Genetic testing is available for Alzheimer’s disease (AD), but the information provided varies significantly depending on the type of AD and the specific genes tested. AD is the most common cause of dementia, characterized by progressive memory loss and cognitive decline. It is broadly categorized into two forms. Late-onset AD, appearing after age 65, is the most common and involves a complex mix of genetic, lifestyle, and environmental factors. The much rarer early-onset form, beginning before age 65, is often linked to specific gene mutations that virtually guarantee the disease.
Genes Associated with Alzheimer’s Disease
The genetics of Alzheimer’s disease (AD) are divided into two distinct categories: deterministic genes and risk genes. Deterministic genes are associated with the early-onset form, which accounts for less than 5% of all cases. Mutations in the APP (amyloid-beta precursor protein), PSEN1, and PSEN2 (presenilin) genes virtually guarantee that a person will develop AD, often before age 65.
The PSEN1 gene is the most common cause of this autosomal dominant AD, accounting for up to 70% of these familial cases. These mutations alter amyloid-beta protein processing, leading to the accumulation of toxic plaques in the brain. Because inheriting one of these mutations makes disease development almost certain, testing is typically only recommended for individuals with a strong family history of early-onset AD.
The most significant genetic factor for common late-onset AD is a risk gene called apolipoprotein E (APOE). This gene has three common variants, or alleles: e2, e3, and e4. The APOE e3 allele is the most common and is considered neutral in terms of risk.
The APOE e4 allele, present in about 25% of the population, increases the risk of developing late-onset AD and is associated with an earlier average age of onset. Having one e4 copy can double or triple the risk, while having two copies can increase the risk by 8 to 12 times. Conversely, the APOE e2 allele is associated with a reduced risk of developing the disease.
Methods of Genetic Testing
Genetic testing for Alzheimer’s can be pursued through two main avenues. Clinical genetic testing is medically supervised and typically ordered by a doctor or genetic counselor. This process is usually initiated for individuals with a strong family history of early-onset disease and involves comprehensive analysis of the deterministic genes (APP, PSEN1, and PSEN2).
Clinical test results are intended for medical decision-making and are conducted in accredited laboratories, often accompanied by pre- and post-test counseling. This testing provides a high degree of certainty and clinical utility based on the patient’s medical and family history.
In contrast, Direct-to-Consumer (DTC) genetic testing is accessible without a doctor’s order, often involving a simple saliva sample collected at home. These tests primarily focus on the APOE risk gene, identifying the presence of the e4 allele. While inexpensive and convenient, DTC tests provide limited information, screening only for a single risk factor.
DTC results may lack medical supervision, requiring the individual to interpret complex risk information without professional guidance. Results obtained from a DTC test usually require confirmation through a clinical genetic test for medical decisions.
Interpreting Genetic Test Results
Interpreting Alzheimer’s genetic testing requires understanding the difference between a definitive cause and a risk factor. A positive result for a deterministic gene mutation indicates a nearly 100% chance of developing early-onset Alzheimer’s disease. Although these cases are rare, a positive finding is highly predictive and influences the age of onset, which can be as early as the 40s or 50s.
For the majority of people, testing involves the APOE risk gene, and results are reported as a genotype, such as e3/e3 or e3/e4. Carrying one copy of the APOE e4 allele (a heterozygous result) significantly increases an individual’s lifetime risk for late-onset AD compared to the general population. A person with two copies (a homozygous e4/e4 result) faces the highest genetic risk, with a 10 to 15-fold increase over the neutral e3/e3 genotype.
A positive APOE e4 result is not a diagnosis and does not guarantee the disease will develop; it only indicates increased susceptibility. The concept of penetrance means that many people with the high-risk e4/e4 genotype will not develop AD, as lifestyle factors interact with genetic risk. Conversely, a negative result (no e4 allele) does not eliminate risk, as many other genetic and environmental factors contribute to the disease.
Practical and Ethical Considerations for Testing
The decision to pursue Alzheimer’s genetic testing involves complex personal and family considerations. Genetic counseling is recommended, both before and after testing, to ensure a full understanding of the probabilistic nature of the results and their emotional implications. This guidance helps individuals weigh the potential psychological impact, such as anxiety or distress, against the desire for knowledge and proactive planning.
Knowing one’s genetic status can offer personal utility, providing motivation to adopt lifestyle changes that may help mitigate the underlying risk. It can also inform decisions about family planning or participation in clinical trials, which often require APOE status. While the Genetic Information Nondiscrimination Act (GINA) offers protection against discrimination in health insurance and employment, these protections do not extend to long-term care, life, or disability insurance.