| |
Risk Factors for Alzheimer's Disease
It is highly likely that the Alzheimer's results from a highly complex and interrelated combination of genetic and non-genetic factors.
These so called risk factors influence a person's risk to developing Alzheimer's disease. Currently, each of these risk factors is the subject of a great deal of research around the world.
Genetic Risk Factors
A person's genetic make up can directly influence the chances for the onset and development of Alzheimer's. A person's genes are inherited from their biological parents and passed along family lines to their biological children.
The so-called genetic risk factors are discussed below.
Family Links
There are two main types of Alzheimer's Disease :
- Familial Alzheimer's Disease (FAD): is a very rare form of Alzheimer's Disease which runs in families. Also known as Early Onset Alzheimer's or Younger Onset Alzheimer's.
- Sporadic Alzheimer's Disease: is the most common form of Alzheimer's Disease, but researchers are still trying to work out how this develops. Also known as Late Onset Alzheimer's.
Familial Alzheimer's Disease (FAD) - Early Onset Alzheimer's
Familial Alzheimer's Disease (FAD) is a very rare form of Alzheimer’s, and runs in very few families. If a parent has a specific mutated gene, then any children have a 50% chance of inheriting and developing the disease.
The presence of the specific mutated gene means that the person will eventually develop Alzheimer’s disease, usually in their 40’s or 50’s .
This form of Alzheimer’s affects a very small number of people. The total known number of FAD cases worldwide is about 200 people.
All instances of FAD that have been studied so far have a much earlier onset, and as many as 50 percent of FAD cases are now known to be caused by defects in one or more of three genes located on three different chromosomes inside the person's cells :
- Amyloid Precursor Protein (APP) Mutation: Some families have mutations in a gene called amyloid precursor protein (APP), which causes an abnormal form of the amyloid protein to be produced.
- Presenilin 1 Mutation: Other families have mutations in a gene called presenilin 1, which causes an abnormal presenilin 1 protein to be produced.
- Presenilin 2 Mutation: Presenilin 2 is a gene very similar to presenilin 1, and when this gene is mutated, then it causes an abnormal presenilin 2 protein to be produced.
Any of these mutations are believed to cause FAD.
Furthermore, even if only one of these mutations is present, and it is present in only one of the two matching genes inherited from their parents, then the person will still inevitably develop FAD. This type of genetic inheritance is known as autosomal dominant inheritance.
There is no evidence at this stage that any of these mutations play a major role in the far more common sporadic (i.e. late-onset) Alzheimer's.
Scientists are striving to reveal the normal function of Amyloid Precursor Protein (APP) and the presenilin proteins to determine how mutations of these genes cause the onset of FAD.
Sporadic Alzheimer's - Late Onset Alzheimer's
Sporadic Alzheimer's, also known as Late Onset Alzheimer's, is the most common form of Alzheimer's by far, and tends to occur much later in life than FAD. That is, it can affect adults of any age, but it usually occurs after age 65.
This form Alzheimer's can affect people who may or may not have a family history of the disease.
There is currently no evidence that autosomal dominant inheritance of mutated genes causes Sporadic or Late Onset Alzheimer's. However, genetics does appear to play a significant role in the development of this far more common form of the disease.
Different variations, or alleles, of particular genes produce variations in inherited characteristics, such as height, skin color, eye color, blood type, and so on.
In the early 1990s, researchers at Duke University in Durham, North Carolina, found an increased risk for late-onset Alzheimer's in people who inherited one or two copies of a particular variation of a gene called apolipoprotein E (APOE) - the variation known as APOE e4.
Apolipoprotein E is a protein that has various functions, such as helping the blood to carry cholesterol throughout the body.
This protein was found in neurons and other supportive brain cells (called glia) of healthy brains, but it is also found in excessive amounts with the plaques found in the brains of people with Alzheimer's.
Researchers are particularly interested in three common alleles of the APOE gene: e2, e3 and e4.
APOE e2
There is evidence to suggest that the relatively rare APOE e2 allele may protect some people against the disease because it seems to be associated with a lower risk for Alzheimer's and a later age of onset if the disease does develop.
APOE e3
The APOE e3 allele is the most common version of APOE found in the general population and current evidence suggests that it plays a neutral role in Alzheimer's risk.
APOE e4
The discovery that increased an risk is associated with the inheritance of the APOE e4 allele has helped explain why there are some of the variations in age of onset of Alzheimer's disease based on whether people have inherited zero, one, or two copies of the APOE e4 allele from their parents.
The more APOE e4 alleles inherited, the lower the age of disease onset.
The inheritance of one or two APOE e4 alleles does not guarantee that the person will definitely develop Alzheimer's.
That is, unlike early-onset FAD, a person can have one or two APOE e4 alleles and still not get the disease.
In addition, a person who develops the disease may not have any APOE e4 alleles.
APOE e4 seems to increases the risk of developing Alzheimer's, but it does not cause the disease.
The ways in which APOE e4 increases the likelihood of developing Alzheimer's are not currently known with any certainty. However, APOE e4 does facilitate beta amyloid buildup in plaques and this seems to contribute to lowering the age of onset of the disease.
Other theories involve interactions with cholesterol levels and effects on nerve cell death that are independent of its effects on plaque buildup.
Other genes
Studies over the last few years indicate that there are additional risk factor genes for late-onset Alzheimer's, and candidates continue to be identified in this area of research.
Using high blood levels of beta amyloid as a marker of a genetic defect, several research groups have reported compelling evidence that a region on chromosome 10 may contain another gene linked with Alzheimer's.
Non-Genetic Risk Factors
Non-genetic risk factors include a range of diverse factors, including :
- Age
- Food and Diet,
- Consumption of Metals,
- Weight, Blood Pressure, Heart Disease and Cholesterol,
- Smoking,
- Diabetes,
- High Homocysteine Levels,
- Head Trauma History,
- Education Level,
- Early Life Experiences, and,
- Hormone Replacement Therapy (HRT).
Each of these risk factors is discussed below.
Age
As a person ages, their brain undergoes a number of changes :
- Some nerve cells, called neurons, in various regions of the brain die, although the neurons most important to learning usually live on.
- Some neurons, and the fibers that connect them to other neurons, shrink and degenerate. This tends to especially occur areas of the brain that are important to learning, memory, planning, problem solving, and other complex mental activities.
- Twisted fibers, called tangles, develop within neurons and protein plaques (see Glossary of Terms on page 60) develop in the areas surrounding neurons.
- Tiny structures inside neurons that metabolize energy for cell functions become more susceptible to damage.
- Inflammation (swelling) of the brain increases, which cause damage to nerve cells.
- Oxidative stress increases. This is caused by the release of special molecules, called free radicals, from normal cellular processes. This can lead to nerve cell damage and death.
In healthy older people, the impact of these changes may be modest, resulting in various degrees of age-related memory decline. In people who have Alzheimer's, however, some of these changes are much more extreme, with devastating consequences. Determining how the brain changes under normal aging conditions and what relevance these have to Alzheimer's is an important area of research.
Food and Diet
There is a growing pool of evidence that suggests that what you eat is very important to your brain. A range of recent studies have reported a link between dietary habits and specific nutritional factors to the risk for Alzheimer's disease and/or cognitive decline.
In particular, the benefits to the brain of a low-fat diet rich in antioxidants such as vitamins E and C throughout life are becoming clearer.
Here's what some of the latest research studies have found :
- A diet rich in foods containing vitamin E may help protect against Alzheimer's in some people, according to a study conducted at Rush-Presbyterian-St. Luke's Medical Center in Chicago and reported in the prestigious Journal of the American Medical Association (JAMA).
Such foods include vegetable oils, nuts, green leafy vegetables, and whole grains. Furthermore, the protective effect was NOT seen when study participants took vitamin E supplements, as opposed to getting more of the vitamin from foods. The most significant protective effect was found among those who had the highest dietary intake of vitamin E (which averaged 11.5 International Units per day); their risk of developing Alzheimer's was 67 percent lower than people who consumed the least amount of vitamin E from food sources.
In addition, the researchers found that vitamin E is associated with protection against more general cognitive decline. Ongoing clinical trials are investigating whether vitamin E might be useful as a treatment for Alzheimer's, and if it can be used to help prevent the disease.
- A study reported at the 2002 International Conference on Alzheimer's Disease found that a low-fat, antioxidant-rich diet was associated with decreased risk of Alzheimer's disease, an association that held up even in people who carry the APOE-4 gene, the only known genetic risk factor for late-onset Alzheimer's.
- Researchers at Case Western Reserve University School of Medicine found that people who ate primarily lean meats (fish and poultry) and fruits and vegetables during midlife had a lower risk of developing Alzheimer's than people who ate a diet higher in fat and sugar and consisting of larger amounts of red and processed meats.
- A Netherlands study, published in the Journal of the American Medical Association (JAMA), reported a link between high dietary intake of vitamins E and C and protection against Alzheimer's disease in certain people. Both vitamins have antioxidant properties that experts believe may help reduce damage to nerve cells caused by oxidative stress, which occurs throughout the body as a natural consequence of aging and may contribute to Alzheimer's disease in ways that are not fully understood.
- Two studies point to the importance of B vitamins and levels of homocysteine, a compound found in the blood that has been linked to increased risk of certain cardiovascular conditions, including stroke and damage to the arteries.
- The first study, published in the American Journal of Clinical Nutrition, found that people with increased levels of homocysteine and deficiencies in vitamin B-12 and folic acid, another B vitamin, achieved lower scores on cognitive tests.
- A second study, reported at a major Alzheimer's conference, found elevated homocysteine levels and low levels of vitamin B-12 in African-Americans with Alzheimer's disease.
Taken as a whole, these and many other studies support the idea that eating the right food throughout your life is just as important to long-term cognitive health as it is to heart health.
A number of long-term, prospective clinical trials are now underway to test the effectiveness of vitamin E and other antioxidants in preventing or postponing cognitive decline and Alzheimer's disease. Several are funded by the National Institute on Aging.
Consumption of Metals
Aluminum
One of the most alarming and controversial hypotheses about the potential risk factors for Alzheimer's concerns aluminum, which became a suspect when researchers found traces of this metal in the brains of Alzheimer's patients.
This is indeed a grave concern because many people use aluminum pots and pans for cooking, and aluminum canteens for drinking in the world.
Many studies since then have either not been able to confirm this finding or have had questionable results. Aluminum does turn up in higher amounts than normal in some autopsy studies of Alzheimer's patients, but this certainly doesn't occur in all. In addition, the aluminum found in some studies may have come from substances used in the laboratory to study the brain tissue after death.
Moreover, various other studies have found that groups of people exposed to high levels of aluminum do not have an increased risk of developing Alzheimer's.
On the whole, scientists can say that it is still very debatable whether exposure to aluminum plays any role in the development of Alzheimer's disease.
Zinc
Zinc has been implicated in Alzheimer's disease in various studies.
Some research reports suggest that too little zinc may be a problem, while other studies suggest that too much zinc is an issue.
Too little zinc was suggested by autopsies that found low levels of zinc in the brains of Alzheimer's disease patients, especially in the hippocampus, the part of the brain involved in learning and memory.
However, other studies suggest that too much zinc might be the problem. In laboratory experiments, zinc caused the formation of soluble beta amyloid from cerebrospinal fluid to form clumps similar to the plaques seen in the brains of Alzheimer's sufferers.
Current experiments with zinc are continuing, with new laboratory tests that closely mimic conditions in the brain.
Weight, Blood Pressure, Heart Disease and Cholesterol
There is growing evidence that many of the well-established risk factors for cardiovascular disease, including high cholesterol and high blood pressure, may also be risk factors for Alzheimer's disease.
Brain infracts, heart disease and mid-life hypertension increase the risk of Alzheimer’s disease and Vascular dementia.
A large study by researchers in Finland supports this thinking. Among the study population of 1,449 people, elevated cholesterol and high blood pressure seemed to be even more strongly linked to the eventual development of Alzheimer's than did carrying APOE-4 gene, the only known inherited risk-factor for the most common form of the disease.
Those people who carried the APOE-4 gene were twice as likely to develop Alzheimer's than those with no genetic risk. However, if those APOE-4 carriers also had high blood pressure, then they were up to five times as likely to develop the disease.
When high cholesterol was also present, the risk jumped to eight times greater than those without APOE-4.
This and a number of other studies around the world are strongly indicating that what's good for the heart - keeping weight, cholesterol and blood pressure in check - may also be good for the brain.
Cholesterol is essential for healthy brain function – it is a component of cell membranes (structures that enclose nerve cells), and it is required for the repair and establishment of new connections between nerve cells. However, studies have shown that high cholesterol in mid-life and late-life can significantly increase the risk of Alzheimer’s Disease. Subsequent studies have indicated that cholesterol lowering drugs may lower the risk of developing Alzheimer’s disease.
Smoking
Smoking, another well-established risk factor for cardiovascular disease, has also been identified as a risk factor for Alzheimer's.
Diabetes
Recent studies have found that having diabetes also seems to increase the risk of developing Alzheimer’s by up to 65%. This risk can be reduced by careful management of diabetes with medications that maintain blood glucose levels within a healthy range.
High Homocysteine Levels
Homocysteine is a by-product of many metabolic reactions occurring in our body. Some studies have found that high homocysteine levels are associated with an increased risk of Alzheimer’s Disease and other dementias. Adequate intake of vitamin B and folate can help reduce homocysteine levels.
Head Trauma History
Some studies have found that Alzheimer's occurs more often in people who have suffered traumatic brain injury earlier in life. For example, people who have received a number of concussions from motorcycle or horse riding accidents seem to be more likely to develop Alzheimer's later in life.
A study of World War II veterans also indicated that moderate to severe head injury increased risk of developing Alzheimer’s disease and other dementias. Other studies have found that this risk is further increased if the head injury resulted in loss of consciousness.
Some sports, such as boxing, also have definite links with Alzheimer’s, especially where a person has been forcefully punched over a number of years and knocked out on one or more occasions.
Further research is required to further study this potential link.
Education Level
Other research suggests that people with more years of formal education are less likely to develop Alzheimer's.
Some experts theorize that longer education may produce a denser network of synapses in the brain. Synapses are the nerve-fiber connections in the brain that enable neurons to communicate with one another.
A dense synapse network may create a kind of "neural reserve" that enables people to compensate longer for the early brain changes associated with Alzheimer's.
However, there could be other answers to this. Further research is required.
Early Life Experiences
Unsurprisingly, the environment in which a person lives – especially early in life - has been implicated as a risk factor for many chronic adult diseases, including Alzheimer's.
However, a recent study has linked a surprising selection of environmental, socio-economic, and early life experience factors to Alzheimer's. For example :
- An increased number of siblings was associated with increased risk of Alzheimer's.
- A rural residence in childhood, combined with fewer than six years of school, was associated with an increased risk for Alzheimer's.
- Growing up in the country, rather than in the suburbs, was associated with an increased risk for Alzheimer's.
These findings were not explained by patients' educational level or whether they carried the APOE gene that is associated with Alzheimer's.
Such results appear to support a possible link between socio-economic or environmental variables and altered brain growth and development, which in turn may affect the risk of developing Alzheimer's disease later in life.
A number of researchers have conducted these types of epidemiological studies to learn about the various factors that can have an impact on the development of Alzheimer's.
Though such findings can be suggestive and interesting, they can also be conflicting or incomplete and highly controversial, because different teams of investigators may use different study methods and because of the complexity of the issues and the mind-boggling number of variables involved.
For example, low educational attainment may actually be a result of other socio-economic or environmental influences in childhood.
Further research is definitely required.
Hormone Replacement Therapy (HRT)
Several studies indicate that Hormone Replacement Therapy (HRT) may help delay the onset of dementia in women.
However, these findings have recently been contradicted by the large Women's Health Initiative study which found that HRT, when given later in life, may have a negative effect on cognition.
The findings of these studies are further complicated by suggestions that the effect of HRT may be dependant on recipient's genetic make-up or other factors. For example, it is possible that HRT has a negative effect on cognition of women who carry ApoE4 allele.
|
