Alzheimer's genes: Are you at risk?

November, 15th, 2023

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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 a number of genes that are linked to Alzheimer’s disease. Some genes increase the likelihood of getting the disease, called risk genes. Others ensure getting the disease, called deterministic genes. Deterministic genes are rare. However, genes are just 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 usually begins after age 65, called late-onset Alzheimer’s disease. The most common gene linked to late-onset Alzheimer’s disease is a risk gene called apolipoprotein E (APOE).

APOE has three common forms:

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

Genes aren’t the only factor

One copy of the APOE gene comes from the mother and another from the father. Having at least one APOE e4 gene doubles or triples the risk of getting Alzheimer’s disease. Some people have two APOE e4 genes, one from each parent. Having two genes increases the risk of getting Alzheimer’s disease even more, about eight- to twelvefold.

But not everyone who has one or even two APOE e4 genes gets Alzheimer’s disease. And many people who don’t have an APOE e4 gene get the disease. That suggests that the APOE e4 gene increases risk but is not a cause. There’s likely more to getting Alzheimer’s disease than just genes, such as lifestyle, race, ethnicity and environment.

Other late-onset genes

As gene research goes on, researchers are finding links between late-onset Alzheimer’s and a number of other genes. Examples include:

• ABCA7. This gene seems to be linked to a greater risk of Alzheimer’s disease. Researchers suspect that it may have something to do with the gene’s role in how the body uses cholesterol.
• CLU. This gene helps the brain clear the protein called amyloid-beta. Research suggests that an imbalance in the making and clearing of amyloid-beta is key to getting Alzheimer’s disease.
• CR1. Not enough of the protein this gene makes 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 they talk to each other is important for them to work well and to form memories.
• 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 changes in this gene are lined to an increased risk of Alzheimer’s disease.
• SORL1. Some forms of SORL1 on chromosome 11 appear to be linked to Alzheimer’s disease.

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

As with APOE, these genes are risk factors, not causes. In other words, having one of these changed genes might increase the risk of Alzheimer’s. But not everyone who has a changed gene will get Alzheimer’s disease.

Young-onset Alzheimer’s

A very small number of people who get Alzheimer’s disease have the young-onset type. Symptoms of this type usually appear between ages 30 and 60. This type of Alzheimer’s disease is strongly linked to genes.

Scientists have found three genes in which changes cause early-onset Alzheimer’s disease. Anyone who gets one of these gene changes from either parent is likely to get Alzheimer’s symptoms before age 65. The genes are:

• Amyloid precursor protein (APP).
• Presenilin 1 (PSEN1).
• Presenilin 2 (PSEN2).

Changes in these genes cause the making of too much of a part of a protein called amyloid-beta peptide. This toxic peptide can build up in the brain to form clumps called amyloid plaques. These plaques are a hallmark of Alzheimer’s disease. A buildup of toxic amyloid-beta peptide and amyloid plaques can lead to the death of nerve cells and the symptoms of Alzheimer’s disease.

As amyloid plaques collect in the brain, proteins called tau proteins don’t work as they should. Instead, they stick together to form tau tangles. These tangles are linked to how Alzheimer’s disease affects the brain.

However, some people who have early-onset Alzheimer’s don’t have changes in these three genes. That suggests that some early-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 early-onset Alzheimer’s, however, genetic testing may be helpful.

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

But for certain treatments, called anti-amyloid therapies, testing for APOE genotype is important. If you’re thinking about taking these medicines, testing can show how likely you are to have side effects. Talk to your health care provider about whether APOE testing makes sense for you.

Testing for the gene changes that have been linked to early-onset Alzheimer’s might be useful for someone showing symptoms or someone who has a family history of early-onset disease. Gene testing for early-onset Alzheimer’s also may affect current and future medicine trials and help with family planning.

However, test results might have other effects. 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 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 are also studying genes that may protect against Alzheimer’s disease. One APOE gene, called APOE Christchurch, seems to be a protector, like APOE e2. More research is needed.

One of the active research trials is the Dominantly Inherited Alzheimer Network (DIAN), which studies individuals with dominant Alzheimer’s mutations (PSEN1, PSEN2 or APP). This 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 have gotten Alzheimer’s after age 65. If your family is interested in participating in this study, visit the website for the National Cell Repository for Alzheimer’s Disease.

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 National Institute on Aging’s Alzheimer’s Disease Education and Referral Center website. Or ask your health care provider what trials might be available.