Alzheimer's genes: Are you at risk?

Certain genes increase the risk of getting Alzheimer's disease.

Genes control how every cell in the body works. Some genes decide basic traits, such as the color of the eyes and hair. Other genes can increase the risk of getting certain diseases, including Alzheimer's disease.

Researchers have found several genes that are linked to Alzheimer's disease. Some genes, called risk genes, increase the likelihood of getting the disease. Others, called deterministic genes, cause the disease. Deterministic genes are rare. Genes are only part of what's involved in getting Alzheimer's disease.

Most common late-onset Alzheimer's gene

The most common type of Alzheimer's disease, called late-onset Alzheimer's disease, usually begins after age 65. The most common gene linked to late-onset Alzheimer's disease is a risk gene called apolipoprotein E, also known as APOE.

Genes can have many variations, also called variants. APOE has three common variants:

• APOE e2. This is the least common form of the gene. It reduces the risk of Alzheimer's.
• APOE e4. This form is a little more common. It increases the risk of Alzheimer's. And it's linked to having more-severe Alzheimer's disease.
• APOE e3. This is the most common form of the gene. It doesn't seem to affect the risk of Alzheimer's.

Genes aren't the only factor

Each person inherits two copies of the APOE gene, one from the mother and one from the father. These copies can affect a person’s risk of Alzheimer's. Having at least one APOE e4 variant doubles or triples the risk of getting Alzheimer's disease. Having two APOE e4 variants increases that risk even more. Someone with two APOE e4 variants is 8 to 12 times more likely to develop Alzheimer's disease.

But not everyone who has one or even two APOE e4 variants gets Alzheimer's disease. And many people who don't have an APOE e4 variant get the disease. That suggests that the APOE e4 variant increases the risk of getting Alzheimer's disease but is not a cause. There's likely more to getting Alzheimer's disease than just genes. Lifestyle, race, ethnicity and environment also may contribute.

Other late-onset Alzheimer's genes

Several other genes have been linked to late-onset Alzheimer's disease. Many were identified in large studies, and researchers are investigating their possible roles. Examples include:

• ABCA7. Some forms of this gene seem to be linked to a greater risk of Alzheimer's disease. Researchers suspect that this may have something to do with the gene's role in how the brain uses cholesterol.
• CLU. This gene helps the brain clear out harmful protein fragments called beta-amyloid. Research suggests that an imbalance in the making and clearing of beta-amyloid is key to getting Alzheimer's disease.
• CR1. This gene creates a protein that is active in the immune system. When you don't have enough of this protein, it might cause chronic swelling and irritation, called inflammation, in the brain. Inflammation is another possible factor in getting Alzheimer's disease.
• PICALM. This gene is linked to how brain nerve cells, called neurons, talk to each other. How neurons talk to each other is important for them to work well and to form memories. PICALM also is linked to the making and clearing of beta-amyloid in the brain.
• PLD3. Scientists don't know much about the role of PLD3 in the brain. But it's recently been linked to a significantly increased risk of Alzheimer's disease.
• TREM2. This gene affects how the brain responds to swelling and irritation, called inflammation. Rare variants of this gene are linked to an increased risk of Alzheimer's disease.
• SORL1. This gene plays an important role in beta-amyloid production. Some forms of SORL1 on chromosome 11 appear to be linked to Alzheimer's disease.

As with APOE, variants of these genes are risk factors, not causes. That means that having one of these genetic variants might increase the risk of Alzheimer's. But not everyone with one of these variants will get Alzheimer's disease.

Researchers continue to learn more about Alzheimer's disease. Knowing more about how the disease works might lead to new ways to prevent and treat it.

Young-onset Alzheimer's

A very small number of people who get Alzheimer's disease have the young-onset type. Symptoms of this type of Alzheimer's usually appear between ages 30 and 60. Young-onset Alzheimer's disease, also called early-onset Alzheimer's, has a strong genetic link.

Scientists have found three genes in which changes cause young-onset Alzheimer's disease. The genes are:

• Amyloid precursor protein, also called APP.
• Presenilin 1, also called PSEN1.
• Presenilin 2, also called PSEN2.

Variants of these genes can lead to changes in the brain that are common in people with Alzheimer's disease. A person who inherits one of these deterministic variants from either parent is likely to get Alzheimer's symptoms before age 65.

Alzheimer’s-related changes in the brain include the formation of hardened clumps of beta-amyloid protein, called amyloid plaques, and snarled tangles of a protein called tau.

A buildup of amyloid plaques and tau tangles can lead to the death of nerve cells and the symptoms of Alzheimer's disease.

Still, some people who have young-onset Alzheimer's don't have changes in any of these three genes. That suggests some young-onset types of Alzheimer's disease are linked to other gene changes or other things that have yet to be found.

Genetic testing

Most experts don't routinely recommend genetic testing for late-onset Alzheimer's. In some instances of young-onset Alzheimer's, however, genetic testing may be helpful.

Usually, healthcare professionals don't test for APOE genes. The results can't fully predict who will get Alzheimer's disease. And healthcare professionals usually can diagnose Alzheimer's disease without the use of genetic testing.

But for treatment with certain medicines, called antiamyloid therapies, testing for APOE genes is important. If you're thinking about taking these medicines, testing can show how likely you are to have side effects. If you carry one or more APOE e4 variants, your risk of side effects is increased. Talk to your healthcare professional about whether APOE testing makes sense for you.

Testing for genetic variants that have been linked to young-onset Alzheimer's might be useful for someone showing symptoms or someone who has a family history of young-onset disease. Gene testing for young-onset Alzheimer's also may affect current and future participation in research trials and help with family planning.

Test results might have other effects, however. For instance, they might affect being able to get a job. And test results might keep you from getting certain types of insurance, such as disability, long-term care and life insurance.

Researchers and genes

Researchers suspect they still haven't found many of the genes that affect the risk of Alzheimer's disease. Learning about those genes may be vital to finding new ways to treat, or even prevent, Alzheimer's disease in the future.

Researchers also are studying gene variations that may protect against Alzheimer's disease. One example is the APOE variant called APOE Christchurch. It seems to protect against the disease, like APOE e2 does. A rare variant of the fibronectin gene, called FN1, also appears to be protective in people with two APOE e4 variants. More research is needed.

Past research on Alzheimer's genes has focused mostly on people of European ancestry. Scientists are broadening their research to include people whose ancestors come from other parts of the world. Recent genetic studies have included African Americans, people from the Caribbean and South America, and people from East Asia. This type of research will help scientists understand if and how geographic ancestry affects a person's risk of Alzheimer's.

One of the active research trials is the Dominantly Inherited Alzheimer Network, also called DIAN. This research trial studies individuals with deterministic Alzheimer's gene changes, such as the PSEN1, PSEN2 or APP variants. The research network includes observational studies and clinical trials.

The Alzheimer's Disease Genetics Study, sponsored by the National Institute on Aging, is looking at gene information from families that have at least two living family members who were diagnosed with Alzheimer's after age 65. If you or your family is interested in learning more about this study, visit the website for the National Centralized Repository for Alzheimer's Disease and Related Dementias.

Other studies are looking at the genes of people with Alzheimer's disease and their family members. To learn more about these studies and whether they need volunteers, visit the Alzheimers.gov website. Or ask your healthcare professional what research trials might be available.