Genetic and Non-Genetic Risk Factors for Alzheimer’s

Genetic Risk Factors

Scientists who study the genetics of Alzheimer’s distinguish between “familial Alzheimer’s disease,” which runs in families, and “sporadic Alzheimer’s disease”, where no obvious inheritance pattern is seen. True familial Alzheimer’s disease accounts for less than 5% of Alzheimer’s cases. Sporadic Alzheimer’s is much more common.

Familial Alzheimer’s Disease
All Familial Alzheimer’s disease known so far has an early onset, and as many as 50 percent of the cases are now known to be caused by defects in three genes located on three different chromosomes, the structures inside cells that house the genetic code. Some families have mutations in a gene called amyloid precurser protein (APP), which causes an abnormal form of the amyloid protein to be produced. Other families have mutations in a gene called presenilin 1, which causes an abnormal presenilin 1 protein to be produced. Still others have mutations in a very similar gene called presenilin 2, which causes an abnormal presenilin 2 protein to be produced.

Even if one of these mutations is present in only one of the two copies of a gene inherited from a person’s parents, the person will inevitably develop that form of early-onset Alzheimer’s (this is called autosomal dominant inheritance). However, the total known number of these cases is small (between 100 and 200 worldwide), and there is as yet no evidence that any of these mutations play a major role in the more common, sporadic or non-familial form of late-onset Alzheimer’s. Scientists are working to reveal the normal function of APP and presenilins and to determine how mutations of these genes cause the onset of familial Alzheimer’s disease.

Sporadic Alzheimer’s Disease
Although there is no evidence that autosomal dominant inheritance of mutated genes causes late-onset Alzheimer’s, genetics does appear to play a role in the development of this more common form of the disease. Research has found an increased risk for late-onset Alzheimer’s in people who inherit one or two copies of a particular variation of a gene called apolipoprotein E (APOE) — the variation known as APOE e4. Different variations, or alleles, of particular genes produce variations in inherited characteristics, such as eye color or blood type. In this case, the variations are in the APOE gene that directs the manufacture of apolipoprotein E, a protein that helps carry blood cholesterol throughout the body, among other functions. It is found in neurons and other supportive brain cells (called glia) of healthy brains, but it is also associated in excess 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. The finding that increased risk is linked with inheritance of the APOE e4 allele has helped explain 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 one inherits, the lower the age of disease onset. The relatively rare APOE e2 allele may protect some people against the disease: 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 is the most common version found in the general population and may play a neutral role in Alzheimer’s risk.

Does everyone who carries the APOE gene develop Alzheimer’s disease?
The inheritance of one or two APOE e4 alleles does not predict Alzheimer’s with certainty. That means that, unlike early-onset familial Alzheimer’s disease, a person can have one or two APOE e4 alleles and still not get the disease, and a person who develops the disease may not have any APOE e4 alleles. APOE e4 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 known with certainty, but one possible mechanism is that it facilitates beta amyloid buildup in plaques and this contributes 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.

Non-Genetic Risk Factors

During the course of normal aging, the brain undergoes a number of changes:

  • Some neurons (nerve cells) in certain brain regions die, although most neurons important to learning are spared;
  • Some neurons and the fibers that connect them to other neurons shrink and degenerate, especially neurons in areas of the brain important to learning, memory, planning and other complex mental activities;
  • Tangles develop within neurons and protein plaques develop in the areas surrounding neurons;
  • Tiny structures inside neurons that metabolize energy for cell functions (mitochondria) become more susceptible to damage;
  • Inflammation (swelling) increases, which can injure nerve cells, such as after a head injury;
  • Oxidative stress, which is caused by the release of molecules called free radicals from normal cellular processes, increases, leading 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 in normal aging and what relevance this has to Alzheimer’s is an important area of research.

Education level
Research suggests that the more years of formal education one has, the less likely one is to develop Alzheimer’s. Some experts theorize that longer education may produce a denser network of synapses, the nerve-fiber connections that enable neurons to communicate with one another. This may create a kind of “neural reserve” that enables people to compensate longer for the early brain changes associated with Alzheimer’s.

Race and Ethnicity
African-Americans and Hispanics are at a higher risk for developing Alzheimer’s. Studies have shown that older African-Americans and Hispanics were almost twice as likely to develop Alzheimer’s as white Americans of the same age. While the reasons for this are unclear, there is some speculation that it may have to do with the fact that these groups have a higher incidence of high blood pressure anddiabetes, which are known to increase one’s chances of developing Alzheimer’s.

High blood pressure and high 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. Studies are showing that what’s good for the heart – keeping cholesterol and blood pressure in check – may also be good for the brain.

Diabetes has been implicated as a risk factor for eventually developing Alzheimer’s disease. There are many ongoing studies attempting to understand the connection, and some diabetes drugs appear to slow the cognitive decline associated with Alzheimer’s disease. By 2050, according to the Centers for Disease Control and Prevention, the number of people with diagnosed diabetes is projected to increase from 11 million to 29 million. Controlling blood sugar levels with diet and medication may help.

Head trauma
Some studies have found that Alzheimer’s occurs more often in people who have suffered traumatic brain injury earlier in life. Ongoing research is pursuing this link further. A history of head injury is clearly a risk factor for Alzheimer’s in people who carry the APOE-4 Alzheimer’s gene.

One of the most publicized and controversial hypotheses about 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. 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 not in all, and the aluminum found in some studies may have come from substances used in the laboratory to study brain tissue. Moreover, various studies have found that groups of people exposed to high levels of aluminum do not have an increased risk. On the whole, scientists can say only that it is still uncertain whether exposure to aluminum plays a role in Alzheimer’s disease.

Dietary factors
The evidence that what you eat matters to your brain is growing fast. Many studies have recently reported that many of the same factors that contribute to poor heart health also increase one’s risk of cognitive decline or developing Alzheimer’s disease. It is very important to eat in moderation and maintain a healthy body weight, as people who are obese double their risk of developing dementia according to the Alzheimer’s Association. Research has found that people who ate foods high in fat and sugar, as well as larger amounts of red and processed meats had a higher risk of developing Alzheimer’s than people who ate more lean meats (fish and poultry) and more fruits and vegetables. Yet another study has shown that vitamin B-12 and folic acid deficiencies coupled with increased levels of homocysteine, a compound found in the blood that has been linked to increased risk of certain cardiovascular conditions, resulted in lower scores on cognitive tests. It is also important to avoid obesity, as people who are obese have an increased risk of developing dementia. Taken as a whole, these and other studies support the notion that eating a balanced diet and eating in moderation throughout your life is just as important to long-term cognitive health as it is to heart health.

Alzheimer’s is more prevalent among women, but this is more likely because women, on average, tend to live longer than men and not because gender is a risk factor for Alzheimer’s.

This project was supported, in part, by a grant, number 90AZ2791, from the Administration on Aging, Department of Health and Human Services, Washington, D.C. 20201. Grantees undertaking projects under government sponsorship are encouraged to express freely their findings and conclusions. Points of view or opinions do not, therefore, necessarily represent official Administration on Aging policy.


Fisher Center for Alzheimer’s Research Foundation