Alzheimer's Disease

Alzheimer's disease has emerged as one of the great mysteries in modern day medicine, with a growing number of clues but still no answers as to its cause. The quest to uncover its cause has the air of a veritable whodunit saga. Though none of the leading theories about the genesis of Alzheimer's disease has resolved the mystery, each has led to certain intriguing findings that suggest further investigation is needed. It is important to examine these theories, not only to understand current thinking on Alzheimer's disease, but also to learn what popular ideas have proved to be incorrect. There have been at least five prominent theories about the cause of Alzheimer's disease:

1. Chemical Theories

A. Biochemical Changes in Growth (Trophic) Factors: Much research is taking place in the examination of naturally occurring substances that may affect the nervous system and that may contribute to the dysfunction or death of brain cells in Alzheimer's. It is possible that one reason for nerve cell death in Alzheimer's patients is a decline in growth-promoting factors that maintain the functioning of brain cells, or, conversely, a spontaneous increase in factors that are toxic to brain cells.

A naturally occurring substance of interest is nerve growth factor (NGF). Experiments in aged rats indicate that specific nerve growth factors can stimulate the growth of new synaptic connections in the hippocampus and, as a result, restore some memory loss. Although there could be neurotoxic as well as growth-enhancing effects in the use of NGF, scientists are investigating methods of safely introducing NGF into the brain, possibly through the transplant of genetically engineered cells.

Other research is exploring whether changes or an imbalance in the metabolism of certain elements like calcium in brain cells may be part of the process by which the cells degenerate and die in Alzheimer's disease.

(GRAPHIC OMITTED: Illustration of brain, page 10)

B. Chemical Deficiencies: One of the ways in which brain cells communicate with one another is through chemicals called neurotransmitters. Studies of Alzheimer's disease brains have uncovered diminished levels of various neurotransmitters that are thought to influence intellectual functioning and behavior. For example, reduced levels of the neurotransmitter acetylcholine (ACh) have been found in Alzheimer's disease. This finding has been coupled with observations that drugs whose side effects lower ACh levels in the brain can cause reversible memory problems. These findings have led to a number of drug studies employing pharmacologic agents to elevate ACh in patients. The treatments have included lecithin, choline, physostigmine, deprenyl, tacrine hydrochloride (THA), and others, used alone or in different combinations with one another. The results of these experiments are difficult to interpret. In some of these studies, a few Alzheimer's disease patients seem to show minor improvement over a brief but not sustained period of time. Typically, any improvement may be on certain narrow test measures--and not usually on significant activities of daily living which would be more important to the person's family and physician. Nonetheless, the researchers' enthusiasm is understandable, for they are dealing with the potential modifiability of underlying physiological phenomena that influence the Alzheimer's disease symptoms. The drugs they are studying now may not be the right ones, but they may point the way to the discovery of more effective pharmacologic agents.

One drug in particular, THA or tacrine (trade name, Cognex), has been studied extensively. Early studies indicated that THA appeared to have a slightly positive effect on patient functioning, but assessment by a skilled observer showed no overall improvement. More recent studies conducted on patients with mild or moderate Alzheimer's, using a higher dosage of tacrine than the earlier studies, showed a statistically significant improvement, both in clinical and caregiver evaluations and in quality of life measurements. These results caused the Food and Drug Administration in the fall of 1993 to approve the drug. Tacrine can, however, have side effects, including elevation of liver functioning tests. The family of the patient should be aware that the patient must take the medication 4 times a day, that blood must be drawn weekly during the dose adjustment phase, and that a third of patients experience significant adverse effects. As is always the case, but particularly while better drugs are being developed, caregivers and patients will have to weigh the possible benefits of the available drug against the cost and the potential problems incurred.

C. Toxic Chemical Excesses: Although some researchers have found increased levels of aluminum, mercury, or other metals in the brains of Alzheimer's disease victims, others have not. And while some investigators have hypothesized that aluminum may play a role in the genesis of Alzheimer's disease, most have regarded aluminum as an effect of the disorder rather than its cause. In other words, instead of aluminum's acting to induce brain tissue changes in Alzheimer's disease, it more likely accumulates in response to such changes. Research continues in an effort to better understand this phenomenon and to determine whether the aluminum deposits are a cause or a consequence of the disease, and, if the latter, whether they contribute further to the impairment already experienced.

2. The Genetic Theory

Genetic aspects of many diseases are confusing. For example, a disorder can occur more frequently in certain families than in others, but still not be genetic. Since family members living together are exposed to the same environment, they would all be at increased risk if an environmental toxin or infectious agent were the causative factor in a particular disease. Furthermore, a disorder can be congenital and not hereditary--that is, prenatal problems can cause developmental defects not brought on by heredity. And an illness can be hereditary but remain in a latent state if some other disease factor does not occur to trigger its onset.

Several connections between Alzheimer's disease and Down's syndrome led researchers initially to look for genetic factors in Alzheimer's disease on chromosome 21--the chromosome that is affected in Down's syndrome. At the present time, several genetic markers have been identified on chromosomes 21 and 14 in that small number of families where Alzheimer's disease has occurred with unusual frequency at relatively early ages. In families where the disease has tended to develop at later ages, other studies suggest that Alzheimer's disease is unusually frequent in persons who have a particular form of the apolipoprotein E (ApoE) gene found on chromosome 19. Only a minority of the general population show this version (ApoE4) of the gene, out of several variants that occur.

Despite these findings, the extent of genetic and hereditary involvement in Alzheimer's disease remains unclear. There are a vast number of people affected with this disorder who are not part of a strong family pattern. Furthermore, the genetic factors associated with the disease clearly vary for different families. This has led some investigators to postulate that there may be a number of subtypes of Alzheimer's disease, with differing risk factors and causes.

The National Institute of Mental Health (NIMH) is supporting research to locate the genes that cause Alzheimer's disease, schizophrenia, and manic depression. Ten diagnostic centers, three of which study Alzheimer's, provide genetic material to a central gene bank. Scientists at the centers use identical diagnostic tests, chosen for their sensitivity and reliability, to select members of families whose blood is sent to the gene bank for processing, storage, and distribution. Participating families must have several members affected by one of the diseases. The centers studying Alzheimer's are: The Johns Hopkins University, Baltimore, Maryland; Massachusetts General Hospital, Boston, Massachusetts; and University of Alabama, Birmingham, Alabama.

3. The Autoimmune Theory

The body's immune system, which protects against potentially harmful foreign invaders, may erroneously begin to attack its own tissues, producing antibodies to its own essential cells. This is called an autoimmune response, and it may take place in the brain. Some scientists speculate that certain late life changes in aging neurons (the major nerve cells of the brain) might be triggering an autoimmune response that evokes symptoms of Alzheimer's disease in vulnerable individuals. Curiously, some antibrain antibodies have been identified in the brains of those with Alzheimer's disease. Their significance, though, is not known, especially since some antibrain antibodies have also been identified in aging brains without Alzheimer's disease. Moreover, even if changes are occurring in brain neurons to trigger an autoimmune response, what originally induces these brain cell changes is not known.

4. The Slow Virus Theory

Because a slow-acting virus has been identified as a cause of some brain disorders that closely resemble Alzheimer's disease (for example, Creutzfeldt-Jakob disease), a slow virus has been postulated in Alzheimer's disease. Various researchers have suggested that suspicious brain tissue changes in Alzheimer's disease victims may be caused by a virus. However, to date a virus has not been isolated from the brains of those with Alzheimer's disease, and no immune reaction has been found in the brains of Alzheimer's patients, comparable to that found in patients with other viral dementias. At present, the possibility of a viral cause of Alzheimer's cannot be either decisively eliminated or confirmed.

5. The Blood Vessel Theory

Defects in blood vessels supplying blood to the brain have been studied as a possible cause of Alzheimer's disease. Hardening of the brain's arteries, also known as cerebroarteriosclerosis, proved not to be a cause of Alzheimer's disease. Thus, the hyperbaric oxygen chamber treatment proved ineffective as a therapy for Alzheimer's.

Stroke, another blood vessel problem that most often occurs later in life, can cause symptoms like those of Alzheimer's disease. But this condition, called multi-infarct dementia, differs from Alzheimer's disease. More recently, the blood vessel theory has been expanded to hypothesize potential defects in the blood-brain barrier, a protective membrane-like mechanism that guards the brain from foreign bodies or toxic agents circulating in the blood stream outside the brain.

There have been several reports of a possible association between serious head injuries involving a loss of consciousness and later onset of Alzheimer's disease. One theory as to why this connection might occur has to do with possible breaks in the blood-brain barrier as a result of these injuries to the brain.

Two critical crossroads reached in the approach to treatment for Alzheimer's disease were (1) the recognition of Alzheimer's disease as a disorder distinct from the normal aging process; and (2) the realization that, in developing therapeutic and social interventions for a major illness or disability, the concept of care can be as important as that of cure. Moreover, in addition to the symptoms of Alzheimer's disease mentioned earlier, other symptoms and aggravating factors may compound the problem. Patient, environmental, and family stresses can converge to exaggerate patient dysfunction and family burden during the clinical course of Alzheimer's disease. Identifying these stresses and making appropriate changes can provide the foundation for more effective treatment and fewer everyday problems.

In the Alzheimer's disease patient, depression or delusions can aggravate dysfunction. These problems, which emerge during the course of the disorder in some individuals with Alzheimer's disease, compound memory impairment; they make the affected individual do worse than would be expected from the dementia alone--causing clinical conditions referred to as "excess disability" states. Depression by itself can mimic dementia--a condition that is sometimes termed pseudodementia. When combined with dementia, depression exacts yet greater incapacity and suffering in the Alzheimer's disease patient. Depression in Alzheimer's disease can be treated. Indeed this highlights one of the truly extraordinary phenomena that can be observed in Alzheimer's disease: By alleviating an excess disability state, actual clinical improvement can result--even though the underlying disease process is advancing. In other words, at a given point in time, the patient's symptoms can be reduced, suffering lowered, capacity to cope buttressed, with family burden eased as a further result. These are traditional goals of treatment for all illnesses.

Researchers in the NIMH Intramural program have developed and are testing a Dementia Mood Assessment Scale, designed to rate mood in Alzheimer's patients. This scale tracks the mood states of the patients over the course of their illness and thus may be helpful in testing various antidepressant treatments.

The patient's immediate environment can also interfere with coping, adding to the level of impairment. Modifying the surroundings can reduce stresses imposed by environmental factors. There is the matter of safety, as in the need to protect the person from wandering toward a stairway and subsequently falling. There is the matter of lowering the individual's frustration level, such as by placing different cues in the immediate environment to combat memory loss and to reduce resulting stress and disorganization. There is the matter of finding the most protective but least restrictive setting for care which at some point may involve a move away from home to a nursing home or other care facility well equipped to deal with those who have Alzheimer's disease.

Stress on the family can take a toll on patient and caregiver alike. Caregivers are usually family members--either spouses or children--and are preponderantly wives and daughters. As time passes and the burden mounts, it not only places the mental health of family caregivers at risk, it also diminishes their ability to provide care to the Alzheimer's disease patient. Hence, assistance to the family as a whole must be considered.

As the disease progresses, families experience increasing anxiety and pain at seeing unsettling changes in a loved one, and they commonly feel guilt over not being able to do enough. The prevalence of reactive depression among family members in this situation is disturbingly high--caregivers are chronically stressed and are much more likely to suffer from depression than the average person. If caregivers have been forced to retire from positions outside the home, they feel progressively more isolated and no longer productive members of society.

An NIMH-funded study shows that caregivers not only have increased rates of infectious illness and depression, but often have suppressed immune systems. Another study of caregivers found depressed mood in 54 percent of caregivers and anger in 67 percent. Researchers hypothesize that the caregivers who hold in their anger may be at greater risk of cardiovascular disease.

The likelihood, intensity, and duration of depression among caregivers can all be lowered through available interventions. For example, to the extent that family members can offer emotional support to each other and perhaps seek professional consultation, they will be better prepared to help their loved one manage the illness and to recognize the limits of what they themselves can reasonably do.

George and Mary Ellen's neighbors had become increasingly concerned as it was obvious something was very wrong. When they noticed that the newspaper had not been taken in one morning, two neighbors came over. When no one answered the door, they tried it, found it unlocked, and entered. George was lying on the floor near the telephone, and Mary Ellen was sitting at the piano trying to pick out a tune. The neighbors called an ambulance for George and then placed a long-distance call to one of his daughters. George, in the hospital suffering from a heart attack, for the first time shared with his children the events of the past months and realized that he must make plans for the future. One of his daughters stayed with him and Mary Ellen for 2 months after he left the hospital. She arranged for someone to come in once a week to clean the house. She also contacted Meals-on-Wheels to ensure nourishing meals for her parents. Through her parents' church, she enrolled Mary Ellen in a 5-day-a-week daycare program for the elderly. Each morning Mary Ellen was picked up by the daycare van and was brought back late in the afternoon. George, relieved of constant anxiety, recovered rapidly and began to catch up on his writing projects. Though he missed the social life they had once enjoyed with their friends, there were times when he and Mary Ellen still felt a close relationship. George now accepted the fact that someday Mary Ellen might have to enter a nursing home, but with the support of his family, friends, church, and community he would be able to deal with whatever came.

Since the components of the problem vary, so too should the focus, nature, and sources of interventions. Interventions should focus on the patient's symptoms, the affected individual's everyday environment, and the family support system. Specific interventions can involve support from the family, the help of a homemaker or other aide in the home, employment of behavioral therapies, and the use of medication. The sources for interventions can range from family support groups such as those available through the Alzheimer's Association (AA), to professional consultations for the patient and family with a mental health specialist, to a variety of community programs such as day or respite care. Information on what assistance is available in a given community can be gained by contacting the local Office on Aging, a Community Mental Health Center or local Medical Society, or a local chapter of the AA. In addition, every State has an agency on aging that provides information on services and programs. The State Agencies on Aging, along with other sources of help, are listed at the back of this brochure.

Though Alzheimer's disease cannot at present be cured, reversed, or stopped in its progression, much can be done to help both the patient and the family live through the course of the illness with greater dignity and less discomfort. Toward this goal, appropriate clinical interventions and community services should be vigorously sought.

While Alzheimer's disease remains a mystery, with its cause and cure not yet found, there is considerable excitement and hope about new findings that are unfolding in numerous research settings. The connecting pieces to the puzzle called Alzheimer's disease continue to be found. At the same time, there are more and more partners involved in the effort, with growing national and international interest. Government, industry, academia, and the volunteer sector are all becoming more and more active; Federal, State, community, corporate, and foundation support for new studies and better services are all on the rise.

The U.S. Department of Health and Human Services established a Departmental Task Force on Alzheimer's Disease, which first met in April 1983. This Task Force, later legislatively mandated as the Council on Alzheimer's Disease, is composed of representatives from the following agencies that have programs related to Alzheimer's disease: the National Institute of Mental Health, the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the National Institute of Allergy and Infectious Diseases, the National Institute for Nursing Research, the Administration on Aging, the Agency for Health Care Policy and Research, the Health Care Financing Administration, the Health Resources and Services Administration, the National Center for Health Statistics, and the Department of Veterans Affairs. The Council, which also includes both the Surgeon General and the Assistant Secretary for Planning and Evaluation as members, is chaired by the Assistant Secretary for Health. The Council's recommendations are sent in an annual report to Congress.

In addition, a non-Federal Advisory Panel on Alzheimer's Disease was established by congressional action. The Panel, which works closely with the Council, consists of 15 national authorities on Alzheimer's disease selected for their depth and breadth of expertise in this area. The Panel has issued four reports, for 1988-89, 1990, 1991, and 1992. The titles are in the reference list. The activities of both the Council and the Panel reflect the scope of concern and interest that is being focused by the Federal Government on Alzheimer's disease.

Acetylcholine - a neurotransmitter found in reduced levels in the brains of Alzheimer's victims.

Alzheimer's Disease Associated Protein (ADAP) - a protein that seems to appear only in the tissue of people with Alzheimer's. It has been found in both the brain and spinal fluid.

Amyloid precursor protein (APP) - a normal, essential substance made by brain cells that contain BETA AMYLOID. In Alzheimer's, APP is cut and releases beta amyloid. Beta amyloid then forms clumps called SENILE PLAQUE.

Apolipoprotein E (ApoE) - a protein that ferries cholesterol through the bloodstream. The ApoE gene has three variants (or alleles), E2, E3, and E4. Each person inherits an allele from each parent. Ninety percent of the population inherit one copy of ApoE3, and 60 percent inherit two copies.

Cortisol - the major natural GLUCOCORTICOID (GC) in humans. It is the primary stress hormone.

Dementia - significant loss of intellectual abilities such as memory capacity, severe enough to interfere with social or occupational functioning.

Hippocampus - an area buried deep in the forebrain that helps regulate emotion and memory.

Multi-Infarct Dementia - dementia brought on by a series of strokes.

Nerve Growth Factor - a substance that occurs naturally in the body and enhances the growth and survival of cholinergic nerves.

Neurotoxic - poisonous to nerves or nerve tissue.

Nucleus basalis of Meynert - A small group of cholinergic nerve cells in the forebrain and connected to areas of the cerebral cortex.

Pseudodementia - a severe form of depression resulting from a progressive brain disorder in which cognitive changes mimic those of dementia.

Advisory Panel on Alzheimer's Disease. Report of the Advisory Panel on Alzheimer's Disease. DHHS Pub. No. (ADM) 89-1644, Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1989. (Available from the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325, GPO S/N 017-024-01387-1, $2.25.)

Advisory Panel on Alzheimer's Disease. Second Report of the Advisory Panel on Alzheimer's Disease, 1990. DHHS Pub. No. (ADM) 91-1791, Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1991. (Available from the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325, GPO S/N 017-024-01442-7, $3.00.)

Advisory Panel on Alzheimer's Disease.Third Report of the Advisory Panel on Alzheimer's Disease, 1991. DHHS Pub. No. (ADM) 92-1917, Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1992. (Available from the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325, GPO S/N 017-024-01483-4, $3.50.)

Advisory Panel on Alzheimer's Disease. Fourth Report of the Advisory Panel on Alzheimer's Disease, 1992. NIH Pub. No. (NIH) 93-3520, Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1993. (Available from the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325, GPO S/N 017-024-01508-3, $3.75.)

Light, E., and Lebowitz, B.D. Alzheimer's Disease Treatment and Family stress: Directions for Research. DHHS Pub. No. (ADM) 89-1569, Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1989. (Available from the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325, GPO S/N 017-024-01365-0, $14.00.)

National Institute of Mental Health. If You're Over 65 and Feeling Depressed ... Treatment Brings New Hope, DHHS Pub. No. (ADM) 90-1653, 1990. (Single copies available from Public Inquiries, NIMH, 5600 Fishers Lane, Room 7C-02, Rockville, MD 20857. Available in packages of 50 from the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325, GPO S/N 017-024-01376-5, $23.00 per package of 50.)

National Institute of Mental Health. Plain Talk About Mutual Help Groups DHHS Pub. No. (ADM) 89-1138, 1989. (Single copies available from Public Inquiries, NIMH, 5600 Fishers Lane, Room 7C-02, Rockville, MD 20857.)

Taylor, R. Evolutions: Brain imaging, The Journal of NIH Research, May 1990, Vol. 2, p. 103.

U.S. Congress, Office of Technology Assessment. Congressional Summary, Losing A Million Minds: Confronting the Tragedy of Alzheimer's Disease and Other Dementias, OTA-BA-324, Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1987.