Alzheimer's disease

Alzheimer's Disease Learn what Alzheimer's is, and how to care for sufferers.

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Definition

Alzheimer's disease (AD) is the most common form of dementia, a neurologic disease characterized by loss of mental ability severe enough to interfere with normal activities of daily living, lasting at least six months, and not present from birth. AD usually occurs in old age, and is marked by a decline in cognitive functions such as remembering, reasoning, and planning.

Description

A person with AD usually has a gradual decline in mental functions, often beginning with slight memory loss, followed by losses in the ability to maintain employment, to plan and execute familiar tasks, and to reason and exercise judgment. Communication ability, mood, and personality may also be affected. Most people who have AD die within eight years of their diagnosis, although that interval may be as short as one year or as long as 20 years. AD is the fourth leading cause of death in adults after heart disease, cancer, and stroke.

Between two and four million Americans have AD; that number is expected to grow to as many as 14 million by the middle of the 21st century as the population as a whole ages. While a small number of people in their 40s and 50s develop the disease (called early-onset AD), AD predominantly affects the elderly. AD affects about 3% of all people between ages 65 and 74, about 19% of those between 75 and 84, and about 47% of those over 85. Slightly more women than men are affected with AD, but this may be because women tend to live longer, and so there is a higher proportion of women in the most affected age groups.

The costs for caring for a person with AD is considerable. The annual cost of caring for one AD patient in 1998 was estimated as about $18, 400 for a patient with mild AD, $30, 100 for a patient with moderate AD, and $36, 100 for a patient with severe AD. The annual direct and indirect costs of caring for AD patients in the United States was estimated to be as much as $100 billion. Slightly more than half of AD patients are cared for at home, while the remainder are cared for in a variety of health care institutions.

— Judith Sims

A disease marked by the loss of cognitive ability, generally over a period of 10 to 15 years, and associated with the development of abnormal tissues and protein deposits in the cerebral cortex.

[After Alois Alzheimer (1864-1915), German neurologist.]

Definition

Alzheimer disease is a neurological disorder characterized by slow, progressive memory loss due to a gradual loss of brain cells. Alzheimer disease significantly affects cognitive (thought) capabilities and, eventually, affected individuals become incapacitated. Alzheimer-related issues can cause emotional and financial upheaval for both the individuals with the disease and their families. Alzheimer disease is the most common form of dementia (loss of intellectual function) and, according to the National Institutes of Health (NIH), it is the fourth leading cause of death in adults.

Description

The condition was first described in 1906 by Alois Alzheimer, a German physician. Alzheimer characterized two abnormal structures in the brain of a woman with dementia that are now considered the hallmarks of the disease: amyloid plaques and neurofibrillary tangles. The nature of Alzheimer disease is progressive. Initially, dementia is manifested by barely noticeable memory deficits. Eventually, the memory loss becomes more severe until it is incapacitating. Other symptoms such as confusion, the inability to articulate words correctly, and hallucinations occur with varying degrees. Emotional problems such as easy agitation, poor judgment, and feelings of withdrawal are also common in the early stages. Affected individuals are also likely to develop seizures, hypertonicity (increased muscle movements), and incontinence. Without treatment or supervision, death often results from malnutrition or pneumonia. From the initial symptoms, disease progression can last up to 25 years, although typically the duration ranges from eight to 10 years.

Demographics

Dementia is thought to affect between 25–50% of individuals 85 years or older. The risk of developing Alzheimer disease increases with age and is independent of sex or geographical location (although there are environmental toxic agents that can impair various cognitive functions, including memory loss). A genetic association has been found for higher risk of developing Alzheimer disease in individuals with mutations in a particular gene who are also African American or Caribbean Hispanics. This association is greatest in individuals with a positive family history of dementia.

Approximately 10% of people 65 years or older are at risk for developing significant memory loss. More than half of these individuals (5% of all individuals 65 years or older) have Alzheimer disease. Approximately four in 10,000 individuals between the ages of 40 and 60 are at risk for having Alzheimer disease.

Causes and symptoms

Although there are several known causes of Alzheimer disease, about 75% of cases are sporadic and occur without a clear cause; this percentage represents people without a family history of the disorder. Scientists assume that these cases are due to a combination of unknown genetic predisposing factors and environmental exposures. Although various narcotics, therapeutic drugs, viruses, and toxins have been implicated in the etiology of the disease, there is currently no proof that they can cause Alzheimer disease.

Genetic basis for Alzheimer disease

Of all persons with Alzheimer disease, up to 25% of cases are thought to be part of a familial-based inheritance pattern and therefore are only determined based on family history or genetic test results. In general, these forms of Alzheimer disease are inherited as an autosomal dominant disorder, meaning that affected individuals have a 50% chance of passing on the mutated gene to their offspring in each pregnancy. There is a late-onset familial form (AD2), three early-onset familial forms (AD1, AD3, AD4), and a form of Alzheimer disease associated with Down syndrome.

Down syndrome and Alzheimer disease

Less than 1% of all cases of Alzheimer disease are due to a chromosomal defect called trisomy 21 (also known as Down syndrome). This occurs when there are three copies of genes found on chromosome 21, usually due to a person having an extra chromosome 21. These individuals usually develop Alzheimer disease after the age of 40. The APP gene, which encodes the amyloid precursor protein and is implicated in the pathogenesis of Alzheimer disease, is localized to chromosome 21; it is felt that people with Down syndrome overproduce this protein, resulting in its accumulation in the brain. The excess protein is thought to cause the disease.

Early-onset familial Alzheimer disease

A low percentage (2%) of Alzheimer cases results from a familial form of the disease in which there is an early onset of symptoms (AD1, AD3, and AD4), usually occurring before the age of 60. Age of onset usually occurs around 40–50 years, but can occur as early as 30 years. The majority of these persons have family members that are also affected. The clinical manifestations are similar to the adult-onset form, with loss of memory and cognitive ability. In this form of Alzheimer disease, there are several chromosomal locations of genes implicated in causing the disease.

AD1 accounts for approximately 10–15% of earlyonset Alzheimer disease and involves a protein called presenilin 1 that has a mutation in the gene that encodes it called PSEN1, which is found on chromosome 14. AD3 accounts for 20–70% of the early-onset familial form and is caused by mutations in APP found on chromosome 21, which encodes a protein called amyloid beta A4. AD4 is extremely rare and is caused by mutations in PSEN2, localized to chromosome 1, and encodes a protein called presenilin 2.

Late-onset familial Alzheimer disease

The late-onset familial form of Alzheimer disease (AD2) accounts for approximately 15–25% of all cases. These familial cases are seemingly indistinguishable from sporadic cases when observed clinically, but can be recognized based on molecular genetic testing. However, there is no clear chromosomal location for a gene directly responsible for the disease. Therefore, this complex type may involve many susceptibility genes. These familial cases are most likely due to multiple genes that make these individuals susceptible to developing the disease. For example, the APOE e4 gene on chromosome 19 associated with late-onset Alzheimer disease reduces the age in which symptoms develop by an unknown mechanism. There are many other candidate genes that are thought to modify Alzheimer disease risks and these genes, with various chromosomal locations, have been linked to the disease in different families.

Development (pathogenesis) of Alzheimer disease

Although scientists know how brain cells of persons with Alzheimer disease are affected, and additionally understand some of the genetic explanations of the disease, the precise cause of Alzheimer disease is still unclear. For example, it is known that accumulations of clumps of proteins called amyloid plaques outside brain cells and accumulation of altered proteins inside the cells called neurofibrillary tangles are characteristic of Alzheimer disease; however, it is unclear how these accumulated proteins cause brain cells to die.

According to the Alzheimer's Disease and Related Disorders Association, Inc., there are seven stages that characterize the disease:

• Stage 1: No decline in function is yet noted. This group includes individuals who may carry predictive gene mutations but have no symptoms, or those who will be affected by other unknown mechanisms.
• Stage 2: Normal function in general, although the person is aware of a subtle cognitive decline.
• Stage 3: Early Alzheimer disease. Persons experience difficulty in performing complex tasks that require cognitive skills.
• Stage 4: Mild Alzheimer disease. Persons require assistance with common tasks such as paying bills and balancing a checkbook.
• Stage 5: Moderate Alzheimer disease. Persons require assistance in making personal everyday decisions such as choosing appropriate clothing for the weather or ordering from a menu.
• Stage 6: Moderately severe Alzheimer disease. Persons require assistance dressing, bathing, and using the toilet. Urinary and bowel incontinence may be present.
• Stage 7: Severe Alzheimer disease. The vocabulary shrinks to only a few words; then little or no verbal communication is heard. The ability to walk is lost, followed by an inability to maintain a sitting posture in a chair. Eventually, the person experiences profound lack of purposeful muscle control, is totally dependent for care, and cannot smile or hold up his or her head.

Diagnosis

Alzheimer disease is diagnosed clinically by a physician, postmortem by a histopathologist (a scientist who studies diseased tissues by their various staining patterns), or genetically by identifying mutations in genes associated with the disease.

The gold standard for diagnosis of Alzheimer disease is through autopsy examination by an experienced pathologist. Detection of amyloid plaques in the brain by histopathology is the most conclusive diagnostic tool. This is performed using antibodies that bind to the particular amyloid proteins and can be visualized by microscopic evaluation, as the antibodies are tagged with a fluorescent or colorimetric molecule. A positive result would involve a significantly greater number of plaques compared to agematched controls. Other brain defects that characterize the disease, such as abnormal nerve cell configurations called intraneuronal neurofibrillary tangles, can also be detected by histopathology by the same methods. A clinical diagnosis by a physician accounts for 80–90% of patients diagnosed with Alzheimer disease.

Clinical diagnosis

A physician can use a number of different tests to assess memory skills, and, combined with any observed changes in the individual's behavior, they can help make a diagnosis of Alzheimer disease. Other tests that are important in diagnosing the disorder can involve laboratory tests that require blood and urine or imaging studies of the brain. By using neuroimaging studies such as magnetic resonance imaging (MRI) scans, physicians have found that patients with Alzheimer disease often have diffuse atrophy (weakening or decrease in size) in a specific area of the brain called the cerebrum.

Genetic diagnosis

It has been shown that there is a significant association of a specific gene called APOE e4 with the development the early-onset form of the disease. There are three different types of Alzheimer disease that have been shown to be caused by mutations in three distinct genes known as APP, PSEN1, and PSEN2. However, determining the genotype (whether a patient carries this associated mutation) is not entirely conclusive. Currently, although APOE e4 mutation analysis can help in diagnosing a patient suspected of having Alzheimer disease, it is not used for predictive testing of these individuals.

Biochemical markers

Although there are no tests to definitively diagnose Alzheimer disease, there are useful biochemical markers that can help distinguish Alzheimer disease from other disorders that involve dementia, including dementia caused by vascular disorders, drugs, or thyroid disease. Fluid that is found in the brain and spinal cord called cerebrospinal fluid can be tested for levels of two proteins, Tau and A[.beta]42, in patients that develop symptoms of dementia. A[.beta]42 accumulation in the brain is associated with reduced levels in the cerebrospinal fluid. Accumulation of the Tau protein in the brain is associated with Alzheimer disease. Therefore, increased Tau protein levels and decreased A[.beta]42 in the cerebrospinal fluid can pinpoint which persons have Alzheimer disease, regardless of the cause or the age of onset.

The score for these tests is numerical and relies heavily on a reference range determined by a patient's age, sex, and the type of equipment used to perform the test. A positive result will only indicate that a patient is at high risk of having Alzheimer disease and requires further analysis for an accurate diagnosis. This test has yet to be widely performed and is, therefore, only available in certain reference laboratories.

Treatment team

Initially, a physician usually recommends counseling by a psychologist or a support group experienced with this disease. After the diagnosis, visits to the physician focus on treating mild behavioral changes such as depression. Eventually, treatment requires 24-hour supervision and nursing care. The caretakers are mostly nurses or professionals who are part of various assisted-living programs.

Treatment

Pharmacological treatment

Treatment of Alzheimer disease is mainly palliative (given for comfort) and focuses on mitigating symptoms. Each symptom is treated based on its severity and the other symptoms that are affecting the individual. Most affected individuals will eventually need professional care in assisted living or nursing homes. They require constant supervision as memory loss becomes incapacitating. There are several pharmacological interventions and treatment regimens that are suggested. Patients who have depression are treated with antidepressants. Tacrine is often prescribed to help with some of the behavioral problems and provides modest cognitive benefits in a small percentage of patients. Aricept, Galantamine, and Exelon are more recent drugs used for a similar purpose, and are not believed to cause liver toxicity; the liver must be monitored in those taking Tacrine. Non-steroidal anti-inflammatory drugs (NSAIDs) are currently being investigated for their use in treating patients with Alzheimer disease.

Coping with the disorder

There are strategies to cope with this disorder and these should be considered in the beginning stages of the disease. Coping mechanisms depend on whether there are family members available for support. If an individual is without family members, relying on community support through neighbors or volunteers of Alzheimer disease organizations will be necessary.

Many precautions can be made early on to avoid difficult or life-threatening situations later, while maintaining everyday activities in the home environment. Dealing with a person with Alzheimer disease with patience is important. Daily tasks should be performed when the person with Alzheimer disease feels best. Informing neighbors of the person's condition is an important first step. Arranging for assistance, depending on the stage of the disorder, will become necessary. As the ability to drive may be compromised fairly early in the disorder, transportation may need to be arranged. There are local chapters of the Alzheimer's Association that offer help with transportation requirements.

In the early period of the disease when memory loss is minimal, it is helpful for family and friends to interact with the affected person, reminding him or her to take medication, eat, keep appointments, and so forth. Family and friends can help sustain the Alzheimer patient's daily living activities. Keeping records is also helpful, particularly if several people are overseeing the patient's care. Additionally, organizing the household so that it is easy to find important items is recommended.

Other helpful coping mechanisms include posting signs to remind patients of important phone numbers, to turn off appliances, and to lock doors. It is important that all electrical cords and appliances are arranged to minimize distraction, and to prevent danger of falling or misuse. Assistance in handling finances is usually necessary. Providing an extra house key for neighbors and setting up a schedule to check on persons with Alzheimer disease is very helpful for both the patient and the family. By utilizing these and other family, neighborhood, and community resources, many people with early Alzheimer disease are able to maintain a successful lifestyle in their home environment for months or years.

Recovery and rehabilitation

For a person with Alzheimer disease, emphasis is placed on maintaining cognitive and physical function for as long as possible. Currently, there is no cure for Alzheimer and, once the symptoms develop, patients do not recover. Instead, they progressively worsen, usually over a period of years. This has many psychosocial and financial ramifications for the patient and the patient's caretakers. Social service workers can help families plan for long-term care, as persons with Alzheimer disease most often eventually require 24-hour assistance with feeding, toileting, bathing, personal safety, and social interaction. Taking care of patients in the later stages can be financially and psychologically draining. Various support systems are available through community mental health centers and national support organizations.

Clinical trials

There are currently many clinical trials for the treatment or prevention of Alzheimer disease sponsored by the National Institutes of Health (NIH). Large multi-center clinical trials such as a Phase III clinical trail are aimed at determining whether anti-inflammatory drugs delay agerelated cognitive decline. (Contact information: UCLA Neuropsychiatric Institute, Los Angeles, California, 90024. Recruiter: Andrea Kaplan, (310) 825-0545 or her email: akaplan@mednet.ucla.edu.) A Phase III clinical trial is also organized to test the drug Risperidone for the treatment of agitated behavior in Alzheimer's patients. (Contact information: Palo Alto Veterans Administration Health Care System, Menlo Park, California, 94025. Recruiter: Erin L. Cassidy, PhD, (650) 493-5000, ext.27013 or her email: ecassidy@stanford.edu.)

Other trials include:

• A study on Valproate to prevent cognitive and behavioral symptoms in patients. Contact information: Laura Jakimovich, RN, MS, (585) 760-6578 or her email: laura_jakimovich@urmc.rochester.edu.
• The drug Simvastatin, a cholesterol-lowering medication, is being studied to learn if it slows the progression of Alzheimer disease. Contact information: Stanford University, Palo Alto, California, 94304. Recruiter: Lisa M. Kinoshita, PhD, (650) 493-0571 or her email: lisakino@stanford.edu.
• A study of the efficacy and dose of the drug NS 2330 to improve cognition. Contact information: Peter Glassman, MD, PhD, (800) 344-4095, ext. 4776 or his email: pglassma@rdg.boehringer-ingelheim.com.
• A study of investigational medications for the treatment of Alzheimer patients. Contact information: Eli Lilly and Company, (877) 285-4559.

There are also many other studies that are investigating various other pharmacological agents such as vitamin E and other currently available drugs.

Prognosis

There is considerable variability in the rate of Alzheimer disease progression. The Alzheimer Disease Association claims that the time from the onset of clinical symptoms to death can range from three to 20 years, with an average duration of eight years. There are probably many environmental and genetic factors that play a role in the progression of the disease. The accumulation of damage and loss of brain cells eventually results in the failure of many different organ systems in the body. According to the National Institute of Neurological Disorders and Stroke, the most common cause of death is due to infection.

Special concerns

Alzheimer disease should be distinguished from other forms of dementia. In some cases, depression can result in dementia-like symptoms. Other examples include chronic drug use, chronic infections of the central nervous system, thyroid disease, and vitamin deficiencies. These causes of dementia can often be treated. It is, therefore, important to obtain an accurate diagnosis to avoid complications associated with the inappropriate treatment and long-term care of these patients. There are also several genetically based syndromes in which dementia plays a role.

Genetic counseling

Genetic counseling is important for family members biologically related to patients with Alzheimer disease because each first-degree relative has as much as a 20% lifetime risk of also being affected. The risk to immediate relatives increases as more family members develop the disease. In the early-onset form of the disease, the inheritance pattern is thought to be autosomal dominant. This means that a carrier (who will eventually be affected) has a 50% chance of passing on the mutated gene to his or her offspring.

The general consensus in the scientific and medical community is to not test children or adolescents in the absence of symptoms for adult-onset disorders. There are many problems associated with predictive testing of asymptomatic individuals who are not yet adults. Children who undergo predictive testing lose the choice later in life (when they are capable of understanding the full ramifications of the disease) to know or not to know this information. It is, therefore, an important consideration that involves ethical and psychological implications.

Resources

BOOKS

Bird, T. D. "Memory Loss and Dementia." In Harrison's Principles of Internal Medicine, 15th ed. Edited by A. S. Franci, E. Daunwald, and K. J. Isrelbacher. New York: McGraw Hill, 2001.

Castleman, Michael, et al. There's Still a Person in There: The Complete Guide to Treating and Coping with Alzheimer's. New York: Perigee Books, 2000.

Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day: A Family Guide to Caring for Persons with Alzheimer Disease, Related Dementing Illnesses, and Memory Loss in Later Life. New York: Warner Books, 2001.

PERIODICALS

Campion, D., et al. "Early-onset Autosomal Dominant Alzheimer Disease: Prevalence, Genetic Heterogeneity, and Mutation Spectrum." Am J Hum Genet 65 (1999): 664–70.

Green, R.C. "Risk Assessment for Alzheimer's Disease with Genetic Susceptibility Testing: Has the Moment Arrived?" Alzheimer's Care Quarterly (2002): 3,208–14.

Rogan, S., and C. F. Lippa. "Alzheimer's Disease and Other Dementias: A Review." Am J Alzheimers Dis Other Demen (2002) 17: 11–7.

Romas, S. N., et al. "Familial Alzheimer Disease among Caribbean Hispanics: A Reexamination of Its Association with APOE." Arch Neurol (2002) 59: 87–91.

Rosenberg, R. N. "The Molecular and Genetic Basis of AD: The End of the Beginning: The 2000 Wartenberg Lecture." Neurology 54 (2000): 2045–54.

OTHER

ADEAR Alzheimer Disease Education and Referral Center. National Institute on Aging about Alzheimer's Disease—General Information. February 10, 2004 (March 30, 2004). http://www.alzheimers.org/generalinfo.htm.

National Institutes of Health. Alzheimer's Disease. February 10, 2004 (March 30, 2004). http://health.nih.gov/result.asp?disease_id=28.

National Library of Medicine. Alzheimer's Disease. MED-LINE plus Health Information. February 10, 2004 (March 30, 2004). http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html.

ORGANIZATIONS

Alzheimer's Association. 919 North Michigan Avenue, Suite 1000, Chicago, IL 60611-1676. (312) 335-8700 or (800) 272-3900; Fax: (312) 335-1110. info@alz.org. http://www.alz.org.

Alzheimer's Education and Referral Center. PO Box 8250, Silver Springs, MD 20907-8250. (800) 438-4380. adear@alzheimers.org. http://www.alzheimers.org.

National Institute on Aging. Building 31, Room 5C27, 31 Center Drive, MSC 2292, Bethesda, MD 20892. (301) 496-1752. http://www.nia.nih.gov.

Bryan Richard Cobb, PhD

A disease of the nervous system characterized by a progressive dementia that leads to profound impairment in cognition and behavior. Dementia occurs in a number of brain diseases where the impairment in cognitive abilities represents a decline from prior levels of function and interferes with the ability to perform routine daily activities (for example, balancing a checkbook or remembering appointments). Alzheimer's disease is the most common form of dementia, affecting 5% of individuals over age 65. The onset of the dementia typically occurs in middle to late life, and the prevalence of the illness increases with advancing age to include 25–35% of individuals over age 85. See also Aging.

Memory loss, including difficulty in remembering recent events and learning new information, is typically the earliest clinical feature of Alzheimer's disease. As the illness progresses, memory of remote events and overlearned information (for example, date and place of birth) declines together with other cognitive abilities. In the later stages of Alzheimer's disease, there is increasing loss of cognitive function to the point where the individual is bedridden and requires full-time assistance with basic living skills (for example, eating and bathing). Behavioral disturbances that can accompany Alzheimer's disease include agitation, aggression, depressive mood, sleep disorder, and anxiety. See also Memory.

The major neuropathological features of Alzheimer's disease include the presence of senile plaques, neurofibrillary tangles, and neuronal cell loss. Although the regional distribution of brain pathology varies among individuals, the areas commonly affected include the association cortical and limbic regions.

Deficits in cholinergic, serotonergic, noradrenergic, and peptidergic (for example, somatostatin) neurotransmitters have been demonstrated. Dysfunction of the cholinergic neurotransmitter system has been specifically implicated in the early occurrence of memory impairment in Alzheimer's disease, and it has been a target in the development of potential therapeutic agents. See also Acetylcholine; Neurobiology; Noradrenergic system.

A definite diagnosis of Alzheimer's disease is made only by direct examination of brain tissue obtained at autopsy or by biopsy to determine the presence of senile plaques and neurofibrillary tangles. A clinical evaluation, however, can provide a correct diagnosis in more than 80% of cases. The clinical diagnosis of Alzheimer's disease requires a thorough evaluation to exclude all other medical, neurological, and psychiatric causes of the observed decline in memory and other cognitive abilities.

Although the cause of Alzheimer's disease is unknown, a number of factors that increase the risk of developing this form of dementia have been identified. Age is the most prominent risk factor, with the prevalence of the illness increasing twofold for each decade of life after age 60. Research in molecular genetics has shown that Alzheimer's disease is etiologically heterogeneous. Gene mutations on several different chromosomes are associated with familial inherited forms of Alzheimer's disease.

A major strategy for the treatment of Alzheimer's disease has focused on the relation between memory impairment and dysfunction of the acetylcholine neurotransmitter system. Other treatment strategies to delay or diminish the progression of Alzheimer's disease are being explored. Behavioral and pharmacological interventions are also available to treat the specific behavioral disturbances that can occur in Alzheimer's disease.

Alzheimer's disease is a mysterious, progressive degeneration of the brain that shares some of the characteristics of dementia: memory disorders, changes in personality, deterioration in personal care, impaired reasoning ability, and disorientation. It is the fourth biggest killer in the developed world after heart disease, cancer, and stroke. There are millions of sufferers worldwide. The disease can occur at any age but it is more common among the elderly. Unlike some other forms of secondary dementia, Alzheimer's disease is generally regarded as incurable.

Several theories have been proposed to explain the development of the disease. One theory is based on the observation that high concentrations of aluminium may accumulate in the brain. Several groups of research workers have suggested that aluminium taken in the diet over a long period of time may contribute to the development of the disease, but this suggestion has not been generally accepted. Nevertheless, to be on the safe side, aluminium utensils should not be used for cooking acidic foods (e.g. fruits) because the mineral can be absorbed into the food. Some researchers suggest that the disease is due to an accumulation of a protein (amyloid protein) that congests the brain. In 1992, scientists in the United States showed that a genetic defect may stimulate the production of this protein in some sufferers. A recent theory suggests that Alzheimer's disease may be an inflammatory response which can be slowed or even stopped by aspirin-like drugs. These and other suggestions remain controversial. Despite billions of dollars being spent on research and many theories being postulated, no definitive cause is known. It is possible that there are several forms of the disease and that a number of genetic and environmental factors (including diet) contribute to their development.

(Alois Alzheimer, German neurologist, b. 1854), a presenile dementia characterized by confusion, memory failure, disorientation, restlessness, agnosia, hallucinosis, speech disturbances, and the inability to carry out purposeful movement. The disease usually begins in later middle life with slight defects in memory and behavior that become progressively more severe. Also known as primary progressive aphasia.

Definition

Alzheimer's disease (AD) is the most common form of dementia, a neurologic disease characterized by loss of mental ability severe enough to interfere with normal activities of daily living, lasting at least six months, and not present from birth. AD usually occurs in old age, and is marked by a decline in cognitive functions such as remembering, reasoning, and planning.

Description

A person with AD usually has a gradual decline in mental functions, often beginning with slight memory loss, followed by losses in the ability to maintain employment, to plan and execute familiar tasks of daily living, and to reason and exercise judgment. Communication ability, mood, and personality may also be affected. Most people who have AD die within eight years of their diagnosis, although that interval may be as short as one year or as long as 20 years. AD is the fourth leading cause of death in adults after heart disease, cancer, and stroke.

Between two and four million Americans have AD; that number is expected to grow to as many as 14 million by the middle of the twenty-first century as the population as a whole ages. While a small number of people in their 40s and 50s develop the disease (called early-onset AD), AD predominantly affects the elderly. AD affects about 3% of all people between ages 65 and 74, about 19% of those between 75 and 84, and about 47% of those over 85. Slightly more women than men are affected with AD, but this may be because women tend to live longer, leaving a higher proportion of women in the most affected age groups.

The cost of caring for a person with AD is considerable, and has been estimated at approximately $174,000 per person over the course of the disease. Most people with AD are cared for at home; the cost of extended nursing home care adds substantially to this estimate.

Causes & Symptoms

The cause or causes of AD are unknown. Some strong leads have been found through recent research, and these have also given some theoretical support to several new experimental treatments.

AD affects brain cells, mostly those in brain regions responsible for learning, reasoning, and memory. Autopsies of persons with AD show that these regions of the brain become clogged with two abnormal structures—neurofibrillary tangles and senile plaques. Neurofibrillary tangles are twisted masses of protein fibers inside nerve cells, or neurons. Senile plaques are composed of parts of neurons surrounding a group of brain proteins called beta-amyloid deposits. While it is not clear exactly how these structures cause problems, some researchers now believe that their formation is in fact responsible for the mental changes of AD, presumably by interfering with the normal communication between neurons in the brain.

What triggers the formation of plaques and tangles is unknown, although there are several possible candidates. Inflammation of the brain may play a role in their development, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) seems to reduce the risk of developing AD. Restriction of blood flow may be part of the problem, perhaps accounting for the beneficial effects of estrogen that increases blood flow in the brain, among its other effects. Highly reactive molecular fragments called free radicals damage cells of all kinds, especially brain cells, which have smaller supplies of protective antioxidants thought to protect against free radical damage.

Several genes have been implicated in AD, including the gene for amyloid precursor protein, or APP, responsible for producing amyloid. Mutations in this gene are linked to some cases of the relatively uncommon early-onset forms of AD. In 2001, scientists discovered a new rare mutation of the APP gene that might lead to new understanding on how the disease develops and new treatment possibilities. Other cases of early-onset AD are caused by mutations in the gene for another protein, called pre-senilin. AD eventually affects nearly everyone with Down syndrome, caused by an extra copy of chromosome 21. Other mutations on other chromosomes have been linked to other early-onset cases.

Potentially the most important genetic link was discovered in the early 1990s on chromosome 19. A gene on this chromosome, called apoE, codes for a protein involved in transporting lipids into neurons. ApoE occurs in at least three forms—apoE2, apoE3, and apoE4. Each person inherits one apoE from each parent, and therefore can either have one copy of two different forms, or two copies of one. Compared to those without ApoE4, people with one copy are about three times as likely to develop late-onset AD, and those with two copies are almost four times as likely to do so. Despite this important link, not everyone with apoE4 develops AD, and people without it can still have the disease. Why apoE4 increases the chances of developing AD is not known.

There are several risk factors that increase a person's likelihood of developing AD. The most significant one is age; older people develop AD at much higher rates than younger ones. Another risk factor is having a family history of AD, Down syndrome, or Parkinson's disease. People who have had head trauma or hypothyroidism may manifest the symptoms of AD more quickly. No other medical conditions have been linked to an increased risk for AD.

Many environmental factors have been suspected of contributing to AD, but population studies have not borne out these links. Among these have been pollutants in drinking water, aluminum from commercial products, and metal dental fillings. To date, none of these factors has been shown to cause AD or increase its likelihood. Further research may yet turn up links to other environmental culprits, although no firm candidates have been identified.

The symptoms of AD begin gradually, usually with short-term memory loss. Occasional memory lapses are of course common to everyone, and do not by themselves signify any change in cognitive function. The person with AD may begin with only the routine sort of memory lapse—forgetting where the car keys are—but progress to more profound or disturbing losses, such as forgetting that he or she can even drive a car. Becoming lost or disoriented on a walk around the neighborhood becomes more likely as the disease progresses. A person with AD may forget the names of family members, or forget what was said at the beginning of a sentence by the time he hears the end.

As AD progresses, other symptoms appear, including inability to perform routine tasks, loss of judgment, and personality or behavior changes. Some patients have trouble sleeping and may suffer from confusion or agitation in the evening ("sunsetting"). In some cases, people with AD repeat the same ideas, movements, words, or thoughts, a behavior known as perseveration. Some patients may exhibit inappropriate sexual behaviors. In the final stages of the disease, people may have severe problems with eating, communicating, and controlling their bladder and bowel functions.

The Alzheimer's Association has developed a list of 10 warning signs of AD. A person with several of these symptoms should see a physician for a thorough evaluation:

• memory loss that affects job skills
• difficulty performing familiar tasks
• problems with language
• disorientation of time and place
• poor or decreased judgment
• problems with abstract thinking
• misplacing things
• changes in mood or behavior
• changes in personality
• loss of initiative

Other types of dementing illnesses, including some that are reversible, can cause similar symptoms. It is important for the person with these symptoms to be evaluated by a professional who can weigh the possibility that his or her symptoms may have another cause. Approximately 20% of those originally suspected of having AD turn out to have some other disorder; about half of these cases are treatable.

Diagnosis

Diagnosis of AD is complex, and may require office visits to several different specialists over several months before a diagnosis can be made. While a confident provisional diagnosis may be made in most cases after thorough testing, AD cannot be definitively diagnosed until autopsy examination of the brain for senile plaques and neurofibrillary tangles.

The diagnosis of AD begins with a thorough physical exam and complete medical history. Except in the disease's earliest stages, accurate history from family members or caregivers is essential. Since there are both prescription and over-the-counter drugs that can cause the same mental changes as AD, a careful review of the patient's drug, medicine, and alcohol use is important. AD-like symptoms can also be provoked by other medical conditions, including tumors, infection, and dementia caused by mild strokes (multi-infarct dementia). These possibilities must be ruled out as well through appropriate blood and urine tests, brain magnetic resonance imaging (MRI) or computed tomography scans (CT), tests of the brain's electrical activity (electroencephalographs or EEGs), or other tests.

In 2001, researchers demonstrated that postitron emission tomography (PET) scans could help predict who might develop memory impairment. Although PET scanning is a relatively new and expensive technology, it is becoming more readily available. Several types of oral and written tests are used to aid in the AD diagnosis and to follow its progression, including tests of mental status, functional abilities, memory, and concentration. Still, the neurologic exam is normal in most patients in early stages.

One of the most important parts of the diagnostic process is to evaluate the patient for depression and delirium, since each of these can be present with AD, or may be mistaken for it. (Delirium involves a decreased consciousness or awareness of one's environment.) Depression and memory loss are both common in the elderly, and the combination of the two can often be mistaken for AD. Depression can be treated with drugs, although some antidepressants can worsen dementia if it is present, further complicating both diagnosis and treatment.

A genetic test for the ApoE4 gene is available, but is not used for diagnosis, because possessing even two copies does not ensure that a person will develop AD.

Treatment

The mainstay of treatment for a person with AD continues to be the establishment of daily routines and good nursing care, providing both physical and emotional support for the patient. Modifications of the home to increase safety and security are often necessary. The caregiver also needs support. Regular medical care by a practitioner with a non-defeatist attitude toward AD is important so that illnesses can be diagnosed and treated properly.

People with AD are also often depressed or anxious, and may suffer from sleeplessness, poor nutrition, and general poor health. Each of these conditions is treatable to some degree. It is important for the person with AD to eat well and continue to exercise. Professional advice from a nutritionist may be useful to provide healthy, easy-to-prepare meals. Finger foods may be preferable to those requiring utensils to be eaten. Regular exercise (supervised for safety if necessary) promotes overall health. A calm, structured environment with simple tools that support orientation (like calendars and clocks) may reduce anxiety and increase safety.

Diet and Supplements

DIET. The incidence of AD is lower in countries whose citizens have a diet that is lower in fats and calories. There have been a few reports that a diet rich with fish improves mental function in patients with AD or dementia. AD patients treated with essential fatty acids showed greater improvement in mood and mental function than patients on placebo. Because of its disease-preventing properties, red wine in moderation may be beneficial to AD patients.

VITAMIN E. Studies have shown that AD patients have lower blood levels of vitamin E than age matched control subjects. A large, two year study of moderately affected AD patients found that taking 2,000 IU of vitamin E daily significantly delayed disease progression as compared to patients taking placebo. This delay was equivalent to that seen with patients taking the drug selegiline. Vitamin E is also thought to delay AD onset. High levels of vitamin E put the patient at higher risk for bleeding disorders.

THIAMINE (VITAMIN B₁). Several small studies to determine the effectiveness of thiamine (vitamin B₁) on AD have been carried out. Daily doses of 3 g for two to three months have improved mental function and AD assessment scores. Other studies have shown that thiamine had no effect on AD patients. Side effects include nausea and indigestion.

COBALAMIN (VITAMIN B₁₂). Although results are conflicting, some studies have found that AD patients have lower levels of cobalamin (vitamin B₁₂) than others. Some studies have shown that cobalamin supplementation improves memory and mental function in AD patients whereas other studies have found no effect.

ACETYL-L-CARNITINE. Acetyl-L-carnitine is similar in structure to the neurotransmitter acetyl-choline. Studies have shown that 2 g or 3 g of acetyl-L-carnitine daily slows the progression of AD, especially in patients who developed the disease before age 66. Patients who developed disease after 66 years of age worsened with treatment. Side effects include increased appetite, body odor, and rash.

DHEA. DHEA (dehydroepiandrosterone) is a steroid hormone. There may be a link between decreasing levels of DHEA in the elderly and development of AD. Studies on the effect, if any, of DHEA on AD are needed. Side effects include acne, hair growth, irritability, insomnia, headache, and menstrual irregularity.

MELATONIN. Melatonin is a hormone that helps to regulate mood and sleep cycles. The effect of melatonin treatment on AD is unknown but it may be beneficial in regulating sleep cycles. The usual dose is 3 mg taken one to two hours before bedtime. Side effects are drowsiness, confusion, headache, decreased sex drive, and decreased body temperature.

Herbals and Chinese Medicine

GINKGO. Ginkgo, the extract from the Ginkgo biloba tree is the most commonly used herbal treatment for AD. Several studies have been performed to test the effectiveness of ginkgo for treating AD. The dose range studied were 120–160 mg daily divided into three doses. Although results have been mixed, the evidence suggests that ginkgo is an effective treatment for patients with mild to moderate AD. Side effects are not common but include headache, allergic skin reaction, and gastrointestinal disturbance. Ginkgo also decreases blood coagulation. Individuals with coagulation or platelet disorders should use extreme caution and consult a physician before using ginkgo.

PHYTOESTROGENS. Phytoestrogens may be beneficial in the treatment of AD based on the findings that women with AD who are on hormone replacement therapy have improved mental function and mood. Estrogens may prevent AD, therefore, phytoestrogens may have the same effect. Phytoestrogens are mainly found in soy products.

CLUBMOSS. Huperzine A is a compound isolated from clubmoss (Huperzia serrata). Studies have shown that taking 0.1–0.4 mg daily improves mental function in AD patients. Side effects are nausea, muscle cramps, vomiting, and diarrhea.

Therapies

Music therapy has been shown to be effective in treating the depression, agitation, wandering, feelings of isolation, and memory loss associated with AD. AD patients have benefited from listening to favorite music or participating in musical activity. Participation in a music therapy group was more effective at improving memory and decreasing agitation than being part of a verbal (talking) group.

A wide variety of other therapies have been beneficial in the treatment of the psychologic symptoms of AD. These include:

• Light therapy in the evening to improve sleep cycle disturbances.
• Supportive therapy through touch, compliments, and displays of affection.
• Sensory stimulation through massage and aromatherapy.
• Socio-environmental therapies use activities fitted to previous interests, favorite foods, and pleasant surroundings.
• Cognitive therapy to reduce negative perceptions and learn coping strategies.
• Insight-oriented psychotherapy addresses the patient's awareness of his or her disease.
• Dance therapy.
• Validation therapy.
• Reminiscence therapy.
• Reality-oriented therapy.

Nursing Care and Safety

The nursing care required for a person with AD is easy to learn. Caregivers will usually need to spend increasing amounts of time grooming the patient as the disease progresses. The patient may require assisted feeding early on to make sure that he or she is taking in enough nutrients. Later on, as movement and swallowing become difficult, a feeding tube may be placed into the stomach through the abdominal wall. A feeding tube requires more attention, but is generally easy to care for if the patient is not resistant to its use. Incontinence becomes the most difficult problem to deal with at home, and is a principal reason for pursuing nursing home care. In the early stages, limiting fluid intake and increasing the frequency of toileting can help. Careful attention to hygiene is important to prevent skin irritation and infection from soiled clothing.

In all cases, a person diagnosed with AD should not be allowed to drive, because of the increased potential for accidents and the increased likelihood of wandering very far from home while disoriented. In the home, simple measures such as grab bars in the bathroom, bed rails on the bed, and easily negotiable passageways can greatly increase safety. Electrical appliances should be unplugged and put away when not in use. Matches, lighters, knives, or weapons should be stored safely out of reach. The hot water heater temperature may be set lower to prevent accidental scalding. A list of emergency numbers, including the poison control center and the hospital emergency room, should be posted by the phone.

Care for the Caregiver

Family members or others caring for a person with AD have an extremely difficult and stressful job that becomes harder as the disease progresses. It is common for caregivers to develop feelings of anger, resentment, guilt, and hopelessness, in addition to the sorrow they feel for their loved one and for themselves. Depression is an extremely common consequence. Becoming a member of an AD caregivers' support group can be one of the most important things a family member does, not only for him or herself, but for the person with AD as well. The location and contact numbers for AD caregiver support groups are available from the Alzheimer's Association; they may also be available through a local social service agency, the patient's physician, or pharmaceutical companies that manufacture the drugs used to treat AD. Medical treatment for depression may be an important adjunct to group support.

Outside Help, Nursing Homes, and Governmental Assistance

Most families eventually need outside help to relieve some of the burden of around-the-clock care for a person with AD. Personal care assistants, either volunteer or paid, may be available through local social service agencies. Adult daycare facilities are becoming increasingly common. Meal delivery, shopping assistance, or respite care may be available as well. Many families consider nursing home care when AD advances to the late-stage.

Several federal government programs may ease the cost of caring for a person with AD, including Social Security Disability, Medicare, and Supplemental Security Income. Each of these programs may provide some assistance for care, medication, or other costs, but none of them will pay for nursing home care indefinitely. Medicaid is a state-funded program that may provide for some or all of the cost of nursing home care, although there are important restrictions. Details of the benefits and eligibility requirements of these programs are available through the local Social Security or Medicaid office, or from local social service agencies.

Allopathic Treatment

The only two drugs approved for AD, tacrine hydrochloride (Cognex) and donepezil hydrochloride (Aricept), increase the brain levels of the neurotransmitter acetylcholine, thereby increasing the communication ability of the remaining neurons. These drugs can modestly increase cognition and improve the ability to perform normal activities of daily living. The most significant side effect of tacrine is an increase in the liver enzyme alanine aminotransferase (ALT). Patients taking tacrine must have a weekly blood test to monitor their ALT levels. Other frequent side effects include nausea, vomiting, diarrhea, abdominal pain, indigestion, and skin rash. Donepezil has two advantages over tacrine: fewer side effects and once daily dosing. Donepezil does not appear to affect liver enzymes and the frequency of abdominal side effects is lower.

Estrogen, the female sex hormone, is widely prescribed for post-menopausal women to prevent osteoporosis. Several preliminary studies have shown that women taking estrogen have lower rates of AD, and those who develop AD have a slower progression and less severe symptoms.

Preliminary studies have also suggested a reduced risk for developing AD in older people who regularly use nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen (Advil), and naproxen (Aleve), although not acetaminophen. A 2001 study reported that those subjects who used NSAIDs for at least two years were up to 80% less likely to develop Alzheimer's. Further study on the effects of NSAIDs on AD are underway.

Selegiline, a drug used in the treatment of Parkinson's disease, appears to slow the development of AD. Selegiline is thought to act as an antioxidant, preventing free radical damage. However, it also acts as a stimulant, making it difficult to determine whether the delay in onset of AD symptoms is due to protection from free radicals or to the general elevation of brain activity from the stimulant effect.

Psychiatric symptoms, such as depression, anxiety, hallucinations (seeing or hearing things that aren't there), and delusions (false beliefs) may be treated with drugs if necessary.

Expected Results

While Alzheimer's disease may not be the direct cause of death, the generally poorer health of a person with AD increases the risk of life-threatening infection, including pneumonia. In addition, other diseases common in old age (cancer, stroke, and heart disease) may lead to more severe consequences in a person with AD. On average, people with AD live eight years past their diagnosis, with a range from 1-20 years.

Prevention

There is currently no sure way to prevent Alzheimer's disease, though some of the drug treatments discussed above may eventually be proven to reduce the risk of developing the disease. The most likely current candidates are estrogen, phytoestrogens, NSAIDs, vitamin E, and selegiline. In 2001, researchers found preliminary indications that onest of Alzheimer's might be tied to cholesterol levels. Although results must be confirmed by other scientists, lowering cholesterol in the diet might help prevent onset of the disease.

Resources

Books

Bridges, Barbara J., Therapeutic Caregiving: A Practical Guide for Caregivers of Persons with Alzheimer's and Other Dementia Causing Diseases. BJB Publishing 16212 Bothell Way S.E., Suite F171 Mill Creek, Washington 98012-1219.

Carrier, Louise, and Henry Brodaty. "Mood and Behaviour Management." In Clinical Diagnosis and Management of Alzheimer's Disease. 2nd edition, edited by Serge Gauthier. London: Martin Dunitz, 1999.

Larkin, Marilynn. When Someone You Love Has Alzheimer's: What you must know, what you can do, what you should expect.. Dell, 1995.

Luskin, Frederic M., Ellen M. DiNucci, Kathryn A. Newell, and William L. Haskell. "Complementary/Alternative Therapies in Select Populations: Elderly Persons." In Complementary/Alternative Medicine: An Evidence Based Approach. Edited by John W. Spencer and Joseph J. Jacobs. St. Louis: Mosby, 1999

Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day. The John Hopkins University Press, 1995.

Periodicals

Gottlieb, Scott R."NSAIDs Can Lower Risk of Alzheimer's." British Medical Journal 323 no. 7324 (December 1, 2001):1269.

Mitka M."PET and Memory Impairment." JAMA, Journal of the American Medical Association 286 no. 16 (October 24, 2001):1961.

Ott, Brian R., and Norma J. Owens. "Complementary and Alternative Medicines for Alzheimer's Disease." Journal of Geriatric Psychiatry and Neurology 11 (1998):163-173.

"Alzheimer Chemical Engineers Suggest Alzheimer Onset Tied to Cholesterol." Pain and Central Nervous System Week (December 24, 2001):3.

Stephenson Joan. "Alzheimer Treatment Target?" JAMA, Journal of the American Medical Association 286 no. 14 (October 10, 2001):1704.

"Wiser Now." Better Directions. PO Box 35 Spencerville, MD 20868.(800) 999-0795.

Organizations

Alzheimer's Association. 919 North Michigan Ave., Suite 1000 Chicago, IL 60611. (800) 272-3900 (312) 335-8882. http://www.alz.org/.

National Institute of Aging, Alzheimer's Education, and Referral Center. (800) 438-4380.

Other

Alzheimer's Disease Books and Videotapes. http://www.alzheimersbooks.com

[Article by: Belinda Rowland; Teresa G. Odle]

Alzheimer's disease is a neurodegenerative disorder characterized by loss of memory along with other cognitive changes, including aphasia (language impairment), apraxia (difficulty carrying out motor activities despite intact motor function), and agnosia (difficulty recognizing or identifying objects despite intact sensory function). There is a significant impairment in social and occupational functioning, as well as a behavioral disturbance commonly occurring in the disorder that may include apathy, loss of interest in daily activities, delusions, hallucinations, preservation, disinhibition, and depression. The cognitive, functional, and behavioral components have different manifestations at different stages of the disease, and the course of the disease is characterized by gradual onset and continuing cognitive decline.

The functional change is generally hierarchical, beginning with changes in instrumental activities of daily living (using the telephone, shopping, food preparation, housekeeping, accessing transportation, taking medications, handling finances) and later affecting the basic activities of daily living (toiletting, feeding, dressing, grooming, physical ambulation, and bathing). The onset of the disorder is insidious, and the disease progresses over ten to twenty years. In the early stages the individual may require supervision or assistance for activities such as managing finances and shopping. In the later stages, 24-hour help may be required. Social skills are often preserved until the later stages, and individuals may be very impaired or be at significant risk before the disease is recognized.

Causes

The cause of Alzheimer's disease is not understood completely. Age is the biggest risk factor, but other risk factors may be involved, including a low level of education and significant head injury. A family history of the disease also increases the risk. With familial Alzheimer's the inheritance is autosomal dominant, and chromosomes 1, 14, 19, and 21 have been identified as important in the inheritance. It appears that individuals with the gene apolipoprotein E4 have an increased risk, while the genes apoE2 and apoE3 may have a protective function. ApoE status, however, is not considered a part of predictive testing and apoE4 is not considered a cause of the disease. The genetics of Alzheimer's disease suggest a heterogeneous disorder, and several other genes are being investigated.

Alzheimer's disease is the most common type of dementia in older people. Prevalence estimates of dementia in Canada suggest that 8 percent of all Canadians age 65 and over have some type of dementia. Of these, 5.1 percent have Alzheimer's disease. In the larger population, rate for Alzheimer's disease was 1 percent in the 65 to 74 age group and 26 percent in those over 85 years. For all types of dementia the rates were 2.4 percent and 34.5 percent respectively. These rates are comparable to those found in incidence studies conducted in New York.

Diagnosis and Treatment

The diagnosis of Alzheimer's disease is made by taking a history documenting the changes in capacity compared with previous abilities. It is usually necessary to obtain collateral information from a close relative or friend in order to ascertain changes, particularly in the early stages of the disorder. An individual's general medical and surgical histories also need to be reviewed, including neurological and psychiatric histories. A complete physical examination, including a neurological examination, is imperative, along with a mental status screening test and blood work. A computed tomographic scan of the head may be helpful in some cases, particularly in patients under sixty years of age, or when there is rapid unexplained decline in cognition or function, a duration of dementia of less than two years, recent and significant head trauma, unexplained neurologic symptoms such as new onset of severe headache or seizures, and in various other instances. Other radiologic evaluations may be done, as well as certain specialized evaluations not usually part of routine clinical practice, including functional MRI and proton emission tomography (PET).

Management of Alzheimer's disease includes attention to specific problems such as safety, driving capacity, medication compliance, managing finances, and nutrition. Assistance by family members, friends, and professional persons such as lawyers and accountants can be very helpful, as can access to support services such as adult day centers and local Alzheimer's support groups. Identifying and specifically treating depression, agitation, and sleeplessness with medication and environmental modification is also important.

Judicious use of certain drugs to treat various symptoms of the disease can be undertaken as appropriate. These often include cholinesterase inhibitors such as donepezil, revistigmin, and taccine. In addition, some individuals advocate up to 2000 IU of vitamin E per day, gingko biloba, and other compounds. These therapies tend to provide symptomatic treatment and potential stabilization of the disorder for a period of time. Future therapies may include biomedical engineering for beta amyloid protein and immunization.

A diagnosis of Alzheimer's disease can be confirmed only with a brain biopsy, or through microscopical study of the brain after death. The typical lesions found include neurofibrillary tangles, senile (amyloid) plaques, and neuritic plaques. The latter is composed of a central core of homogeneous material, primarily beta amyloid, and a reactive outer zone with fibrillary and cellular material. Tau protein is the main constituent of the paired helical filaments of the neurofibrillary tangles. Other constituents include ubiquitin, a widely distributed protein. Attempts to standardize neuropathological diagnosis of Alzheimer's disease have been undertaken by Zaben Khachaturian and by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD).

Diagnosis can be confusing because there are other disorders that cause dementia, including multiple strokes, Pick disease, Lewy body dementia, and disorders associated with other neurodegenerative diseases such as progressive palsy (PSP), Parkinson's disease, and Huntington's disease. Differential diagnosis is therefore an important consideration.

As with many diseases, a number of ethical and legal issues are raised when dealing with those afflicted with Alzheimer's disease. These issues revolve around questions of daily living, such as whether it is safe for an individual to drive, to continue to live at home, and to handle financial responsibilities; and around scientific questions, particularly how cognitively impaired persons can take part in research programs. Disclosing the diagnosis of Alzheimer's disease to family members and others also causes concerns. Disclosure of the diagnosis should include a discussion of prognosis, advance planning, treatment options, support groups, and future plans.

(SEE ALSO: AARP; Dementia; Geriatrics; Gerontology; National Institute on Aging)

Bibliography

Canadian Study of Health and Aging Working Group (1994). "The Canadian Study of Health and Aging: Risk Factors for Alzheimer's Disease in Canada." Neurology 44:2073–2080.

—— (1994). "Canadian Study of Health and Aging: Study Methods and Prevalence of Dementia." Canadian Medical Association Journal 150:899–912.

—— (2000). "The Incidence of Dementia in Canada." Neurology 55:66–73.

Folstein, M. F.; Folstein, S. E.; and McHugh, P. R. (1975). "Mini Mental State: A Practical Method for Grading the Cognitive State of Patients for the Clinician." Journal of Psychological Research 12:189–198.

Gauthier, S., ed. (1999). Clinical Management and Diagnosis of Alzheimer's Disease, 2nd edition. London: Martin Dunitz.

Khachaturian, Z. S. (1985). "Diagnosis of Alzheimer's Disease." Archives of Neurology 42:1097–1105.

Mayeux, R., and Sano, M. (1999). "Drug Therapy: Treatment of Alzheimer's Disease." New England Journal of Medicine 341:1670–1679.

Mirra, S. S. et al. (1991). "The Consortium to Establish a Registry for Alzheimer's Disease (CERAD): Standardization of the Neuropathologic Assessment of Alzheimer's Disease." Neurology 41:479–486.

Patterson, C. J. S. et al. (1999). "Management of Dementing Disorders: Conclusions from the Canadian Consensus Conference on Dementia." Canadian Medical Association Journal 160.

— B. LYNN BEATTIE

Alzheimer's disease (AD) is a diagnosis applied to a group of degenerative brain disorders with similar clinical and pathological characteristics. It is the most common cause of dementia, with onset of symptoms after the age of fifty-five years. It is recognized as a major public health concern in societies with an aging population. AD affects four million people in the United States. At least 90 percent of those affected are over sixty-five years of age. In 1998 direct health care costs were estimated to be $50 billion. Indirect costs, such as lost productivity and absences from work, were estimated to be $33 billion.

First Description of Ad

In 1907, Alois Alzheimer, a German physician from Bavaria, published the case of one of his patients. The patient, Mrs. Auguste D., at the age of fifty-one years developed an unfounded jealousy regarding her husband. This behavioral change was followed closely by a subtle and slow decline in other cognitive abilities, including memory, orientation to time and to physical location, language, and the ability to perform learned behaviors. All of her difficulties gradually progressed in severity. Within three years, the patient did not recognize her family or herself, could not maintain her self-care, and was institutionalized. She died a short four and a half years after her illness began. Her brain was removed at autopsy. Using a novel (at the time) silver stain to highlight changes in brain sections, Dr. Alzheimer viewed the tissue under his microscope. He described what are now the pathologic lesions of the disease that bears his name: loss of neurons, senile plaques found in the brain substance but outside of the neurons, and neurofibrillary tangles found inside neurons.

Dr. Alzheimer's patient had developed dementia. Dementia is an acquired and continuing loss of thinking abilities in three or more areas of cognition (which include memory, language, orientation, calculation, judgment, personality, and other functions) severe enough that the individual can no longer function independently at work or in society. There is no decrease in level of consciousness. Early in the illness, physical strength is maintained, though later the individual may "forget" how to perform certain physical functions, such as using tools or utensils, dressing, or performing personal hygiene activities. Onset of dementia may occur over days, months, or years. Its course may be static or progressive. Causes of dementia, other than AD, include other neurodegenerative disease, central nervous system infection, brain tumor, metabolic disease, vitamin deficiency, and cerebrovascular disease.

An Evolving Understanding of Dementia

Within three years of the publication of Dr. Alzheimer's first case, the term "Alzheimer's disease" was applied to patients who developed significant difficulty in memory and other areas of cognition at an age less than sixty-five years. Individuals who developed such symptoms later in life, generally after the age of sixty-five, were said to be suffering from senility, a process considered a normal part of aging. The phrase "hardening of the arteries," implying narrowing of arterial size with a reduction in blood flow to the brain, was used by physicians and by laypersons to designate the reason for senility. However, a causal relationship between arterial narrowing and senility had not been established scientifically.

Critical research reports were published in 1968 and 1970 providing evidence that senility and the disease Alzheimer described were similar both clinically and pathologically. Patients in each category developed similar and multiple cognitive deficits. Patients in each category developed plaques and tangles, and the majority of those diagnosed with senility did not have evidence of "hardening of the arteries." Over the next decade senile dementia, Alzheimer's type, would replace senility as the accepted common cause of late-life dementia.

In 1984, consensus criteria for a clinical diagnosis of AD were established. Cardinal features include the insidious onset of decline in at least two areas of cognition, gradual progression of severity in these spheres resulting in dementia, onset of symptoms between the ages of forty and ninety years (most often after age sixty-five), and absence of another medical condition that by itself could cause dementia. Pathological study of tissue after death should reveal the characteristic findings of senile plaques in age-associated numbers (numbers larger than expected for the individual's age) and of neurofibrillary tangles. Using these criteria, both Alzheimer's disease as a presenile disorder and senile dementia, Alzheimer type, are subsumed into the broader diagnosis, Alzheimer's disease.

Genetics of Alzheimer's Disease

There are three areas of evidence that indicate a genetic basis for AD. First, it occurs as a Mendelian, autosomal dominant disease of early onset (occurring before the age of sixty) in multiple families. However, the number of such families with autosomal dominant inheritance is small. Second, it is generally the case that if an individual has a first-degree relative (parent or sibling) with AD, he or she has a greater risk of developing the disease than a person with no affected first-degree relative. Finally, AD is more likely to occur in each of a pair of identical twins than it is to occur in a pair of fraternal twins.

Recognizing these observations, in the mid-1980s researchers initiated scientific efforts to identify genes of importance in the disease, using the then-emerging recombinant DNA technology. By 1995, three causative genes and one susceptibility gene had been identified: APP, PS1/2, and APOE.

App

In 1991, a British research group identified mutations in the APP gene that occurred only in patients with AD in very rare families. (Less than twenty such families have been reported in the medical literature.) The mutations were not found in family members who did not have AD. The APP gene codes for amyloid precursor protein, one of whose degradation products is a main constituent of the senile plaques of AD.

Ps1 and Ps2

In 1992, using linkage analysis of data from early-onset, autosomal-dominant families, researchers in Seattle, Washington; Jacksonville, Florida; and Antwerp, Belgium, almost simultaneously determined that a then-unknown gene for early-onset AD was located on chromosome 14. In 1995, a research scientist in Toronto, Canada, identified this gene as PS1, which codes for the protein called presenilin1. Individuals who have mutations in the gene consistently develop AD. Also in 1995, using comparative genomic techniques, the Seattle research group cited above identified the PS2 gene, which codes for the protein termed presenilin 2. Using data from a few large, genetically isolated families with early-and late-onset disease, they determined that mutations in the gene consistently occur only in patients with AD.

Table 1

APP, PS1, and PS2 are causative genes: When mutated, each causes AD. If a person has a mutated gene, he or she will develop the disease at about the same age as others who have the same mutation. The risk of developing the disease approaches 100 percent.

Apoe

In 1993 researchers in Durham, North Carolina, reported that one form (allele) of the APOE gene occurred more commonly in patients with late onset AD than was expected given its occurrence in the population as a whole. Numerous additional research groups corroborated the finding. The APOE gene occurs in three forms (alleles), determined by the DNA sequence. The three forms are termed APOEε2, APOEε3, and APOEε4, and they code for apolipoprotein E molecules differing from one another by only one or two amino acids. APOE is a susceptibility gene; it imparts an increased risk of disease occurrence but by itself does not cause the disease. The presence of the ε4 form (APOEε4) in either one or two copies in an individual increases the likelihood that the individual will develop AD. Occurrence may depend on other genetic factors or environmental factors or some combination from each category.

Additional families exist with early-onset, autosomal-dominant AD with no APP, PS1, or PS2 mutations. Such families provide evidence that there may be additional causative genes. Whole-genome-scan analyses reported in the late 1990s provide evidence of additional susceptibility genes on chromosomes 9, 10, and 12. The genes located on these chromosomes have yet to be identified.

Rationale for a Genetic Approach to Alzheimer's Disease

Alzheimer's disease, broadly defined, is a complex genetic disorder: Multiple causative and susceptibility genes acting singly or in concert produce similar symptoms and pathologic changes in patients. In each of its forms, it manifests age-dependent penetrance, meaning that the older an individual becomes, the more likely it is that he or she will develop the disease. Disease manifestations (such as age of onset or rate of progression) may be influenced by environmental exposures (alcohol use, head injury) or other health conditions (such as cerebrovascular disease). Identification of AD genes will lead to a better understanding of the cellular processes that cause dementia.

Currently, amyloid production from amyloid precursor protein is the focus of much research, although debate continues about its role. Amyloid production and deposition in the brain are affected by each of the four known AD genes. Decrease in amyloid production or increase in amyloid metabolism with a resulting decrease in deposition may result in delayed age of onset or slower progression of disease. Thus, alteration of amyloid processing of sufficient magnitude might result in disease prevention. Once process-altering treatments become available, knowing who is at risk for the disease will be important.

Genetic Testing and Alzheimer's Disease

DNA testing can be performed to determine whether an individual has a mutation in one of the causative genes and/or whether he or she carries one or two copies of the APOEε4 susceptibility gene. Whether to test and which test to perform will depend on three conditions: family history of dementia, age of onset of disease, and clinical status of the individual. If a person has dementia, the test result could be useful in determining that the cause of the dementia is a form of AD. If a person has no symptoms of dementia, an estimate of the individual's risk could be developed, using the test. In the case of such estimates, both the actual accuracy of the test and the tested individual's understanding of its accuracy are of concern. While the consensus is that presymptomatic testing for causative mutations may be performed with appropriate counseling, debate over the safety and utility of APOE testing for individuals who do not show symptoms of Alzheimer's is ongoing.

In 2001, there was no treatment that prevented, much less cured, AD. Information regarding the risk of developing AD is useful only in life planning activities (such as purchasing or offering health insurance coverage or long-term care insurance coverage, or choosing retirement age) or in family planning. An individual's ability to cope with either an increased or a decreased risk may vary. Misuse of the information resulting in insurance or employment discrimination is possible. Absence of a causative gene mutation or of an APOEε4 susceptibility gene in either symptomatic or presymptomatic disease does not preclude AD as the cause of dementia or mean that the individual has no risk of developing AD in later years.

Bibliography

Mace, Nancy L., and Peter V. Rabins, eds. The 36-Hour Day, 3rd ed. Baltimore: The Johns Hopkins University Press, 1999.

St. George-Hyslop, Peter H. "Piecing Together Alzheimer's." Scientific American (Dec. 2000): 76-83.

Terry, Robert D., et al., eds. Alzheimer Disease, 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins, 1999.

Internet Resources

"Ethical, Legal, and Social Issues." Human Genome Project, U.S. Department of Energy Office of Science. http://www.ornl.gov/TechResources/Human_Genome/home.html.

"Progress Report on Alzheimer's Disease, 1999." National Institute on Aging. Bethesda: National Institutes of Health, 1999. http://www.nih.gov/nia/.

—P. C. Gaskell Jr.

For more information on Alzheimer disease, visit Britannica.com.

Alzheimer'S Disease, the most common cause of dementia in the United States, is characterized by a slowly progressive mental deterioration. It is named for Dr. Alois Alzheimer, a German doctor who, in 1906, noticed unusual patterns in the brain of a woman who had died of a perplexing mental illness. Alzheimer's disease is not only a problem for those afflicted but is also of great consequence for their families and society; since 1980 it has been the subject of intensive medical research. The first symptom is usually loss of ability to remember new information. The abilities to speak, dress, and be oriented to time, along with loss of old memories ensue, and ultimately even loss of memory of one's own identity occurs. The onset is usually after age sixty-five, and the disease can progress over a period of just a few years to up to two decades. Alzheimer's disease is extremely common, with conservative estimates of 5 percent of the population over age sixty-five affected. The incidence rises with increasing age, so that at least 15 to 20 percent of all individuals over age eighty are afflicted.

Changes in mental abilities are associated with three neuropathological changes in the brain: the formation of abnormal tangles within nerve cells; the widespread deposition of a characteristic protein (amyloid); and the death of nerve cells important for communicating between one brain area and another. A small percentage of individuals with Alzheimer's have inherited one of several mutant genes, each of which appears to be able to cause the disease. One such cause of Alzheimer's disease is a mutation in the gene responsible for making the amyloid protein, which accumulates in the brain of patients with Alzheimer's disease as senile plaques. Another gene partly responsible for the disease (whose specific identity is still unknown) has been found to be located on chromosome 14. Yet another genetic influence on risk of developing Alzheimer's disease, probably present in half of all cases, is inheritance of the E4 allele of apolipoprotein E. Scientists are also studying education, diet, environment, and viruses to learn what role they might play in the development of Alzheimer's disease.

A number of drugs have been used to treat Alzheimer's disease. The U.S. Food and Drug Administration (FDA) approved the first, Cognex (tacrine) in 1993. Aricept (donepezil) became available in 1996.The FDA approved Exelon (rivastigmine) in 2000 and Reminyl (galantamine) in 2001. Each of these drugs increases the amount of acetylcholine available in the brain. Of the four drugs, Cognex has the most adverse side effects.

Although treatment and knowledge of Alzheimer's disease has improved dramatically, the cause of the disease remained unknown at the beginning of the twenty-first century.

Bibliography

Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day: A Family Guide to Caring for Persons with Alzheimer's Disease, Related Dementing Illnesses, and Memory Loss in Later Life. Baltimore: Johns Hopkins University Press, 1981. 3d ed. 1999.

Schneider, Edward L., and John W. Rowe, eds. Handbook of the Biology of Aging. 3d ed. San Diego: Academic Press, 1990.

Whitehouse, Peter J., Konrad Maurer, and Jesse F. Ballenger, eds. Concepts of Alzheimer Disease: Biological, Clinical, and Cultural Perspectives. Baltimore: Johns Hopkins University Press, 2000.

—Bradley Hyman/F. B.

A disease in which mental capacity decreases because of the breakdown of brain cells.