The German physician Alois Alzheimer first described the disease in 1907 after he had cared for a patient with an unusual mental illness. Dr. Alzheimer observed anatomic changes in his patient's brain and described them as abnormal clumps and tangled bundles of fibers. Nearly a century later these abnormal findings, now described as amyloid plaques and neurofibrillary tangles, along with abnormal clusters of proteins in the brain, are recognized as the characteristic markers of AD.
The disease knows no social or economic boundaries and affects men and women almost equally. While 90% of AD victims are over age sixty-five, AD can strike as early as the thirties, forties, and fifties. Most patients are cared for at home as long as possible, a situation that can be emotionally and physically devastating for the affected individuals and their families.
The financial consequences of caring for patients with AD also are devastating. The Alzheimer's Association (AA) and the National Institute of Aging estimate that the costs of diagnosis, treatment, nursing home care, informal care, and lost wages are about $100 billion each year. Their families provide about 75% of the total care for people with AD. Half of all nursing home residents have AD or a related disorder. In 2004 the cost of one year's stay in a nursing home was estimated to be $42,000 per year, but the cost can exceed $70,000 per year in some areas (http://www.alz.org/AboutAD/Statistics.asp).
The AA asserts that if a cure or prevention is not found, by 2050 the number of Americans with AD is estimated to range from 11.3 million to 16 million, with a middle estimate of 13.2 million. On the other hand, discovery of a treatment that could delay the onset of AD by five years could reduce the number of individuals with the disease by nearly 50% after fifty years.
SUSPECTED CAUSES
AD is not a normal consequence of growing older, and researchers continue to seek its cause. It is a disease of the brain that is influenced by genetic and nongenetic factors.
Researchers have found some promising genetic clues to the disease and have observed the different patterns of inheritance, ages of onset (when symptoms begin), genes, chromosomes, and proteins linked to the development of AD. Mutations in four genes, situated on chromosomes 1, 14, 19, and 21, are thought to be involved in the disease.
The first genetic breakthrough was reported in the February 1991 issue of the British journal Nature. Investigators reported that they had discovered that a mutation in a single gene could cause this progressive neurological illness. Scientists found the defect in the gene that directs cells to produce a substance called amyloid protein. Researchers at the Massachusetts Institute of Technology found that low levels of the brain chemical acetylcholine contribute to the formation of hard deposits of amyloid protein that accumulate in the brain tissue of AD patients. In normal people the protein fragments are broken down and excreted by the body. Amyloid protein is found in cells throughout the body, and researchers do not know how it becomes a deadly substance in the brain cells of some people and not others.
In 1995 three more genes linked to AD were identified. One gene appears to be related to the most devastating form of early-onset AD, which can strike people in their thirties. When defective, the gene may prevent brain cells from correctly processing a substance called beta amyloid precursor protein. The second gene is linked to another early-onset form of AD that strikes before age sixty-five. This gene also appears to be involved in producing beta amyloid. Researchers believe that the discovery of these two genes will allow them to narrow their search for the proteins responsible for early-onset AD and give them clues to the causes of AD in older people.
The third gene, known as apolipoprotein E (apoE), was reported as associated with AD in 1993, but its role in the body was not known at that time. Researchers have since found that the gene plays several roles. Within the body, it regulates lipid metabolism within the organs and helps to redistribute cholesterol. In the brain, apoE participates in repairing nerve tissue that has been injured. There are three forms (alleles) of the gene: apoE-2, apoE-3, and apoE-4. Until recently, people with two copies of apoE-4, one from each parent, were thought to have a greatly increased risk of developing AD before age seventy. From one-half to one-third of all AD patients have at least one apoE-4 gene, while only 15% of the general population has an apoE-4 gene. In 1998 researchers discovered that the apoE-4 gene seems to affect when a person may develop AD, not whether the person will develop the disease.
Another recently discovered gene, A2M-2, appears to affect whether a person will develop AD. Nearly one-third (30%) of Americans may carry A2M-2, a genetic variant that more than triples their risk of developing late-onset AD compared with siblings with the normal version of the A2M gene. The discovery of A2M-2 opens up the possibility of developing a drug that mimics the A2M gene's normal function. This has the potential to protect susceptible persons against brain damage or perhaps even reverse it.
Symptoms of Alzheimer's Disease
AD begins slowly. The symptoms include difficulty with memory and a loss of cognitive function (intellectual abilities). The patient with AD also may experience confusion; language problems, such as trouble finding words; impaired judgment; disorientation in place and time; and changes in mood, behavior, and personality. How quickly these changes occur varies from person to person, but eventually the disease leaves its victims unable to care for themselves. In their terminal stages, patients with AD require care twenty-four hours a day. They no longer recognize family members or themselves, and they need help with such daily activities as eating, dressing, bathing, and using the toilet. Eventually, they may become incontinent, blind, and unable to communicate. Finally, their bodies may "forget" how to breathe or make the heart beat. Many patients die from pneumonia.
Testing for Alzheimer's Disease
A complete physical, psychiatric, and neurologic evaluation usually can produce a diagnosis of AD that is about 90% accurate. For many years the only sure way to diagnose the disease was to examine brain tissue under a microscope, which was not possible while the AD victim was still alive. An autopsy of someone who has died of AD reveals a characteristic pattern that is the hallmark of the disease—tangles of fibers (neurofibrillary tangles) and clusters of degenerated nerve endings (neuritic plaques) in areas of the brain that are crucial for memory and intellect. Also, the cortex of the brain is shrunken.
In 1996 a San Francisco biotechnology firm developed a diagnostic test for AD. The test, which involves analysis of blood and spinal fluid, produced conclusive results in 60% of older patients with dementia.
In 2000 researchers at Brigham and Women's Hospital in Boston found that the use of MRI techniques could measure the volume of brain tissue in areas of the brain used for memory, organizational ability, and planning. In addition, the use of these measurements could accurately identify persons with AD and predict which people would develop AD. That same year scientists at New York University Medical Center, the Mayo Clinic, and the National Hospital for Neurology and Neurosurgery in London reported using MRI to identify parts of the brain affected by AD before symptoms appear and measure brain atrophy to monitor the progression of AD.
In 2005 researchers Chad Mirkin and William Klein at Northwestern University announced development of yet another diagnostic test that detects small amounts of protein in spinal fluid. The test is called a bio-barcode assay and is as much as a million times more sensitive than other tests. First used to identify a marker for prostate cancer, the test is used to detect a protein in the brain called amyloid-beta-derived diffusible ligand (ADDL). ADDLs are small soluble proteins. To detect them the researchers used nanoscale particles that had antibodies specific to ADDL. The researchers' findings were reported in the February 9, 2005, issue of the Proceedings of the National Academy of Science.
Investigators continue to look at other biological markers, such as blood tests, for AD and at neuropsycho-logical tests, which measure memory, orientation, judgment, and problem solving, to see if they can accurately predict whether healthy, unaffected older adults will develop AD or whether those with mild cognitive impairment will go on to develop AD.
Physicians and neuroscientists have long been eager for a simple and accurate test that can distinguish people with AD from those with cognitive problems or dementias arising from other causes. An accurate test would allow the detection of AD early enough for the use of experimental medications to slow the progression of the disease and would identify people at risk of developing AD. However, the availability of tests raises ethical and practical questions: do patients really want to know their risk of developing AD? Will health insurers use test results to deny insurance coverage?
Treatments for Alzheimer's Disease
As of 2006 there was still no cure or prevention for AD, and treatment has focused on managing symptoms. Medication can reduce some of the symptoms, such as agitation, anxiety, unpredictable behavior, and depression. Physical exercise and good nutrition are important, as is a calm and highly structured environment. The object is to help the patient with AD maintain as much comfort, normalcy, and dignity as possible.
By 2006 there were five FDA-approved prescription drugs for the treatment of AD. The first drugs to be approved were cholinesterase inhibitors, which are drugs designed to prevent the breakdown of acetylcholine. Cholinesterase inhibitors keep levels of the chemical messenger high, even while the cells that produce the messenger continue to become damaged or die. About half of the people who take cholinesterase inhibitors see modest improvement in cognitive symptoms. Until 1997 tacrine (marketed as Cognex) was the nation's only AD medication, but tacrine rarely is prescribed today because of associated side effects, including possible liver damage. However, there are three other cholinesterase inhibitors currently used that produce some delay in the deterioration of memory and other cognitive skills—donepezil (Aricept), approved in 1996; rivastigmine (Exelon), approved in 2000; and galantamine (Reminyl), approved in 2001.
Memantine (Namenda) was approved by the FDA in October 2003 for treatment of moderate to severe AD. It is classified as an uncompetitive low-to-moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist, and it is the first Alzheimer drug of this type approved in the United States. According to the AA, it seems to work by regulating the activity of glutamate, one of the brain's specialized messenger chemicals involved in information processing, storage, and retrieval.
As of 2006 NIH affiliates, pharmaceutical companies, and the AA were involved in clinical trials of about twenty new drugs to treat AD. All of the drugs being tested are intended to improve the symptoms of AD and slow its progression, but none are expected to "cure" AD. The investigational drugs aim to address three aspects of AD—improve cognitive function in people with early AD; slow or postpone the progression of the disease; and control behavioral problems such as wandering, aggression, and agitation of patients with AD.
Other research under way in 2006 involved the use of NSAIDs. Such as ibuprofen or naproxen, to reduce the risk of developing AD, because AD involves inflammatory processes in the brain. Another National Institute on Aging-funded study was trying to find out whether antioxidants, such as vitamin E, can prevent persons with mild memory impairment from progressing to AD.
Research to see if estrogen reduces the risk of AD or slows the disease has been done, and one study showed that estrogen does not slow the progression of the already-diagnosed disease. Also, a study on combination hormone therapy (estrogen and progestin) showed that women older than age sixty-five participating in the study had twice the rate of dementia, including AD, compared with women who did not take the medication. Substances already used to reduce cardiovascular risk factors, such as statin drugs and folic acid, also are being studied to determine whether they also reduce AD risk.
In 2005 the National Institute of Aging and AA launched the AD Genetics Study, recruiting subjects from families in which two siblings developed AD after age sixty. The study aims to compare the genes of the afflicted siblings with those from another family member who does not have AD in an effort to find the genes that contribute to AD (http://ncrad.iu.edu/).
Caring for the AD Patient
AD can affect every member of the patient's family. While medication may suppress some symptoms and occasionally slow the progression of the disease, eventually most AD patients require constant care and supervision. Until recently nursing homes and residential care facilities were not equipped to provide this kind of care and, if they accepted AD patients at all, admitted only those in the very earliest stages of the disease. Since 2000 a growing number of nursing homes have welcomed AD patients despite the fact that they are more difficult and costly to care for than older adults without AD. Although this change was primarily financially motivated, as nursing home occupancy rates dropped in response to the growth of alternative housing for older adults, it does offer families with ample financial resources—the average annual stay costs $75,000 and varies somewhat depending on geography and intensity of services—an alternative to caring for the AD patient at home ("The MetLife Market Survey of Nursing Home and Home Care Costs," MetLife, September 2005, http://www.metlife.com/WPSAssets/41453139101127828650V1F2005%20NH%20and%20HC%20Market%20Survey.pdf).
SECOND VICTIMS
The suffering of a patient with AD is only part of the devastating emotional, physical, and financial trauma of AD. People who care for loved ones with AD are considered "second victims" of the disease. Caregivers often neglect their own needs, including their health and social lives, and the needs of other family members. As a result, they may develop more stress-related illnesses and are at greater risk for depression.
Many professionals recommend support groups for caregivers of patients with AD, made up of family members, friends, and health care professionals. These groups encourage members to share information and ideas, give and receive mutual support, and exchange coping skills with each other. A study of 206 spouses of patients with AD found that caregivers benefited greatly from support groups and counseling. Those who received this kind of support were able to care for the patients at home for almost one year longer than caregivers who lacked support (Mary S. Mittelman et al, "A Family Intervention to Delay Nursing Home Placement of Patients with Alzheimer Disease: A Randomized Controlled Trial," Journal of the American Medical Association, vol. 276, no. 21, December 4, 1996).
CAREGIVING CAN COMPROMISE HEALTH AND WELL-BEING
For many people, caring for a person with AD can, over time, become an enormous burden. Caregivers may neglect their own health and other needs because no one else is available to care for their AD-affected spouse or parent.
Deputy Secretary of Health and Human Services Claude Allen and panelists Michael O'Grady, John Hoff, Josefina Carbonell, Donald Showers, Katryna Gould, and Bill Kays at a December 2003 town hall meeting, "Ensuring the Health and Wellness of Our Nation's Family Caregivers" (http://aspe.hhs.gov/daltcp/CaregiverEvent/overview.htm), reported that about one third of caregivers describe their own health as "fair to poor." The stress associated with family caregiving has been found to compromise immune function, increasing the risks of infectious diseases, such as colds and flu. It also is linked to increased risk for depressive symptoms, as well as chronic diseases, such as heart disease, diabetes, and cancer.
Key research findings about the relationship between caregiving and compromised health include:
- Spouses who suffer from chronic conditions, serve as caregivers, and report stress related to their caregiving efforts have a mortality rate that is nearly two-thirds (63%) higher than their noncaregiving peers. Caregivers experienced more depression and anxiety and a reduced level of health. They also were less likely to get adequate rest, to have time to rest when they were sick, or to have time to exercise (Richard Schulz and Scott R. Beach, "Caregiving as a Risk Factor for Mortality," Journal of the American Medical Association, vol. 282, no. 23, December 15, 1999).
- The stress of caring for older adults with dementia has been shown to compromise caregivers' immune systems for as long as three years after their caregiving ends (Janice Kiecolt-Glaser and Ronald Glaser, "Chronic Stress and Age-related Increases in the Proinflammatory Cytokine IL-6," Proceedings of the National Academy of Sciences, June 30, 2003).
- Caregivers remain at risk for depression and anxiety after the older adults with dementia they have cared for are placed in long-term health care facilities. Depressive symptoms and anxiety in caregivers were as severe after caregivers institutionalized their relatives compared with when they served as in-home caregivers (Richard Schulz et al, "Long-term Care Placement of Dementia Patients and Caregivers Health and Well-being," Journal of the American Medical Association, vol. 292, no. 8, August 25, 2004).
- Caregivers who provide care thirty-six or more hours weekly are more likely than noncaregivers to experience symptoms of depression or anxiety. For spouses serving as caregivers the rate is six times higher; for those caring for a parent the rate is twice as high (Carolyn Cannuscio et al, "Reverberation of Family Illness: A Longitudinal Assessment of Informal Caregiver and Mental Health Status in the Nurses' Health Study" American Journal of Public Health, vol. 92, no. 8, August 2002).
Research also has demonstrated that at-risk care-givers are less likely than their peers who do not provide care for older relatives to engage in health-promoting behaviors that are important for chronic disease prevention and health promotion. The town hall panelists observed that in view of caregivers' risks of developing health problems, there is an urgent need to exhort family caregivers to engage in activities such as regular exercise and preventive medical care that will benefit their own health, well-being, and longevity.
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