Genetic testing for Alzheimer’s disease risk typically involves analyzing a person’s DNA to look for specific gene mutations that are linked to Alzheimer’s disease. The two main types of genetic testing available are:
APOE Testing
APOE testing looks at variants of the apolipoprotein E (APOE) gene. Everyone inherits one of three possible variants (ε2, ε3, or ε4) from each parent. Having the ε4 variant increases a person’s risk of developing Alzheimer’s disease and lowers the average age of onset. One copy of the ε4 variant increases risk 2-3 fold, while two copies increase risk up to 15 fold. However, inheriting the ε4 variant does not guarantee a person will develop Alzheimer’s. Many with the ε4 variant never get the disease.
Rare Mutation Testing
Rare mutation testing looks for mutations in three genes that directly cause Alzheimer’s disease in a small percentage of families. These genes are amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). Mutations in these genes cause the early-onset, dominantly inherited form of Alzheimer’s that typically develops before age 65. If a mutation is found, the person will almost certainly develop Alzheimer’s, often at an early age.
Genetic testing is typically done on a blood or saliva sample sent to a clinical lab for analysis. The tests can identify whether a person has genetic variants that increase their risk for developing Alzheimer’s disease. However, the tests cannot definitively determine whether someone will or will not get the disease. Counseling about risk and limitations is an important part of the testing process.
Benefits of Genetic Testing for Alzheimer’s Disease
Genetic testing for Alzheimer’s disease can provide several benefits for individuals who choose to undergo testing. Some of the key benefits include:
- Allows for early monitoring and potential treatment – If genetic testing identifies an increased risk, this enables closer monitoring for early symptoms and the potential to start treatment sooner, which could slow the progression of the disease. Certain medications for Alzheimer’s are more effective when started early.
- Life planning – Test results may motivate at-risk individuals to make lifestyle changes and plans for long-term care. This can involve financial planning, completing advance directives, making living arrangements, and more. Knowing one’s risk status empowers planning.
- Clinical trial eligibility – Those found to be at high genetic risk may qualify for clinical trials of new Alzheimer’s drugs and treatments. Trial participants can access experimental therapies before market approval. Genetic testing assists trial organizers in recruiting eligible high-risk candidates.
Genetic testing empowers those at increased genetic risk for Alzheimer’s to make informed choices about their healthcare and lives. While testing has limitations, the potential benefits are significant, especially the possibilities for early monitoring/treatment and planning ahead while cognitively healthy. Healthcare providers can help patients weigh the pros and cons of testing.
Limitations of Testing
Genetic testing for Alzheimer’s disease risk does have some limitations to be aware of. The presence of risk genes like APOE4 does not guarantee someone will develop Alzheimer’s disease. Likewise, the lack of risk genes does not rule out the possibility of developing the disease. The genes identified so far only account for a portion of genetic risk. Other factors like lifestyle and environment also play a role.
Genetic test results may cause emotional distress or anxiety, especially for those who learn they have a higher genetic risk. Some may feel helpless knowing their risk, while others can experience survivor’s guilt if they lack the risk genes. Receiving genetic risk information can impact family dynamics and relationships as well. Proper genetic counseling provides crucial context, so individuals understand their level of risk and how to respond appropriately.
While genetic testing offers benefits, it’s important to have realistic expectations about its predictive abilities. Testing is just one tool that contributes insights for disease prevention, early intervention, and life planning. With the guidance of medical professionals, individuals can make informed decisions about genetic testing and properly handle the implications. More research is still needed to better understand Alzheimer’s genetic links and develop improved risk assessment methods.
Testing Guidelines
Genetic testing for Alzheimer’s disease (AD) is not recommended for everyone. Professional organizations like the American Academy of Neurology and the American College of Medical Genetics and Genomics have issued guidelines on who should consider genetic testing for AD. Here are some of the key recommendations:
- Individuals who have a family history of AD – If multiple family members across generations have suffered from AD, there may be an inherited genetic mutation increasing risk. Genetic counseling is recommended to determine if testing could identify this.
- Symptomatic individuals with early-onset AD – If the onset of symptoms occurred before age 65, genetic factors likely play a role. Testing may help determine if a genetic mutation is involved.
- Individuals with a known mutation in the family – If a specific genetic mutation leading to AD has been identified in a family member, at-risk relatives can get tested for this mutation.
- Enrollment in clinical trials – Many research studies and clinical trials for AD prevention and treatment require genetic testing to identify eligible participants who are at increased genetic risk.
- Curiosity alone is not enough – Experts do not recommend undergoing genetic testing simply out of curiosity if no family history or symptoms suggest increased genetic risk. The implications of testing must be carefully considered.
The guidelines emphasize that genetic testing should be accompanied by genetic counseling to fully understand the risks, benefits, and results. Testing is a very personal decision that each individual must make carefully with their medical providers. Following expert recommendations can help ensure the appropriate use of genetic testing for Alzheimer’s disease.
Genetic Risk Factors
The biggest genetic risk factor for Alzheimer’s disease is the apolipoprotein E (APOE) gene. This gene provides instructions for making a protein called apolipoprotein E. This protein helps carry cholesterol and other fats in the bloodstream.
Research shows there are three common forms of the APOE gene – ε2, ε3, and ε4. The ε4 variant of this gene increases a person’s risk for developing Alzheimer’s disease and is associated with an earlier age of disease onset. About 25-30% of the population has one or two copies of the ε4 allele.
Having one ε4 allele increases Alzheimer’s disease risk by 2-3 times, while having two ε4 alleles increases risk by 8-12 times compared to the most common ε3 allele. The ε2 allele may provide some protection against Alzheimer’s. The ε4 allele is not a diagnostic test on its own, but testing for it can help assess an individual’s risk.
Besides APOE, researchers have identified more than 20 additional gene variants that may influence Alzheimer’s risk to a lesser degree. However, more research is needed to fully understand how genetic variations interact to impact disease risk and development. Genetic testing can identify APOE status and other genetic markers that may inform risk assessment.
Other Genetic Mutations
Rare mutations in the genes APP, PSEN1, and PSEN2 can substantially increase a person’s risk of developing Alzheimer’s disease, even at a relatively young age.
APP, PSEN1, and PSEN2 are involved in the production of amyloid-beta, the protein that builds up in the form of plaques in the brains of people with Alzheimer’s. Mutations in these genes can lead to an overproduction of amyloid-beta or a change in its structure, resulting in it becoming prone to forming plaques.
Mutations in APP account for about 15 percent of early-onset Alzheimer’s cases, while mutations in PSEN1 and PSEN2 each account for around 5 percent of early-onset cases. Having a mutation in one of these genes leads to the development of Alzheimer’s, often beginning before age 65, known as early-onset familial Alzheimer’s disease.
The PSEN1 gene has over 180 known mutations that increase Alzheimer’s risk. Some PSEN2 mutations can not only lead to Alzheimer’s but also other conditions like frontotemporal dementia. The APP gene has over 30 known mutations linked to Alzheimer’s disease.
Genetic testing can identify whether someone has these rare mutations. If a mutation is found, it is essentially a guarantee that the person will develop Alzheimer’s, often at a relatively young age, unless new treatments are developed to prevent the disease.
Genetic Counseling
Genetic counseling plays a critical role in the process of genetic testing for Alzheimer’s disease (AD). Counseling sessions before and after testing can help patients and families make informed choices about whether to pursue testing, understand the implications of test results, and cope with the emotional impact of learning one’s genetic risk.
Before testing, genetic counselors educate patients on the benefits, limitations, and potential consequences of testing. They explain the meaning of possible test results and the likelihood of developing AD if a mutation is found. Counselors discuss the possibility of unclear or uninformative results. Importantly, they allow patients to consider and voice their motivations, expectations, and concerns about testing. Counselors ensure patients make autonomous decisions free from coercion.
After testing, counselors help patients understand and come to terms with their results. If a pathogenic mutation is found, they explain the risk is not 100% certain and steps to reduce risk through lifestyle changes. They provide resources for support groups, research studies, and planning for the future. Counselors allow patients to process their emotions and grieve the loss of health they may experience.
If no mutation is found, counselors explain the patient still has a general population risk of AD and need for healthy aging. For variants of unknown significance, counselors explain the uncertainty and potential for reclassification with future research.
Genetic counselors play a vital role in ensuring patients and families make informed choices, understand their results, and receive emotional support through the complex process of AD genetic testing. Their guidance leads to better outcomes and the ability to cope with the impacts of testing.
Future Outlook
Research is ongoing to identify additional genetic markers associated with Alzheimer’s disease risk. Scientists are looking beyond single gene mutations to evaluate the combined effects of multiple common gene variants. This approach, known as polygenic risk scoring, may allow for more accurate risk assessment in the future.
Polygenic risk scores analyze small variations in hundreds or thousands of genes to calculate an individual’s inherited susceptibility. Early studies suggest these polygenic models can identify people with 2 to 3 times increased lifetime risk for Alzheimer’s dementia. Ongoing research aims to improve the predictive accuracy of polygenic risk scores.
In the coming years, polygenic testing may become a preferred method for evaluating genetic risk. By accounting for the small effects of many genes, polygenic scores may provide better risk stratification than testing for individual gene variants alone. However, additional validation is needed before polygenic testing for Alzheimer’s disease enters clinical practice.
Researchers are also working to identify new rare genetic variants that may substantially increase Alzheimer’s risk in some families. Advances in genetic sequencing technology will enable the discovery of novel disease-associated mutations. Incorporating newly identified variants into clinical genetic testing may further enhance risk assessment and early detection.
