Alzheimer's Research on Causes and Risk Factors - Genetic Risk Factors

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Genetic (Inherited) Factors

Topics:
- Are there genes that are known to cause Alzheimer's?
- Do genes play a role in the most common form of Alzheimer's?
- Does everyone who carries the APOE gene develop Alzheimer's disease?
- Are there likely to be other genes discovered that increase risk for Alzheimer's?
- How does the identification of genes for Alzheimer's help advance understanding of the disease?


Are there genes that are known to cause Alzheimer's?

Scientists who study the genetics of Alzheimer's distinguish between familial AD (FAD), which runs in families, and sporadic Alzheimer's disease, where no obvious inheritance pattern is seen. Sporadic Alzheimer's, which tends to occur later in life, is much more common than FAD.

All FAD known so far has an early onset, and as many as 50 percent of FAD 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, and 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 now working to reveal the normal function of APP and presenilins and to determine how mutations of these genes cause the onset of FAD.


Do genes play a role in the most common form of Alzheimer's?

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. 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. 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 inherited, 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 FAD, 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.


Are there likely to be other genes discovered that increase risk for Alzheimer's?

Studies over the last several years strongly suggest that there are additional risk factor genes for late-onset Alzheimer's, and candidates continue to be identified in this exciting new area of research. Already, using high blood levels of beta amyloid as a marker of a genetic defect, several groups have reported strong evidence that a new region on chromosome 10 may house another gene for Alzheimer's. Building on the improving understanding of the genetics of Alzheimer's disease, scientists will continue to look for clues as to which protein structures hasten the initiation of the disease process, what mechanisms cause it, and what the sequence of events is. Once they understand these, they can then look for new ways to diagnose, treat or even prevent Alzheimer's Disease.


How does the identification of genes for Alzheimer's help advance understanding of the disease?

The discovery of genes associated with Alzheimer's initiated the modern era of Alzheimer's research. Building on this basic research, which was primarily funded by the National Institutes of Health (NIH), scientists zeroed in on the proteins made by these genes, uncovering major clues to the biological sequence of events in the development of Alzheimer's. Understanding the gene products and the pathways through which these proteins are processed now allows the design of treatments targeted to the early events that underlie Alzheimer's pathology. By interfering with the disease early on, this approach aims to arrest the disease before it affects brain function and causes clinical symptoms.

A major advance made possible by this genetic research was the development of the first animal models of Alzheimer's disease, which were created by inserting mutated human APP genes into mouse eggs and raising the mice to adulthood. Scientists can then observe the formation of amyloid plaques and other hallmarks of Alzheimer's biology in the brains of these "transgenic" mice as they age. Since then, numerous transgenic animal models of Alzheimer's disease have been developed, allowing scientists to understand better how a complex array of pathways both inside and between cells can interact to affect the production of Alzheimer's plaques. These animal models are also beginning to provide a means of testing the efficacy of different treatments on reducing build up of plaques and on cognitive function.