Causes

The cause or causes of Alzheimer's disease are unknown. Some strong leads have been found through recent research, however, and these have also given some theoretical support to several new experimental treatments.
At first AD destroys neurons (nerve cells) in parts of the brain that control memory, including the hippocampus, which is a structure deep in the deep that controls short-term memory. As these neurons in the hippocampus stop functioning, the short-term memory of the person fails, and the ability to perform familiar tasks decreases. Later AD affects the cerebral cortex, particularly the areas responsible for language and reasoning; this language skills are lost and the ability to make judgments is changed. Personality changes occur, which may include emotional outbursts, wandering, and agitation. The severity of these changes increases with the progression of the disease. Eventually many other areas of the brain become involved, the brain regions affected atrophy (shrink and lose function), and the person with AD becomes bedridden, incontinent, helpless, and non-responsive.

Autopsy of a person with AD shows that the regions of the brain affected by the disease become clogged with two abnormal structures, called neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are twisted masses of protein fibers inside nerve cells, or neurons. In AD, tau proteins, which normally help bind and stabilize parts of neurons, is changed chemically, become twisted and tangled, and no longer can stabilize the neurons. Amyloid plaques consist of insoluble deposits of beta-amyloid (a protein fragment from a larger protein called amyloid precursor protein (APP) mixed with parts of neurons and non-nerve cells. Plaques are found in the spaces between the nerve cells of the brain. While it is not clear exactly how these structures cause problems, many researchers believe that their formation is responsible for the mental changes of AD, presumably by interfering with the normal communication between neurons in the brain and later leading to the death of neurons. As of 2000, three drugs for the treatment of AD symptoms have been approved by the United States Food and Drug Administration (FDA). They act by increasing the level of chemical signaling molecules in the brain, known as neurotransmitters, to make up for this decreased communication ability. All act by inhibiting the activity of acetylcholinesterase, which is an enzyme that breaks down acetylcholine, an important neurotransmitter released by neurons that is necessary for cognitive function. These drugs modestly increase cognition and improve one's ability to perform normal activities of daily living.

What triggers the formation of plaques and tangles and the development of AD are unknown. AD likely results from many interrelated factors, including genetic, environmental, and others not yet identified. Two types of AD exist: familial AD (FAD), which is a rare autosomal dominant inherited disease, and sporadic AD, with no obvious inheritance pattern. AD is also described in terms of age at onset, with early on-set AD occurring in people younger than 65, and late-onset occurring in those 65 and older. Early on-set AD comprises about 5-10 of AD cases and affects people aged 30 to 60. Some cases of early on-set AD are inherited and are common in some families. Early-onset AD often progresses faster than the more common late-on-set type.
All FAD, which are relatively uncommon, that have been identified so far are the early on-set type. As many as 50% of the FAD cases are known to be caused by three genes located on three different chromosomes. Some families have mutations in the APP gene located on chromosome 21, which causes the production of abnormal APP protein. Others have mutations in a gene called presenilin 1 located on chromosome 14, which causes the production of abnormal presenilin 1 protein, and others have mutations in a similar gene called presenilin 2 located on chromosome 1, which causes production of abnormal presenilin 2. Presenilin 1 may be one of the enzymes that clips APP into beta-amyloid; it may also be important in the synaptic connections between brain cells.

There is no evidence that the mutated genes that cause early on-set FAD also cause late on-set AD, but genetics does appear to play a role in this more common form of AD. Discovered by researchers at Duke University in the early 1990s, potentially the most important genetic link to AD was on chromosome 19. A gene on this chromosome, called APOE (apolipoprotein E), codes for a protein involved in transporting lipids into neurons. APOE occurs in at least three forms (alleles), called APOE e2, APOE e3, and APOE e4. Each person inherits one APOE from each parent, and therefore can either have one copy of two different forms, or two copies of one. The relatively rare APOE e2 appears to protect some people from AD, as it seems to be associated with a lower risk of AD and a later age of onset if AD does develop. APOE e3 is the most common version found in the general population, and only appears to have a neutral role in AD. However, APOE e4 appears to increase the risk of developing late onset AD with the inheritance of one or two copies of APOE e4. Compared to those without APOE e4, 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. Having APOE e4 can also lower the age of onset by as much as 17 years. However, APOE e4 only increases the risk of developing AD and does not cause it, as not everyone with APOE e4 develops AD, and people without it can still have the disease. Why APOE e4 increases the chances of developing AD is not known with certainty. However, one theory is that APOE e4 facilitates beta-amyloid buildup in plaques, thus contributing to the lowering of the age of onset of AD; other theories involve interactions with cholesterol levels and effects on nerve cell death independent of its effects on plaque buildup. In 2000, four new AD-related regions in the human genome were identified, where one out of several hundred genes in each of these regions may be a risk factor gene for AD. These genes, which are not yet identified, appear to make a contribution to the risk of developing late-onset AD that is at least as important as APOE e4.

Other non-genetic factors have also been studied in relation to the causes of AD. Inflammation of the brain may play a role in development of AD, 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, which 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. Vitamin E is one such antioxidant, and its use in AD may be of possible theoretical benefit.

While the ultimate cause or causes of Alzheimer's disease are still unknown, there are several risk factors that increase a person's likelihood of developing the disease. The most significant one is, of course, age; older people develop AD at much higher rates than younger ones. There is some evidence that strokes and AD may be linked, with small strokes that go undetected clinically contributing to the injury of neurons. Blood cholesterol levels may also be important. Scientists have shown that high blood cholesterol levels in special breeds of genetically engineered (transgenic) mice may increase the rate of plaque deposition. There are also parallels between AD and other progressive neurodegenerative disorders that cause dementia, including prion diseases, Parkinson's disease, and Huntington's disease.
Numerous epidemiological studies of populations are also being conducted to learn more about whether and to what extent early life events, socioeconomic factors, and ethnicity have an impact on the development of AD. For example, results from one study indicated that rural residence in childhood, along with fewer than six years of schooling, was associated with increased AD risk. However, the low educational attainment that was identified as a risk factor might be a marker or surrogate for other deleterious socioeconomic or environmental influences in childhood, thus illustrating the difficulties in interpreting epidemiological findings, due to the complexity of the issues and the large number of variables involved.

Many environmental factors have been suspected of contributing to AD, but epidemiological 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 factors.

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