After completing this continuing education article, the pharmacist should be able to:
Alzheimer's disease (AD) has been one of the most intriguing enigmas in the medical field since it was first recognized in 1906 by Dr. Alois Alzheimer. This progressive and degenerative neurologic disorder is characterized by a gradual decline in cognition and behavior. In 2004, the National Center for Health Statistics reported that AD is the 7th leading cause of death among the elderly in the United States. It is the most common form of dementia, accounting for >65% of all dementia in the elderly.1,2 AD will continue to be a challenge for the elderly population, especially as the baby-boomer generation ages.
It is estimated that AD now affects ~4.5 million individuals in the United States?twice the number affected in 1980. The disease affects ~5% of men and women aged 65 to 74 years. In addition, an estimated 50% of the population =85 years may have AD.3,4 The increase in the number of cases may be attributed to the increase in the aging population, as well as increased awareness about the disease.
Furthermore, it is estimated that, by the year 2050, ~11 million to 16 million individuals will be affected by AD.4 Currently, ~28 million individuals are affected worldwide.4 More than one half of individuals with AD are cared for at home, whereas the remainder are cared for in various long-term care facilities.4
The increased number of AD cases continues to have a significant impact on individuals and families and on the health care industry as well, because of the complexity of the disease. Despite the advances made in attempting to understand the etiology of this disorder, many questions remain unanswered and much remains to be discovered.
On average, an individual will live 8 years after diagnosis of AD or as long as 20 years from the onset of symptoms.3,4 Caring for individuals with AD requires significant resources. For instance, 1 to 4 family members may act as caregivers for an individual with AD. Results of a study showed that in 1996 the average annual cost of caring for a patient with AD was ~$18,400 to $36,000, depending on the severity of the condition.5,6 Since 1996, the costs have risen consistently. Research suggests that the estimated worldwide annual cost for care of patients with AD and other dementia is ~$248 billion.5,7 Whereas the issue of cost is an important factor, the management of AD can be both emotionally and physically challenging for patients, family members, and caregivers.
This continuing education article will review current theories, ongoing research, and therapies available for patients with AD. It also will provide pertinent information for pharmacists to utilize when assisting the patient with AD, as well as for family members and caregivers who are affected by this debilitating disease.
Although the exact etiology of AD still is unknown, research suggests that it can be attributed to both inherited and environmental factors. The 3 standard neuropathologic features of AD include amyloid plaques; neurofibrillary tangles; and a third factor, which has been described only in the last 3 decades?synaptic and neuronal cell death that involves a progressive or gradual loss of connections between neurons.6,8,9 As the death of the neurons progresses and spreads through the brain, brain atrophy occurs in the affected areas.9 Whereas researchers have known about these features of AD for several years, they are still learning more about them and their roles in the development and progression of AD. The progression of AD often is unpredictable, and the severity varies from patient to patient.
There are 2 distinct forms of AD: (1) familial and (2) sporadic.10 Familial AD is considered very rare and typically occurs before the age of 60. It also is referred to as early-onset AD. Less than 5% of the cases are early-onset, and this form is believed to be caused by gene mutations on chromosomes 1, 14, and 21.10,11
As for sporadic AD, genes may not be the direct cause of the disease but may influence the risk of developing it. Sporadic AD also is referred to as late-onset AD, because many cases occur in individuals after the age of 60, with the vast majority in their 70s and 80s.10,11 There are, however, exceptions to the general observations regarding age at onset.
The apolipoprotein E (apo E) gene, which is found on chromosome 19, is the best studied susceptibility gene in sporadic AD.10 The apo E gene is responsible for the manufacturing of a protein that moves cholesterol and other fats throughout the body.10 It is postulated that this protein may be involved in the structure and function of the fatty membrane that surrounds a brain cell.10 The apo E gene occurs in many forms or alleles. The 3 forms that occur most frequently are apo E-II, apo E-III, and apo EIV.10-12 Furthermore, the apo E-IV gene may increase an individual's chance of developing late-onset AD. It is estimated that between 35% and 50% of individuals with AD carry some form of the apo E-IV gene.10
Current research indicates that AD may be triggered by several factors, including age, genetics, serious head injuries, and inflammation of the brain, as well as environmental factors. Age is the most well-documented risk factor. Other possible risk factors include the following13-15:
Signs and Symptoms
Recognizing the warning signs associated with the development of AD is crucial in order to initiate early intervention, as well as to differentiate AD from other forms of dementia. In many cases, an individual's symptoms may progress gradually over time and may not be obvious initially. Patients may exhibit cognitive or intellectual symptoms, such as acalculia (inability to perform simple mathematical calculations), aphasia (inability to communicate effectively), apraxia (inability to perform daily activities such as brushing teeth or combing hair), amnesia, and agnosia (loss of the ability to interpret sensory stimuli) as the disease progresses. Behavioral signs and symptoms?such as depression, apathy, and anxiety?typically are present in the early stages, and delusions, hallucinations, and psychosis are prevalent during the latter stages.16,17 In the advanced stages, individuals also may present with extrapyramidal symptoms, such as gait disturbance, myoclonus, tremor, and urinary incontinence.16
Potential Warning Signs
Some warning signs of AD are as follows16:
Because AD progresses in severity over time, the disease generally is characterized by the following stages: mild, moderate, and severe. During the mild stage, the individual may start to experience some memory loss, which may be insignificant enough that others may not notice a problem. Short-term memory usually is affected first.
As the disease progresses from mild to moderate, the signs may become more noticeable to family and friends, because the patient may exhibit difficulty in self-care and in accomplishing everyday tasks. At this stage, some behavioral changes often are noted, such as frustration, anger, and anxiety. Usually at this stage, the need for caregiver assistance may become essential for the safety of the individual.
In the severe stage of AD, individuals typically are characterized as being solely dependent on the caregiver. Some patients in this stage may experience loss of bladder and bowel control and episodes of aggression. Table 1 lists, for each stage of AD, behavioral and cognitive changes as well as how the disease may affect the individual's daily routine.18
To date, there is no definitive diagnostic test to ascertain whether an individual has AD. Diagnosis, however, can be determined by a careful evaluation of the symptoms manifested by the patient, a comprehensive assessment of the patient's medical history in consultation with family members, and a thorough neurologic examination, possibly utilizing computerized tomography or magnetic resonance imaging (MRI).19
In addition, the Mini Mental State Examination (MMSE) can be used to evaluate memory, recognition, comprehension, and attention. The maximum score that a patient can obtain is 30 points. Mild dementia is suggested by a score in the range of 20 to 24, moderate dementia is suggested by a score range of 13 to 20, and a score of =12 indicates severe dementia. Typically, an individual with AD has a decline of 2 to 4 points per year on the MMSE.19 Today, clinicians can diagnose AD with up to 90% accuracy, but a confirmation of the diagnosis can be made only at time of autopsy.12
Because there is no definitive biological test for confirming AD, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Association combined efforts and created criteria to facilitate diagnosing of AD. The criteria also are intended to aid physicians in making a distinction between AD and other forms of dementia. Dementia typically is confirmed by the following criteria20:
As individuals get older, some will develop a memory deficit greater than what is anticipated for their age group. Because other aspects of cognition are not affected, these individuals may not meet all the accepted criteria for developing AD. These individuals are believed to have mild cognitive impairment (MCI). Furthermore, it is estimated that ~40% of these individuals will develop AD within 3 years.20
Others, however, do not seem to develop AD, at least in the time frame studied so far (up to ~6 years). Learning more about the development and characteristics of MCI is critical for helping health care professionals to obtain knowledge for early diagnosis of AD.20
FDA-approved Pharmacologic Agents
Currently there are no pharmacologic agents to halt the progression of Alzheimer's disease. There are, however, FDA-approved agents for treating AD that can stabilize or possibly slow the progression of the classic symptoms associated with the disease. It should be emphasized that these agents only slow the progression of the disease. They are intended to assist in enhancing cognitive function, to delay continual cognitive decline, and to prevent or decrease the incidence of disruptive behavior, as well as enabling the patient to maintain a reasonable quality of life and independence for as long as possible.12,13
To date, the FDA has approved 2 classes of drugs, acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) antagonists, for treating certain cognitive symptoms of Alzheimer's disease, such as memory problems and other mental deficits.
The first AD medications to be approved were AChE inhibitors. Three of these drugs are now commonly prescribed?donepezil, approved in 1996; rivastigmine, approved in 2000; and galantamine, approved in 2001. Tacrine, the first AChE inhibitor, was approved in 1993, but it is rarely prescribed today because of its associated side effects, including possible hepatoxicity.
Donepezil hydrochloride is a reversible, selective inhibitor of AChE chemically known as (+)-2,3-dihydro-5, 6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1 H-inden-1-one hydrochloride. Donepezil is believed to exert its pharmacologic action by enhancing cholinergic function. Donepezil is approved by the FDA for the treatment of mild-to-moderate dementia associated with AD.21 In 2006, the FDA also approved donepezil for the treatment of severe dementia associated with AD, thereby making it the only pharmacologic agent approved to treat all 3 stages of AD.22-24
The most common adverse effects associated with the use of donepezil include headache, nausea, diarrhea, anorexia, and fatigue. Dosing is 5 mg per day initially but may be increased to 10 mg per day at bedtime after 4 to 6 weeks. Donepezil is available in 5-and 10-mg tablets as well as in an oral disintegrating-tablet formulation. Donepezil should be administered in the evening just prior to bedtime and can be administered without regard to food. The oral disintegrating formulation should be allowed to dissolve on the tongue, followed by consumption of some water.
In a recent Mayo Clinic study, results showed that donepezil slows the rate of brain shrinkage in some individuals with MCI, which is a pre-AD condition. The study included 131 participants with MCI. The participants were divided into 3 different groups, the members of which took donepezil, vitamin E, or a placebo. The participants were given a series of MRIs to evaluate brain shrinkage. The results showed that brain shrinkage in individuals treated with donepezil who were apo E-IV carriers was 4.5% per year, compared with 6.14% for those who took the placebo. Vitamin E had no effect on brain shrinkage in any of the study participants.25
A review of 13 additional studies, using a combined total of ~7300 participants, showed that donepezil, rivastigmine, and galantamine seem equally effective in the treatment of mild-to-moderate AD.26
Rivastigmine is classified as an intermediate- acting or pseudoirreversible inhibitor of AChE that crosses the blood-brain barrier. It is approved for the treatment of mild-to-moderate dementia of AD.27
Initial dosing is 1.5 mg twice a day. If the drug is tolerated for at least 2 weeks, then the dosing may be increased to 3 mg twice daily. Increases to 4.5 and 6 mg twice a day should be attempted only after at least 2 weeks at the previous dose. The maximum dose is 6 mg twice daily. Common adverse effects include nausea, vomiting, abdominal pain, and loss of appetite.20,27
Rivastigmine is available in 1.5-, 3-, 4.5-, and 6-mg capsules. It also is available in a 2-mg/mL oral solution.
The emergence of newer therapies may be instrumental in the quest for treating AD. Researchers are investigating the possibility of a topical drug-delivery system, which appears to minimize adverse effects. The results of the IDEAL study, which involved 1195 patients, were presented at the International Conference on Alzheimer's Disease and Related Disorders in Madrid, Spain, in 2006.28,29 The study included a 24-week experiment, with ~600 participants from 21 countries. The participants ranged in age from 50 to 85 and were diagnosed with moderate-stage AD. They were given a placebo or a small or large version of the rivastigmine patch. In addition, ~600 other participants with the same criteria were administered a standard dose of rivastigmine bid in the oral formulation or a placebo.
The researchers reported that, when comparing the placebo results with those with the patch, the patch induced "significant benefits" with regard to the patient's cognitive function as well as the ability to perform routine daily activities. The findings further showed that the outcomes of individuals with the patch were equivalent to those achieved by those on the oral formulation.
The patch appeared to lessen the incidence of adverse effects. In the study group, 7% of the participants with the patch experienced nausea, whereas 23% of those taking the oral formulation experienced nausea.
The investigators found that the topical formulation was well-tolerated. Approximately 8% of the study participants using this drug-delivery system experienced moderate-to-severe erythema of the skin. It is possible that this patch may be available sometime in 2007, pending FDA approval.28,29
Galantamine (Razadyne; formerly Reminyl)
Galantamine hydrobromide is a tertiary alkaloid and is a competitive and reversible inhibitor of AChE. Although the precise mechanism of galantamine's action is unknown, it is theorized to exert a therapeutic effect by enhancing cholinergic function. This action is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase.30
The manufacturer's recommended dose is 4 mg bid with meals, titrated monthly to 12 mg bid. Common adverse effects associated with the use of galantamine hydrobromide include nausea, vomiting, and diarrhea.30 Galantamine should be administered with food and water. It is available as 4-, 8-, and 12-mg tablets and as an oral solution of 4 mg/mL, as well as extended-release capsules in 8-, 16-, and 24-mg dosages for once-a-day dosing.
Memantine (Namenda) In October 2003, the FDA approved memantine for the treatment of moderate-to-severe AD. This agent is classified as the first NMDA receptor antagonist. It aids in protecting nerve cells in the brain from an excess of glutamate, which is the neurotransmitter that plays a role in neurodegenerative diseases such as AD.31 The presumption is that this agent exerts its action as an uncompetitive open-channel NMDA receptor antagonist that binds to the NMDA-receptor-operated cation channels.31
Clinical studies have shown that memantine actually may improve memory function and prolong independence and quality of life in some patients with AD.31 This agent can be used as monotherapy or in conjunction with AChE inhibitors. Research has shown that the use of memantine in conjunction with a cholinesterase inhibitor has produced improvement with regard to the performance of everyday functions.
Memantine is available in 5-and 10-mg tablets. The usual starting dosage regimen is 5 mg once daily, with the dosage eventually titrated up to the desired dose of 20 mg per day. The dosage is increased in increments of 5 to 10 mg per day in 2 divided doses, then to 15 mg per day (administered as 5 mg and 10 mg in separate doses), then to 20 mg daily as 10 mg bid. This agent can be taken with or without meals. The recommended minimal time interval between dosage increases is 1 week. Following oral administration, memantine is highly absorbed, with peak concentrations reached in 3 to 7 hours.
The manufacturer cautions that, in certain cases, some agents such as carbonic anhydrase inhibitors and sodium bicarbonate, which increases urinary pH, may decrease the urinary elimination of memantine, resulting in increased plasma levels of this agent.31 The most frequently reported side effects include ataxia, hypokinesia, anemia, dizziness, headache, and constipation.
Pharmacists may receive inquiries from patients about alternative/complementary medications. Herbal and dietary supplements such as ginkgo biloba, coenzyme Q, omega-3 fatty acids, or vitamin E often are promoted for preventing or treating AD. To date, no scientific studies have proven the effectiveness of the use of these agents with regard to AD. Ongoing trials are studying the effects of ginkgo biloba, coenzyme Q10, and vitamin E to determine their effects regarding AD. More information on these trials can be found at the US National Institutes of Health Clinical Trials Web site at www.clinicaltrials.gov. Pharmacists can be instrumental in screening for potential drug interactions as well as possible contraindications. Pharmacists always should advise patients to discuss the use of these agents with their primary health care provider prior to using them.
Recent Developments: Clinical Trials and Ongoing Research Studies
Currently, >100 clinical studies are being conducted to explore other means of understanding and treating AD. These clinical trials may one day bring relief to the millions affected by this disease. For more in-depth information on these clinical trials, visit www.clinicaltrials.gov. Examples of these clinical trials are listed in Table 2.32,33
Researchers are continually investigating possible causes and preventive measures with regard to AD. Presently, clinical trials are studying the possible link between AD and diabetes. One of the trials is researching whether the diabetes agent rosiglitazone can either slow or halt the progression of AD.34 In preliminary trials, the use of rosiglitazone demonstrated beneficial results in patients who did not have the apo E-IV gene.34 Because the current diabetes epidemic in the United States is largely attributed to the growing number of obese patients, some researchers theorize that it is possible to utilize the increase in obesity as an indicator in predicting increases in cases of AD.34 Studies also suggest that individuals with weight issues at middle age may be at a greater risk for the development of AD.33,34
Geldmacher et al conducted a small study on the use of the diabetes agent pioglitazone and its effects on nondiabetics with AD. This study was conducted to determine the safety of long-term use of this agent in this patient population. The researchers also investigated whether the drug could possibly slow the progression of AD. The results suggested that those taking pioglitazone experienced less worsening of the disease on some assessments. Due to the promising results of this effort, a more comprehensive study involving a larger group may be beneficial.35,36
The results of another trial were published in the February 2006 issue of the Archives of General Psychiatry. This study, based on a sample of ~12,000 Swedish twins, of whom 25% were identical, found that 80% of the risk of AD is due to genetics.37,38 Thus, it appears that genetic factors may outweigh environmental factors with regard to the risk of developing AD. Furthermore, in studying identical twins, it was found that the development of AD in one twin did not mean that the other twin would definitely develop AD. In 45% of the cases, if one male identical twin developed AD, then the other twin would, too. The rate among female identical twins was 60%.37,38 The differences between men and women could possibly be attributed to the fact that women tend to have a longer life span than men.
An article in the on-line July 2006 issue of Lancet Neurology reported that increased blood levels of specific forms of amyloid beta (A?) proteins were associated with an increased incidence of AD as well as other forms of dementia. In the study, 1756 individuals over the age of 55 years were evaluated for 9 years. During that time period, 392 participants developed some form of dementia. The research demonstrated that subjects with low blood levels of A?1-42 and high levels of A?1-40 at the start of the study had a greater than 10-fold risk of likely developing dementia, compared with those participants with low levels of each protein.39
In recent studies, researchers at Northwestern University have developed an innovative orally administered agent that is designed to specifically target suppression of brain cell inflammation and neuron loss that is often associated with AD. The compound, known as MW01-5-188WH, exerts its therapeutic action by selectively inhibiting cytokines by glia.40,41 Glia are integral components of the central nervous system and are overactivated in certain neurodegenerative diseases such as AD.41
In another recent study, researchers developed a computer-aided analysis technique to identify early cellular damage in patients with AD. The methods may enable earlier diagnosis of AD, thus possibly slowing the progression of the disease. The 13 study patients, with MCI, and 13 elderly control subjects underwent MRI of the brain and performed recall tasks. On the MRI images, apparent diffusion coefficient values were measured in the gray and white regions by using the computer-analysis program. The findings were compared between the 2 groups. The results showed that individuals with MCI who seem to be likely to further progress to AD may be able to commence early treatment interventions.42
An AD Vaccine
At a recent conference on AD, researchers suggested that they are making progress in the development of a vaccine for AD. An older trial for a vaccine was discontinued in 2002 when 6% of the study participants developed encephalitis, while others developed brain shrinkage.The new methods of approach do not seem to pose these adverse events. Currently, 2 trials in different phases are investigating the passive immunization approach.41
Other Pharmacologic Agents Used in the Management of AD
In some cases, it may be necessary for physicians to prescribe other classes of pharmacologic agents, such as antianxiety drugs, antipsychotics, and antidepressants. These agents may be used to treat patients with AD who are exhibiting specific behavioral symptoms, such as depression, agitation, hallucinations, or sleep disturbances. In these instances, the patients were not responding to nonpharmacologic behavioral strategies. These agents are prescribed as per physician discretion and based on specific patient need.
Caregiver Strategies and Nonpharmacologic Therapies
It is important to note that most individuals with AD do not die from the disease itself but rather from complications of a secondary illness such as pneumonia. In some cases, when patients with AD are unable to care for themselves, the risk increases of developing other health concerns?such as pneumonia, infections, and injuries or complications due to falls.
A diagnosis of AD affects not only the patient, but the caregivers as well. According to the Alzheimer's Association, approximately 1 in every 10 individuals has a family member with AD. Caregivers must learn to cope with the progressive physical and mental changes in their loved ones and to deal with the emotional and physical stress often associated with caring for such a patient. The care of a patient with AD requires significant time and resources and can be demanding, difficult, and overwhelming at times.
Because AD is a progressive disease, decisions about care need to be planned in advance. These decisions depend on the home environment, the availability of family members and/or the ability of caregivers to provide assistance in day-to-day activities, maintaining financial resources, and routine medical care.
The Role of the Pharmacist
In almost every area of pharmacy practice, pharmacists are very likely to encounter a patient with AD and/or a caregiver. Therefore, it is imperative for pharmacists to keep abreast of new developments in research and pharmacologic therapies regarding the disease.
Pharmacists can be a vital resource for both patients and their caregivers, thereby improving quality of life. A comprehensive understanding of the etiology, pathophysiology, and stages of AD, as well as pharmacologic therapy, is imperative to provide effective care to the patient.
Pharmacists can assist patients with AD through monitoring drug regimens for potential drug interactions as well as possible contraindications. More importantly, pharmacists always should try to demonstrate empathy toward patients with AD and their caregivers, keeping them informed about new developments in the fight against this condition and suggesting resources of information for them.
Caring for a patient with AD involves more than drug treatment. Caregivers should be encouraged to join a local support group and to take care of themselves and seek assistance when warranted.
During counseling, pharmacists can provide patients and their caregivers with various suggestions for techniques that may aid in the management of AD, such as the use of memory aids or schedules. Examples of memory aids include a list of daily routines, important telephone numbers in case of an emergency, and instructions on how to perform various tasks. In addition, pharmacists can make recommendations for creating a safe environment and establishing an exercise routine, if appropriate.44
Currently, there are no cures for AD, but progress has been made over the last 15 years (Table 345). The prospect for possible treatments and a cure lies in the ongoing research. Maybe one day hope will become reality and benefit the millions of individuals affected by the disease. It is clear that, as the number of AD cases continues to increase, more research is needed to solve the mystery of this disease that affects the lives of so many individuals.
Yvette C. Terrie, BSPharm, RPh is a Clinical Pharmacy Writer based in Haymarket,Va.
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Pharmacy Times/Ascend Media Office of Continuing Professional Education is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program is approved for 2.5 contact hours (0.25 CEUs) under the ACPE universal program number of 290-000-06-017-H01. The program is available for CE credit through January 1, 2010.
(Based on the article starting on page 103) Choose the 1 most correct answer.
1. Alzheimer's disease (AD) was first recognized in what year?
2. Since 1980, the number of cases of AD in the United States has:
3. AD accounts for what percentage of dementia among the elderly population?
4. AD affects what percentage of individuals over 85 years of age in the United States?
5. What are the 2 forms of AD?
6. Which of the following is the most well-documented risk factor associated with the development of AD?
7. A score of 21 on the Mini Mental State Examination is indicative of what stage of dementia?
8. The apolipoprotein E (apo E) gene is found on which chromosome?
9. Between 35% and 50% of individuals with AD carry some form of what gene?
10. How many individuals are affected by AD worldwide?
11. How many pharmacologic classes are currently FDA-approved for treating dementia associated with AD?
12. What is the average life span of a patient with AD following diagnosis?
13. The average cost of caring for a patient with AD is estimated to be:
14. Which drug is rarely prescribed because of its adverse effects?
15. Memantine is classified as a (an):
16. MPC-7869, r-flurbiprofen is classified as a (an):
17. Which agent(s) is (are) approved for the treatment of severe dementia?
18. Common adverse effects such as anemia, dizziness, and headache are associated with the use of:
19. Which of the following agents has been studied for a topical formulation?
20. Which of the following pharmacologic agents is available in an extended-release form?
TESTING AND GRADING PROCEDURES
NEW SCORING OPTIONS
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1. Alzheimer's Disease Among the 2004 Top Causes of Death in the US. Reuters Health Information Web site. Available at: www.medscape.com/viewarticle/530368_print.
2. Alexander M, Larson EB. Patient Information: Alzheimer's Disease. UpToDate Patient Information Web site. Available at: http://patients.uptodate.com/topic.asp?file=mentl_h/4657.
3. Alzheimer's Fact Sheet. National Institute on Aging Web site. Available at: www.nia.nih.gov/Alzheimers/Publications/adfact.htm. Accessed November 9, 2006.
4. Alzheimer's Disease Statistics. Alzheimer's Association Web site. Available at: www.alz.org/AboutAD/statistics.asp.
5. Worldwide Cost of Alzheimer's Care at $248 Billion. Alzheimer's Association Web site. Available at: http://search.alz.org/search/searchright.asp?ct=ALZ&qu=28+million.
6. Alzheimer's Disease: Unraveling the Mystery. National Institutes of Health; 2002. NIH publication 02-3782.
7. Global Bill for Alzheimer's Nears Quarter-Trillion Dollars. Medicine Online Web site. Available at: www.medicineonline.com/news/10/9252/Global-Bill-for-Alzheimers-Nears-Quarter-Trillion-Dollars.html. Accessed October 9, 2006.
8. Pathophysiology of Alzheimer's Disease. Alzheimer's Disease Web site. Available at: www.alzheimersdisease.com/hcp/about/pathophysiology/pathophysiology.jsp.
9. New Discoveries, New Insights, Progress Report on Alzheimer's Disease 2004-2005. US Department of Health and Human Services. Page 6.
10. Genes and Alzheimer's Disease. Alzheimer's Association Web site. Available at: www.alz.org/AboutAD/causes.asp.
11. Alzheimer's Disease Genetics Fact Sheet. National Institute on Aging Web site. Available at: www.nia.nih.gov/Alzheimers/Publications/geneticsfs.htm.
12. Risk Factors for Alzheimer's Disease. Alzheimer's Disease.com Web site. Available at: www.alzheimersdisease.com/hcp/about/pathophysiology/risk-factors.jsp.
13. What Causes Alzheimer's? Fisher Center for Alzheimer's Research Foundation Web site. Available at: www.alzinfo.org/research/causes/default.aspx.
14. Risk Factors for Alzheimer's Disease. Alzheimer's Disease.com Web site. Available at: www.alzheimersdisease.com/hcp/about/pathophysiology/risk-factors.jsp.
15. Tavee J, Sweeney PJ. Alzheimer's Disease. Cleveland Clinic Web site. Available at: www.clevelandclinicmeded.com/diseasemanagement/neurology/alzheimers/alzheimers.htm.
16. Steps to Diagnosis. Alzheimer's Association Web site. Available at: www.alz.org/alzheimers_disease_steps_to_diagnosis.asp.
17. About Alzheimer's. Alzheimer's Foundation of America Web site. Available at www.alzfdn.org/alzheimers/symptoms.shtml.
19. About Alzheimer's Disease. Alzheimer's Disease Research Center, Washington University Web site. Available at: http://alzheimer.wustl.edu/adrc2/Education/aboutAD.html#Introduction.
20. Alzheimer's Disease: Unraveling the Mystery. National Institutes of Health; 2002. NIH publication 02-3782, page 43.
21. New Discoveries, New Insights, Progress Report on Alzheimer's Disease 2004-2005. US Department of Health and Human Services. Page 11.
22. Aricept package insert. Teaneck, NJ: Eisai Inc.
23. Aricept Use Expanded to Severe Alzheimer's Dementia. Available at: www.medicinenet.com/script/main/art.asparticlekey=76912.
24. FDA Approves Expanded Use of Treatment for Patients with Severe Alzheimer's Disease. FDA Web site. Available at: www.fda.gov/bbs/topics/NEWS/2006/NEW01491.html.
25. Drug Slows Pre-Alzheimer's Brain Shrinkage. US Department of Health and Human Services Web site. Available at: www.healthfinder.gov/news/newsstory.asp?docID=533824.
26. Trio of Drugs May Improve Alzheimer's Disease. Medscape Web site. Available at: www.medscape.com/viewarticle/522307.
27. Exelon package insert. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2004.
28. Alzheimer's Patch Could Replace Pills. US Department of Health and Human Services Web site. Available at: www.healthfinder.gov/news/newsstory.asp?docID=533885.
29. Exelon Patch, the First Transdermal Therapy for Alzheimer's Disease, May Provide Promising New Approach to Treatment of Dementia. Medical News Today Web site. Available at: www.medicalnewstoday.com/medicalnews.php?newsid=47681.
30. Galantamine package insert. Titusville, NJ: Ortho-McNeil Neurologics; 2005.
31. Namenda package insert. St. Louis, Mo: Forest Laboratories; 2003.
32. National Institutes of Health Clinical Trials Web site. Available at: www.clinicaltrials.gov.
33. Drugs in Clinical Trials. Alzheimer Research Forum Web site. Available at: www.alzforum.org/dis/tre/drc/default.asp.
34. Diabetes Drug May Prevent Alzheimer's. MedicineNet.com Web site. Available at: www.medicinenet.com/script/main/art.asp?articlekey=61219.
35. Geldmacher DS, Fritsch T, McClendon MJ, Lerner AJ, Landreth GE. P2-408: A double-blind, placebo-controlled, 18-month pilot study of the PPAR-gamma agonist pioglitazone in Alzheimer's disease. Alzheimer's and Dementia, Journal of the Alzheimer's Association Web site. Available at: www.alzheimersanddementia.com/article/PIIS1552526006036326/fulltext.
36. New Discoveries, New Insights, Progress Report on Alzheimer's Disease 2004-2005. US Department of Health and Human Services. Pages 59-60.
37. Who Gets Alzheimer's Disease. Available at: www.alzheimers.factsforhealth.org/what/whogetsad.asp.
38. Gatz M. Role of Genes and Environments for Explaining Alzheimer Disease. Arch Gen Psychiatry. 2006;663:168-174.
39. Khamsi R. Blood analysis may reveal Alzheimer's risk. NewScientist.com Web site. Available at: www.newscientist.com/article.ns?id=dn9492.
40. Ranaivo HR, Craft JM, Hu W, et al. Glia as a Therapeutic Target: Selective Suppression of Human Amyloid-?-Induced Upregulation of Brain Proinflammatory Cytokine Production Attenuates Neurodegeneration. J Neurosci. 2006;26:662-670. Available at: www.jneurosci.org/cgi/content/full/26/2/662.
41. Drug Compounds Effective in Alzheimer's. Northwestern University Web site. Available at: www.northwestern.edu/univrelations/media_relations/releases/2004/11/aminopyridazines.html.
42. Microscopic brain damage detected in early Alzheimer's disease. Radiology Society of North America Web site. Available at: www2.rsna.org/pr/target.cfm?ID=288.
43. A vaccine for Alzheimer's? Medscape Web site. Available at: www.medscape.com/viewarticle/541229.
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One study linked multiple pregnancies to an increased risk of developing atrial fibrillation later in life, and another investigated the association between premature delivery and cardiovascular disease.
Clinical features with downloadable PDFs