Brain; Discovery

What genetic testing can reveal about your Alzheimer's disease risk

Brain; Discovery

Alzheimer's genetic testing
A genetic counselor can walk you through the complexities of genetic testing for Alzheimer's disease and help you determine if it’s right for you.

Chris Hemsworth has made headlines in the last year for more than his latest “Thor” movie. The actor announced he had learned through genetic testing that he has two copies of the genetic variant APOE4, which has been associated with increased odds of developing Alzheimer's disease.

Hemsworth’s story, which was featured on National Geographic’s Limitless, a docuseries about living better longer, has increased media focus around genes associated with Alzheimer's disease, a degenerative brain disorder that affects the way we store and retrieve memories. It also has piqued people’s interest in seeking saliva- or blood-based genetic testing and counseling, which has both inherent benefits and drawbacks.

For instance, some news reports have exaggerated how much genetic testing can tell people about their risk of developing Alzheimer's disease.

Every person has a baseline 10% to 15% risk of developing Alzheimer's during their lifetime. Factors such as family history and diet, exercise, drinking, and smoking habits can increase that number.

While having variants in certain genes can increase your Alzheimer's disease risk, genetics alone rarely determine whether you will or will not get the disease. In fact, most people with genetic variants of APOE4, otherwise known as the apolipoprotein E gene allele 4, will never develop Alzheimer's disease.

If you are concerned about your risk, a genetic counselor can help discuss whether testing is recommended for you, what genetic testing can and cannot reveal about your risk of developing late-onset (after 65) or early-onset (before 65) Alzheimer's disease, and how your lifestyle may further affect your risk.

How genes cause or affect Alzheimer's risk

DNA is the body’s instruction manual and genes are the individual instructions that code for proteins to be built. Properly built proteins are what our body needs to live a healthy life. We have two copies of each gene, one from each parent, and small changes called variants within a gene are common. Think of variants like spelling – if you change just one letter in the word “top” it becomes “tip.” The words are different, but the meaning is pretty much the same and unlikely to cause functional problems. Similarly, most genetic variants will never cause disease.

A group of genes and a combination of lifestyle factors typically influence the development of a multifactorial disease like Alzheimer's – not one single gene.

Today’s genetic technology can only look at disease caused by single genes, not multifactorial genetic disease, which means if you get a negative result, that doesn’t mean you have ruled out the possibility of developing Alzheimer's disease.

Genes associated with Alzheimer's disease

Late-onset Alzheimer's disease is the most common form of the disease. APOE is the most common gene linked to late-onset Alzheimer's disease, specifically the e4 variant of this gene (APOE4). About one in four people have one copy of their APOE gene “spelled” as this e4 variant.

Mr. Hemsworth had two copies of APOE4, putting him in a category with only 2% to 3% of the population, according to data from the National Institute on Aging.

APOE4 does not cause Alzheimer's disease – it only slightly increases a person’s lifetime risk of developing the disease:

  • If you have one copy of APOE4, your risk increases about 5% from the general population’s risk, making the lifetime risk approximately 15% to 20%. This genetic risk is less than the increase in risk caused by lifestyle factors and family history.
  • If you have two copies of APOE4 (one from each parent), your risk increases to about a 35% chance of developing the disease by the age of 75.

Often, your family history can tell us more about your Alzheimer's disease risk than genetic testing can. For example, if you have one first-degree relative who has been diagnosed with Alzheimer's disease, your risk increases about 10% from the general population, approximately a 20% to 25% lifetime risk.

Marc Diamond, M.D., (center) founded and directs the Center for Alzheimer’s and Neurodegenerative Diseases at UT Southwestern. Working with colleagues such as Ihab Hajjar, M.D., a Professor in the departments of Neurology and Internal Medicine, and Sarah Shahmoradian, Ph.D., an Assistant Professor in Biophysics, Dr. Diamond leads research into the basic mechanisms of neurodegenerative diseases, especially Alzheimer's disease.

Early-onset Alzheimer's disease (before age 65) occurs in about 5% of people with the disease. Researchers have found three genes associated with early-onset Alzheimer's: APP, PSEN1, and PSEN2. Disease-causing variants in these genes cause autosomal dominant Alzheimer's disease and increase the risk of developing Alzheimer's disease to nearly 100%.

When a disease is dominant, only one copy of the gene has to have a disease-causing variant in order to have symptoms. So, if a parent has one copy of the gene with a disease-causing variant, there is a 50% chance of passing on the gene with the variant to each of their children. Any individual who inherits a copy of APP, PSEN1, or PSEN2 containing a disease-causing variant is expected to show symptoms. If there are multiple family members with early-onset Alzheimer's disease, there is a high likelihood (60-70%) that a monogenetic cause can be identified in an individual with symptoms.

Disclosing to someone they have one of these variants can raise new questions and concerns. While we can’t tell you when you will begin to develop symptoms or how quickly the disease will progress, we will connect you to our memory disorders team to get a baseline neurocognitive evaluation.

Conversely, if a genetic test shows you do not have disease-causing variants in the APP, PSEN1, and PSEN2 genes, that doesn’t mean you will never get Alzheimer's disease. In fact, because most people who are diagnosed with early onset do not have a familial form of Alzheimer's disease; these genes are only found in 10% to 15% of people with early-onset Alzheimer's disease. This form of the disease can also be multifactorial or caused by other factors that have yet to be discovered.

Who should consider genetic testing

We don’t routinely recommend genetic testing for late-onset Alzheimer's disease because it has many causes and is unlikely to be due to variants in single genes. However, testing for early-onset Alzheimer's disease may be helpful depending on your family history and if you develop symptoms at an early age.

Symptoms can include:

  • Mood changes, such as confusion, depression, or fearfulness
  • Memory loss, such as confusion about time or places
  • Difficulty solving problems or making decisions
  • Trouble completing daily tasks
  • Spatial or visual problems, such as poor balance or difficulty reading
  • Difficulty finding the right words
  • Losing items
  • Social isolation

People with a first-degree relative (parent or sibling) who has been diagnosed with early-onset Alzheimer's disease could consider genetic testing if the affected relative is no longer available to test. The results can help with family decision-making, planning for the future, and potentially open opportunities to participate in clinical trials for advanced preventative therapies.

Some direct-to-consumer genetic tests do look for APOE4. If you take one, talk with a genetic counselor about what the results may mean for you. Many clinical genetics teams, including ours, do not test for the APOE4 variant. APOE testing cannot be used as a predictive test; the results will not tell an individual if they will or won’t develop Alzheimer's disease. About 42% of people with Alzheimer's disease do not have the APOE4 variant and most people with APOE4 variants do not go on to develop the disease. It is because this variant doesn’t significantly increase a person’s risk of developing Alzheimer's disease or change medical recommendations that many genetics teams do not offer this test in a clinical setting.

Reduce your risk of developing Alzheimer's

While you can’t change the genes you inherit or lower your baseline risk, it’s never too late to start taking steps to reduce furthering your risk of Alzheimer's disease. Research shows that several lifestyle factors are key to fending off memory disorders, including:

  • Exercise regularly to improve vascular health and reduce the risk of obesity, which is itself a risk factor. Some studies suggest the Mediterranean diet can be especially beneficial.
  • Avoid tobacco, limit drinking, and eat a healthy diet to decrease whole-body inflammation and oxidative stress, a process that destroys brain cells.
  • Manage blood pressure, because hypertension damages the blood vessels and can harm areas of the brain that deal with cognition.
  • Manage and correct hearing loss that comes with age, since inactivity in that area of the brain can result in brain structure changes and tissue loss.
  • Get adequate sleep to reduce levels of the protein beta-amyloid in the brain, which can form into amyloid plaques that are characteristic of Alzheimer's disease.

It’s understandable to be worried about your Alzheimer's disease risk when it’s trending in the news or if you have a relative with the disease. Before you make assumptions or fret about your risk, talk with a genetic counselor. We’ll assess your family history, and current health and lifestyle factors to give you an idea of your potential risk. We can also recommend whether genetic testing could be valuable for you – it’s a personal decision – and we’ll talk through your potential results.

To discuss genetic testing for Alzheimer's disease risk, call 214-645-8300 or request an appointment online.