Alzheimer’s disease (AD) is a progressive neurological disorder characterized by the deterioration of cognitive functions, including memory, thinking, and behavior, which ultimately leads to a loss of independence. The condition involves complex pathological changes in the brain, such as the accumulation of amyloid plaques and neurofibrillary tangles. While advanced age is the strongest predictor for developing the common form of the disease, genetics play a significant part in determining an individual’s susceptibility to Alzheimer’s. Genetic factors are estimated to play a role in up to 80% of late-onset AD cases. This strong genetic link has led to the development of genetic testing options, which can offer insight into an individual’s inherited risk.
Genes Associated with Alzheimer’s Risk
The genes associated with Alzheimer’s disease fall into two distinct categories: risk genes and deterministic genes. The difference between these two groups is based on the certainty of disease development if a variant is inherited. Risk genes are associated with the common late-onset form of Alzheimer’s, and they increase the probability of developing the disease but do not guarantee it.
The most well-known and strongest risk gene identified to date is the Apolipoprotein E gene, or APOE. This gene provides instructions for making a protein that helps carry cholesterol and other fats in the bloodstream. It has three common variants, or alleles: APOE-e2, APOE-e3, and APOE-e4. The APOE-e3 variant is the most common and is considered neutral in its effect on Alzheimer’s risk. The APOE-e2 variant is the least common and may offer some protection against the disease.
The APOE-e4 variant, present in about 15% to 25% of the population, is associated with an increased risk for late-onset Alzheimer’s and a potentially earlier age of onset. Individuals inherit two copies of the APOE gene, one from each parent, and the combination of these two alleles determines their genetic risk profile. The majority of Alzheimer’s cases are linked to this category of risk genes, which interact with environmental and lifestyle factors to influence overall risk.
In contrast, deterministic genes are rare and are responsible for the early-onset familial form of Alzheimer’s, which accounts for less than 5% of all AD cases. These are single-gene mutations inherited in an autosomal dominant pattern, meaning a person has a very high probability of developing the disease, often before age 65. The three genes most commonly implicated are the Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2). Mutations in these genes lead to the abnormal production of the amyloid-beta protein.
Accessing Genetic Testing
Individuals interested in genetic testing for Alzheimer’s disease risk can pursue one of two primary pathways: clinical testing or direct-to-consumer (DTC) testing. Clinical testing is ordered by a healthcare professional, such as a neurologist or a genetic counselor, and is considered the comprehensive, medically supervised approach. This process typically includes pre- and post-test genetic counseling to ensure the individual understands the implications and can process the results with professional support. Clinical testing is often reserved for individuals with a strong family history of early-onset AD or for those participating in specific research or clinical trials.
The alternative is DTC testing, where companies market test kits directly to the public, usually involving a saliva or cheek swab sample sent to a lab. These tests are generally much more limited in scope, most commonly analyzing only the APOE gene and its e4 variant. While DTC testing offers convenience, it often lacks the crucial clinical context and professional interpretation provided by a healthcare team.
The testing itself is straightforward, regardless of the pathway chosen, requiring either a blood draw or a saliva sample. The sample is analyzed to determine the specific alleles of the APOE gene or to check for mutations in the deterministic genes like PSEN1. Many medical organizations advise caution regarding DTC testing due to the potential for misinterpretation of the results without professional guidance.
Understanding the Test Results
Interpreting the results of an APOE genetic test requires understanding that it provides a measure of probabilistic risk, not a definitive diagnosis of Alzheimer’s disease. Since everyone inherits two copies of the APOE gene, the result will show a combination of the e2, e3, and e4 alleles. The most common result is e3/e3, which is considered a neutral risk profile, similar to the general population.
A result indicating the presence of the APOE-e4 allele means the individual has an increased, but not certain, risk of developing late-onset Alzheimer’s. Having one copy of the e4 allele, such as e3/e4, can roughly double or triple the risk compared to the general population. Individuals who inherit two copies, an e4/e4 genotype, face an even higher risk, potentially eight to twelve times greater than those with no e4 alleles. Crucially, even with two copies of APOE-e4, the development of Alzheimer’s is not guaranteed, and many individuals with this genotype never develop the condition.
Conversely, a negative result, meaning no APOE-e4 allele is present, does not equate to zero risk of developing Alzheimer’s. Approximately 42% of people with late-onset AD do not carry the e4 allele, illustrating that non-genetic factors and other genetic variants also contribute significantly to the overall risk. For the rare deterministic genes, a positive result for a mutation in APP, PSEN1, or PSEN2 carries a very high probability of developing the early-onset form of the disease. These results are typically only sought by individuals with a clear, strong family history of early-onset Alzheimer’s.
Preparing for Genetic Counseling
Receiving genetic test results for Alzheimer’s risk, particularly a positive result, can have a profound psychological impact, leading to anxiety or depression. Genetic counseling is considered a necessary step in the testing process, both before and after the test. A trained genetic counselor can help an individual process the complex, probabilistic nature of the information and provide emotional support. They can also facilitate important family conversations about the shared genetic risk and what the results might mean for relatives.
Beyond emotional preparedness, understanding the legal landscape is a practical step. In the United States, the Genetic Information Nondiscrimination Act (GINA) provides federal protection against discrimination in health insurance and employment based on genetic information. This law prohibits employers from using genetic test results in hiring or firing decisions and prevents health insurers from using the information to determine eligibility or premiums.
It is important to recognize the limitations of GINA. The act does not extend its protections to other types of insurance, such as:
- Life insurance.
- Long-term care insurance.
- Disability insurance.
This gap means individuals may want to consider securing those types of policies before undergoing genetic testing. A genetic counselor can provide guidance on these psychosocial and legal considerations, helping the individual create an informed plan for moving forward with their personal health management and risk mitigation strategies.