Alzheimer’s disease is a progressive neurodegenerative condition that primarily affects memory, thinking, and behavior, representing the most common form of dementia. While advanced age is the strongest predictor, genetic factors also play a significant role in determining an individual’s lifetime risk. Understanding the link between genetics and Alzheimer’s has led to the availability of tests for specific gene variants. These tests offer insight into one’s predisposition, but their interpretation and the decision to take them involve important medical and personal considerations.
The Genetic Basis for Alzheimer’s Risk
The genetic influences on Alzheimer’s disease fall into two distinct categories: risk genes and deterministic genes. Risk genes increase the likelihood of developing the common form of the disease, known as late-onset Alzheimer’s, which typically begins after age 65. The most well-known of these is the apolipoprotein E gene, or APOE, which exists in three main forms, called alleles: \(\epsilon2\), \(\epsilon3\), and \(\epsilon4\).
The \(\text{APOE } \epsilon4\) allele is strongly associated with an increased risk for late-onset Alzheimer’s. Inheriting one copy of \(\text{APOE } \epsilon4\) raises the risk compared to the most common \(\epsilon3\) allele, and inheriting two copies confers an even higher risk. However, this gene only represents a probability modifier, meaning that possessing \(\text{APOE } \epsilon4\) copies does not guarantee a person will develop the disease.
Deterministic genes, by contrast, are rare mutations that guarantee the development of Alzheimer’s, usually in an early-onset form before the age of 65. These rare cases, accounting for less than 1% of all Alzheimer’s, are caused by mutations in genes such as Amyloid Precursor Protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2). Because these mutations follow an autosomal dominant inheritance pattern, an affected individual has a 50% chance of passing the gene to their offspring.
Types of Testing Available
Genetic testing for Alzheimer’s risk can be accessed through two primary avenues: clinical testing and direct-to-consumer (DTC) testing. Clinical testing is ordered by a physician or specialist, often a neurologist or genetic counselor. This testing is usually reserved for individuals with symptoms or a strong family history of early-onset disease. This type of testing is typically comprehensive, examining both the deterministic genes and the APOE risk gene.
DTC testing, such as that offered by commercial ancestry companies, can be purchased directly by consumers without a doctor’s order. These kits commonly test for the \(\text{APOE } \epsilon4\) allele, but they generally do not screen for the rare deterministic genes like PSEN1 or APP. While DTC testing offers convenience, it often lacks the regulatory oversight and comprehensive analysis provided by a clinical laboratory.
Interpreting Results
Understanding the results of an Alzheimer’s genetic test requires differentiating between a risk factor and a definitive cause. For the APOE gene, the combination of alleles determines the relative risk level. The \(\epsilon3/\epsilon3\) genotype is considered the neutral baseline, while the \(\epsilon2\) allele may offer a protective effect against the disease.
A result showing the presence of one \(\text{APOE } \epsilon4\) allele, such as \(\epsilon3/\epsilon4\), indicates an increased risk, but this is a statistical probability modifier, not a diagnosis. Individuals with the highest-risk genotype, \(\epsilon4/\epsilon4\), still have a significant chance of not developing the disease, with an estimated lifetime risk through age 85 ranging from 30% to 55%. The majority of people who develop Alzheimer’s do not have this allele, and many people with \(\text{APOE } \epsilon4\) never develop the disease.
A positive result for a deterministic gene, such as a mutation in PSEN1, signifies that the individual will almost certainly develop early-onset familial Alzheimer’s disease. While genetic testing cannot predict the exact age of disease onset, a result indicating a genetic predisposition may encourage proactive lifestyle changes. Actions like increasing physical activity, adopting a heart-healthy diet, and managing cardiovascular risk factors are thought to potentially mitigate the overall risk, though research in this area is ongoing.
Navigating the Decision to Test
The decision to undergo genetic testing carries personal and ethical implications that extend beyond the biological data. Genetic counseling is highly recommended, and often required for clinical testing, to help individuals prepare for the emotional impact of the results. A counselor can assist in understanding complex probabilities and discussing the potential for anxiety or depression that may arise from learning a risk status.
A concern is the potential for discrimination based on genetic information. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits health insurers and employers from using genetic results to make decisions about eligibility or employment. This law provides protection for individuals who choose to be tested, particularly in the employment and health insurance sectors.
GINA does have limitations, as its protections do not extend to life insurance, long-term care insurance, or disability insurance. This gap means that an individual’s genetic test results could potentially be used by these insurers to deny coverage or charge higher premiums. Considering these legal and personal factors with a genetic counselor is a necessary step before proceeding with testing.