The Genetics of Alzheimer's Disease

It’s one of society’s most dreaded diseases. A missed appointment, a forgotten name, or a relative diagnosed with dementia can send people into a spiral of fear that they, too, might develop Alzheimer’s Disease, for which there is no cure and relatively little treatment. Just how real is the risk, and is Alzheimer’s Disease genetic? We talked with Maysen Mesaros, neuroscience genetic counselor for MUSC Health’s Neurology Department, who works with patients diagnosed with cognitive, movement, epileptic, and neuromuscular disorders, to learn more about the genetic components of Alzheimer’s Disease, whether someone should be tested for Alzheimer’s and what results really reveal.   

Q. Is there more than one type of Alzheimer’s Disease?

A. Typically, Alzheimer’s disease can be categorized into 2 subsets: Late onset, which occurs in people after 65, and early onset which occurs before the age of 65.

Q. Is Alzheimer’s Disease genetic?

A. We know that genetic factors are involved in the development of both early and late onset Alzheimer’s disease. However, our understanding of the genetics of early onset Alzheimer’s is stronger than that of late onset. Three genes are known to cause early-onset Alzheimer’s disease. They are called APP, PSEN1 and PSEN2. When someone is born with a mutation in one of these genes, it puts them at a predisposition to develop early-onset Alzheimer’s. When someone has early onset Alzheimer’s due to a mutation in one of these three genes, there is a 50% chance for their first-degree relatives (children, siblings, and parents) to have the same genetic predisposition. Typically, if we are going to find a mutation in one of these genes, it is in an affected patient that has multiple relatives also affected with early onset Alzheimer’s disease. It is rare, however, that we find one of these genetic mutations in early onset Alzheimer’s disease in general. In fact, mutations in those 3 genes are only identified in about 11 percent of early-onset Alzheimer’s overall, and early onset makes up just 5 percent of all Alzheimer’s diagnoses.

Q. What other factors contribute to Alzheimer’s Disease?

In general, we know Alzheimer’s disease is considered to be a multifactorial condition. This means it’s due to a combination of genetic and environmental factors that mix together and cause disease. In contrast to the three genetic forms of early onset Alzheimer’s disease, where a single genetic mutation leads to disease development, most of the time, multiple genes are likely involved in the development of Alzheimer’s disease. Changes in multiple genes each add a little bit of susceptibility to Alzheimer’s disease, and when mixed with environmental factors such as aging, disease eventually can develop. You can think of multifactorial disease as a jar of marbles. You may start with 10 or 15 marbles in your jar and each of those marbles represents a small genetic risk factor for Alzheimer’s disease. As you age or are exposed to other environmental risk factors for Alzheimer’s disease such as cardiovascular disease, more marbles are added to the jar. Eventually, the jar fills up, and that is when disease happens. Unfortunately, we do not have testing that can look at every single “marble” to tell us how disease happened. Today’s genetic testing can only look for a single genetic predisposition to Alzheimer’s disease.

Q. At what age does early onset Alzheimer’s develop?

A. Generally, it begins when people are in their 50s, but people can develop the disease as early as their 30s.

Q. Do you test patients with Alzheimer’s Disease?

Yes. Most patients that I see are symptomatic and have already been seen by a neurologist and have been diagnosed with Alzheimer’s disease. The majority of patients that I see have early-onset Alzheimer’s disease, but I occasionally see some patients with late onset disease who have a strong family history of Alzheimer’s. I also have seen patients that are asymptomatic but have a family history of early onset Alzheimer’s disease and wish to better understand their own risk.

Q. If your patients have already been diagnosed, why do you conduct genetic tests?

A. Testing ultimately does not change their diagnosis, but it may provide clarity and answers to the patient/family as to why the disease developed. Identifying a genetic explanation for Alzheimer’s disease can also help to determine potential eligibility for clinical trials that may exist now or in the future. Additionally, many patients undergo genetic testing to better understand risk for their relatives, such as children, to develop disease. At this time, when we find a genetic explanation for Alzheimer’s disease, it typically doesn’t change the patient’s day-to-day management.

Q. Why is genetic testing important?

A. Genetic testing is important for many reasons, and some of that depends on the patient’s perspective. One reason genetic testing is becoming increasingly important across several diseases is for development of therapies. The more we can understand about disease development, the closer we can get to targeted therapies that go after the root of the problem (genetic mutation) instead of just treating symptoms.

Q. What about late onset Alzheimer’s disease? Is that genetic?

A. One particular gene, the APOE gene, is believed to have a role in the development of late onset Alzheimer’s disease. We all have 2 copies of this gene, one from our mother and our father, and there are 3 different versions of it: e2, e3 and e4. People can have any combination of the versions (i.e. e3/e3, e3/e4, e2/e4, and so on). People who carry the e4 version on one of their copies (e3/e4) have a slightly higher risk -- 2-3 times higher -- than the general population for developing Alzheimer’s disease. So, if the general population has a 10-percent lifetime risk for Alzheimer’s, someone with this APOE risk factor has a 25 -30 percent lifetime risk of developing the disease. This still means that the majority of people who carry this risk factor won’t develop Alzheimer’s in their lifetime. This makes testing for the APOE gene very tricky and controversial because of the ambiguity of risk.

Q. So should people get tested for APOE? Do people come to you requesting a test?

A. Testing is available, but it’s very important for people to understand that predictive testing really isn’t very informative because the risk associated with APOE is still relatively low. Predictive testing requires a lot of education and counseling about the potential implications.

Q. Can insurance companies discriminate against people who have a documented risk for developing Alzheimer’s?

A. The federal Genetic Information Nondiscrimination Act (GINA) prevents employers and health insurance from discriminating against someone based solely on a genetic test result. GINA does not, however, protect patients against discrimination from long-term care insurance, disability, and life insurance. If someone is already affected or if these plans (i.e. life insurance) are already in place, they’re not likely to be asked about genetic testing. The situation is most problematic for people who are thinking about genetic testing for predictive purposes (asymptomatic) and don’t have those plans in place yet.

Q. What else would you like readers to know about genetic testing?

A. My role as a genetic counselor is to help patients and families understand their risk for genetic disease. Sometimes that conversation does result in genetic testing, but I don’t automatically test everyone who comes through my door. It’s my job to help people understand the medical, psychological, and familial implications of being tested. It’s very individualized to patients and families, and requires shared decision-making.