Biology of Alzheimer's disease
No one knows precisely what causes the dementing disorder known as AD, and there is still no successful treatment for it. But researchers in the fields of epidemiology, genetics and molecular and cell biology continue to make headway in understanding some of the mechanisms underlying the disease.
What we do know is that AD affects important areas of the brain such as the hippocampus, which is involved in memory, and the cerebral cortex, which governs language and other thought processes. The nerve cells in these areas, and the connections between them, are destroyed, and the brain begins to waste away.
Patients without dementia show some of the same kinds of brain changes that occur in people with AD. The difference is that some of these changes are more marked in people with AD. At present, the only way to really tell whether a person has AD is to examine brain tissue after death.
AD at work in the brain
Gumming up the works
The hallmarks of AD are clusters of proteins that accumulate within and between nerve cells. It is not understood how these deposits damage cells, nor do researchers have a clear idea how they contribute to dementia. But even if they turn out not to cause AD directly, they are biological markers of the disease that may help to trace its mechanism.
Beta-amyloid plaques
Very early in the course of AD, waxy protein deposits called plaques begin to build up between cells. Most elderly people have some waxy plaque buildup, but in people with AD the plaques are extensive, and they are concentrated in the hippocampus and the cerebral cortex. Cells around the plaques often look abnormal. Plaques mostly contain protein fragments called beta-amyloid peptide.
Proteins get their instructions from genes, and if the gene suffers a defect, called a mutation, the protein the gene codes for may also be defective. Beta-amyloid precursor protein (beta-APP) is a protein that is widely present in the body, though its precise role is unknown. As it matures, the protein is cut in several ways, creating fragments of beta-amyloid protein, a small number of which are toxic. However, mutations in the gene that codes for beta-APP cause something to go haywire in the cutting process and to generate an excess of the toxic form of the protein fragment. This toxic form is the beta-amyloid peptide that is found in the plaques of AD.
Beta-amyloid peptide may injure nerve cells in several ways, from disrupting calcium regulation (which kills cells) to triggering an inflammatory response from the body's immune system that makes any existing damage worse. But how these mechanisms relate to the dementia of AD is not clear. Moreover, researchers disagree whether plaques cause AD by destroying cells, or whether they result from damage to cells caused by something else.
Neurofibrillary tangles
Protein clusters found inside nerve cells are called neurofibrillary tangles. These structures resemble threads twisted around each other. The tangles consist mainly of a protein called tau, which ordinarily works with another protein called tubulin to support the structure of cells and to provide a track for transporting nutrients and other cellular components through the cell. For a long time, tau was believed not to be important in AD. But study of a disorder called fronterotemporal dementia suggests that abnormal processing and buildup of tau may contribute to dementia by clogging up the cell and interfering with its function.
Attacking the messenger
For everything they do, brain cells use a variety of chemical messengers called neurotransmitters to communicate. For example, as part of the normal flow of information, the neurotransmitter acetylcholine is produced in some cells (particularly those of the hippocampus) and broken down in other areas by an enzyme called acetylcholinesterase.
In AD, however, the amount of acetylcholine produced is much lower, hampering communication between cells. As if that were not enough, acetylcholinesterase continues to do its job. It is as though an arm-wrestling partner continues to arm wrestle after you have stopped resisting. Drugs called cholinesterase inhibitors aim at blocking the enzyme, to increase the amount of acetylcholine and improve memory and concentration. But to the extent the drugs help at all, they are only of benefit in the early stages of the disease. Once brain cells have been destroyed, the drugs are useless.
Genetic causes and risk factors in AD
About 5% of people with AD have a special family history of the disease. In these cases, not only is more than one family member affected, but the disease often strikes people in their thirties and forties. For this reason, it is called early-onset AD. Up to 50% of cases of early-onset AD are caused by defects in three genes (beta-APP, and presenilin 1 and 2). The remainder of early-onset cases are probably also caused by defective genes, but those genes have yet to be found.
Late onset AD-the more common form of AD that strikes people over 65-also runs in families in about 10-25% of cases, though the pattern is less distinct. Defective genes different from the ones that cause early-onset AD are believed to be implicated, but for now they are unknown. In the vast majority of cases of late-onset AD, there is no clear family history of the disease. Although genes have been linked to a person's risk of getting this form of AD, they do not appear to cause it.
beta-APP
The gene that makes beta-APP was found on human chromosome 21. Geneticists were helped in this discovery by research on families with early-onset AD and on people with Down's syndrome, who show the signs of AD by age 40. (People with Down's have an extra copy of chromosome 21.)
The next task was to look for mutations that might result in an excess of beta-amyloid peptide. Indeed, in several families with familial early-onset AD, mutations were found in the beta-APP gene that either increased the amount of both versions of the peptide, or increased production of the toxic version.
Mutations in the beta-APP gene are responsible for less than 1% of all cases of early-onset AD.
Presenelin 1 and presenilin 2
Defects were also found in a set of genes that interfere with how beta-APP is cut. Disruptions in these genes, called presenelin 1 and presenilin 2, cause about 50% of early-onset familial AD. These mutations act indirectly to increase production of beta-amyloid peptide, expecially the toxic version. They are located on chromosome 14 and chromosome 1, respectively.
ApoE
A fourth gene that possibly has a wider effect than the amyloid gene is a gene that everyone carries called ApoE. ApoE helps the body metabolize fats and is located on chromosome 19. People who have a particular type of the gene (ApoE4)-anywhere from 6 to 37% of the population-have a greater risk of developing the more typical form of AD that occurs after 65.
Unlike APP and the presenilin genes, ApoE4 does not work by increasing production of beta-amyloid peptide. But it may increase a person's risk for AD in a number of other ways. One theory is that ApoE4 and beta-amyloid compete to occupy the space between brain cells. A housekeeping molecule responsible for clearing the area around cells has an easier time removing ApoE than amyloid. Thus, amyloid begins to accumulate and to make mischief. Also, people who inherit ApoE4 from both parents are more likely to develop AD before the age of 70 (as opposed to 80-85, which is the average age at which late-onset AD strikes). But having the ApoE4 gene does not necessarily mean a person will get AD, nor does not having the gene mean they won't.
Environmental causes of AD
Many environmental factors have been presumed to play a role in AD, but findings from studies of low education, smoking, vascular disease and diabetes have been inconclusive. Recently, an analysis of head injuries suggests that people who suffer serious head injuries in early adulthood may be at greater risk of developing AD. Other environmental agents under investigation as causes of AD include viruses, and diet and lifestyle factors.
Methods of research
Animal models
Only humans develop AD, so for a long time, finding a small animal in which the disease could be studied at all was a major obstacle to progress in research. Also, because most of what is known about AD comes from examining human brain tissue after death, scientists know much more about the later stages of the disease than the earlier stages. What is needed is an animal model that reproduces all the characteristics of AD as closely as possible.
Fortunately, scientists have been able to engineer mice with mutant genes that cause amyloid plaques like those affecting the brains of people with AD. These mice also display learning and memory problems as they age. But unlike human nerve cells affected by AD, the mouse nerve cells remain healthy. And the mice do not develop neurofibrillary tangles. Still, work with these mice is very helpful in studying the role of environmental factors, and in assessing treatments based on replacing cells lost or damaged by the disease. Refining the mouse models will shed additional light on how AD works.
Drug treatments
Currently, at least two dozen drugs to treat AD are undergoing clinical trials in the US. Some of these drugs are cholinesterase inhibitors, which only show benefit in mild-to-moderate cases of AD, and which cannot halt or cure the disease. An alternative approach aims at preventing the degeneration of brains cells caused by beta-amyloid peptide. For example, researchers are seeking to interfere with the production of beta-amyloid peptide, to keep the peptide from accumulating even if it is produced and to block the toxic effects of the peptide. Other areas of investigation include the following:
Antiinflammatory drugs: It may be possible to slow the progress of AD with antiinflammatory agents similar to ibuprofen and htmirin. Since the 1990s, many studies have shown that AD occurs much less frequently in people with arthritis than in the general population. Researchers reasoned that the antiflammatory drugs that people with arthritis take somehow repair the cellular damage that leads to AD. A number of antiinflammatory drugs are under trial or investigation for treating AD.
Oestrogen: Women on hormone replacement therapy also have a reduced incidence of AD, and researchers hoped that oestrogen might prove effective both in preventing and in treating the disease. Findings from one effort, the Alzheimer Disease Cooperative Study, were disappointing. But other trials of oestrogen are still under way.
Antioxidants: Just like a car engine generates pollutants, cells as they function generate toxic molecules called free radicals. Usually the body controls this process, known as oxidative stress, by producing antioxidants that counteract free radicals. But in certain situations oxidative stress overwhelms the body's defenses and triggers a chain reaction in which cells, particularly nerve cells, become damaged. Oxidative stress is believed to be a contributing factor to AD, and clinical trials of antioxidants such as vitamin E and ginkgo biloba are ongoing.
Vaccines: Trials of a vaccine intended to immunise patients against accumulation of beta-amyloid plaques are under way in both the US and UK. These studies are based on research using mice that have a version of AD characterised by amyloid plaques. Injecting the mice with a vaccine made of beta-amyloid peptide reduced the number of plaques. Preliminary results of these phase I trials, which test safety, suggest that the vaccine is well tolerated in human recipients.
Peering into the brain
A major goal of research in brain-imaging techniques is to find ways to improve early detection of AD.
Already, computerized tomography (CT) and magnetic resonance imaging (MRI) are sometimes used in diagnosing AD to rule out other causes of dementia, such as tumours or damage from stroke. These techniques can also show how parts of the brain shrink as the disease progresses.
Other techniques, such as single-photon emission computerized tomography (SPECT) and positron emission tomography (PET) highlight patterns of brain activity. Like CT and MRI, they may improve the accuracy of diagnosis. But primarily they are used as research tools to study how the work of healthy brains differs from the work of brains with AD.
At present, it is not possible to detect plaques and tangles using brain-imaging techniques.
Further reading
Alzheimer's disease
Public Health Genetics Unit, Anglia and Oxford Office of the United Kingdom National Health Service Regional Executive www.medinfo.cam.ac.uk/phgu/info_database/Diseases/Alzheimers_Disease/alzheimer.htm
Benjamin J. Sadock and Virginia A. Sadock Kaplan and Sadock's Comprehensive Textbook of Psychiatry, 7th edition. 2 vols. Philadelphia: Lippincott Williams and Wilkins, 2000
Dennis J. Selkoe The origins of Alzheimer disease: A is for amyloid. Journal of the American Medical Association, 283 (2000): 1615-1617.
Peter H. St George-Hyslop Piecing together Alzheimer's. Scientific American, 283 (2000): 52-49.
Research directions in Alzheimer's disease
Wellcome News Supplements. London: The Wellcome Trust, 1998 www.wellcome.ac.uk/en/old/pdf/WNs2-Alz.pdf
Giselle Weiss
4 January 2001
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