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Rabins on Research

“Is Alzheimer’s disease genetic? Do my children have to worry?”

This is one of the most common questions I am asked, whether when I am evaluating a new patient or giving a lecture to the public. This probably reflects the fact that many families identify more than one family member who has suffered from dementia.

The answer is complicated. This is recognized by professional geneticists, who use the phrase ‘complex inheritance’ to describe the genetics of illnesses like Alzheimer’s disease. In fact, we know more about the genetics of Alzheimer’s disease than we do other conditions with similar complex inheritance such as high blood pressure, diabetes, Parkinson’s disease, and depression.

Two to three percent of cases of Alzheimer’s disease are caused by gene abnormalities that are inherited as a ‘dominant’ gene. This means that if a person inherits the abnormal gene and lives long enough they will almost certainly develop the disease. Most cases of this form of Alzheimer’s disease begin before age of 65.

However, 30-60 percent of cases of Alzheimer’s disease are genetically influenced. That is, the person has inherited a tendency to develop Alzheimer’s disease, but it is not inevitable that they will come down with the disease even if they live to very late life. Most of this is related to one gene that is named APOE (pronounced a’ poe ee). All humans have two copies of this gene, one inherited from each parent. The gene comes in 3 forms (called alleles), that have been labeled 2, 3, and 4, and all are ‘normal.’ It is the APOE 4 form of the gene that increases the risk of developing the disease by three fold. This means that a person with one APOE 4 allele has three times the risk of developing Alzheimer’s disease as a person who has no 4 allele. If a person inherits two copies of the 4 allele (one from each parent), the risk of developing Alzheimer disease is 12-15 times higher than someone who does not have a 4 allele.

What does this mean for an individual? We know from population studies that 20-25 percent of people at age 80 have Alzheimer’s disease. Combining that information with the information in the prior paragraph, a person who is 80 years old and has one APOE 4 allele actually has a 30 percent chance of having Alzheimer disease while a person with no APOE 4 has a 20 percent chance.

How can this be? A recent study in the scientific journal Nature offers an answer. Two groups of researchers from around the world reported on more than 50,000 people with Alzheimer’s disease and found that there are 7-10 other genes that also influence the risk of developing Alzheimer’s disease. However, none of these genes contributes more than a 1 or 2 percent risk. The mechanisms by which these genes influence the risk of developing Alzheimer’s disease is now the focus of intense scrutiny. Perhaps this will open the door to discovering how Alzheimer’s disease is caused and eventually lead to the development of new avenues of treatment.

Of course, if two-thirds of cases of Alzheimer’s disease have a genetically influenced origin, that means that environment may play a role in those cases as well as in the cases in which no genetic influence is found. This too is a field of intense scientific scrutiny.