Alzheimer disease (AD).

Sertraline (Zoloft)

Sertraline selectively inhibits presynaptic serotonin reuptake.

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Citalopram (Celexa)

Citalopram enhances serotonin activity by selective reuptake inhibition at the neuronal membrane. It may be beneficial in mood and other neuropsychiatric symptoms in patients in the moderate stage of AD.
Antiparkinson Agents

Class Summary Antiparkinson agents with activity against major depressive disorder may improve the behavioral aspects of AD.

Selegiline (Emsam, Eldepryl, Zelapar)

Selegiline is an irreversible monoamine oxidase inhibitor (MAOI). It has greater affinity for monoamine oxidase (MAO)-B than for MAO-A; however, at antidepressant doses, it inhibits both isoenzymes. MAO-A and MAO-B catabolize neurotransmitter amines in the CNS (eg, norepinephrine, dopamine, serotonin). It is indicated for treating major depressive disorder. At its lowest strength (ie, 6 mg delivered over 24 h), it may be used without the dietary restrictions required for oral MAOIs used to treat depression.
Antianxiety Agents

Class Summary Anxiolytics can temporarily alleviate clinical manifestations of AD such as anxiety. Agents in this category may have effects in serotonergic neurotransmission and some dopaminergic effects in the CNS.
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Lorazepam (Ativan)

Lorazepam is a benzodiazepine and sedative hypnotic with a short onset of effects and relatively long half-life. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, it may depress all levels of the CNS, including limbic and reticular formation. When the patient needs to be sedated for longer than a 24-hour period, this medication is excellent.

Buspirone (BuSpar)

Buspirone is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates, or other sedative or anxiolytic drugs. It is a 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in the CNS. It has anxiolytic effects but may take up to 2-3 wk for full efficacy.
Antipsychotic Agents

Class Summary The US Food and Drug Administration (FDA) has issued black box warnings regarding increased mortality with the use of both typical (first-generation) and all 3 classes of atypical (secondgeneration) antipsychotics as treatment for behavioral disturbances in elderly patients with dementia. The general recommendation is to use such agents as infrequently as possible and at the lowest doses possible to minimize adverse effects, particularly in frail, elderly patients.
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Haloperidol (Haldol, Haldol Decanoate)

Haloperidol is the drug of choice for patients with acute psychosis when no contraindications exist. Haloperidol is a dopamine (D2) antagonist. It is a derivative of butyrophenone, which is noted for its high potency and low potential for causing orthostasis. The drawback is the high potential for extrapyramidal symptoms/dystonia. The parenteral dosage form may be mixed in same syringe with 2 mg of lorazepam for better anxiolytic effects.

Quetiapine (Seroquel, Seroquel XR)

Quetiapine may act by antagonizing dopamine and serotonin effects. It is a newer antipsychotic used for long-term management. Improvements over earlier antipsychotics include fewer anticholinergic effects and less dystonia, parkinsonism, and tardive dyskinesia. Immediate- and extendedrelease formulations are available.

Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)

Risperidone has both D2 and serotonin 5-HT2 antagonism. It improves negative symptoms of psychoses and reduces the incidence of extrapyramidal adverse effects.

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