Alzheimer’s disease is a progressive disorder that gradually destroys memory and thinking skills, eventually affecting the ability to carry out simple tasks. The role of genetics in Alzheimer’s is complex, as its inheritance pattern varies by the form of the disease. Understanding these differences helps clarify how the disease might be passed through families and who may be at increased risk.
Understanding Genetic Inheritance: Dominant Versus Recessive
Genetic inheritance describes how traits, including predispositions to certain conditions, are passed from parents to their children through genes. Each person inherits two copies of most genes, one from each biological parent. These gene copies are called alleles.
A dominant inheritance pattern means that only one copy of a specific gene variant is sufficient to cause a particular trait or disorder. If a parent has a dominant genetic condition, each child has a 50% chance of inheriting the altered gene and developing the condition.
Conversely, recessive inheritance requires an individual to inherit two copies of a specific gene variant—one from each parent—for the trait or disorder to be expressed. Individuals who carry only one copy of a recessive altered gene are typically healthy carriers. If both parents are carriers of the same altered recessive gene, each child has a 25% chance of inheriting both altered copies and being affected by the condition.
Early-Onset Alzheimer’s and Dominant Inheritance
A small percentage of Alzheimer’s disease cases, developing before age 65, are directly caused by specific genetic mutations inherited in an autosomal dominant pattern. This form is early-onset familial Alzheimer’s disease (EOFAD), accounting for less than 5% of all Alzheimer’s cases. Symptoms can appear as early as the 30s or 40s.
Three primary genes are associated with this type: APP (amyloid precursor protein) on chromosome 21, PSEN1 (presenilin 1) on chromosome 14, and PSEN2 (presenilin 2) on chromosome 1. Mutations in any of these genes disrupt the normal processing of amyloid precursor protein, leading to an overproduction of a toxic protein fragment called amyloid-beta peptide. This peptide accumulates in the brain, forming plaques characteristic of Alzheimer’s.
When a person inherits even one copy of a mutated APP, PSEN1, or PSEN2 gene, they are highly likely to develop the disease, usually before age 65. PSEN1 mutations are the most common cause of autosomal dominant EOFAD, accounting for 70% to 80% of such cases.
Late-Onset Alzheimer’s: A Complex Picture
The majority of Alzheimer’s disease cases, occurring after age 65, are classified as late-onset Alzheimer’s. This common form is not inherited in a simple dominant or recessive pattern. Instead, it is a multifactorial condition, resulting from a combination of genetic predispositions, lifestyle choices, and environmental influences.
The APOE (apolipoprotein E) gene is the strongest known genetic risk factor for late-onset Alzheimer’s. This gene has three common alleles: APOE-e2, APOE-e3, and APOE-e4. APOE-e3 is the most common and neutral, while APOE-e2 may offer some protection.
The APOE-e4 allele, present in 15% to 25% of the general population, increases an individual’s risk of developing late-onset Alzheimer’s and may lead to an earlier age of disease onset. Inheriting one copy of APOE-e4 can increase risk by two- to threefold, while inheriting two copies (one from each parent) can raise the risk by eight- to twelvefold. However, carrying APOE-e4 does not guarantee that a person will develop Alzheimer’s, and many individuals with the e4 allele never develop the disease. Similarly, people without APOE-e4 can still develop late-onset Alzheimer’s, underscoring the role of other genetic and environmental factors.
Genetic Information and Risk
Understanding the genetic aspects of Alzheimer’s disease offers insights into individual risk, though implications vary significantly between early-onset and late-onset forms. Genetic testing is available for both types, but results differ. For early-onset Alzheimer’s, testing identifies specific mutations in genes like APP, PSEN1, or PSEN2, which are considered causative and predict a very strong probability of developing the disease.
For late-onset Alzheimer’s, genetic testing primarily focuses on risk factors, such as the APOE-e4 allele. A positive test for APOE-e4 indicates an increased predisposition but not a certain diagnosis, as many people with this allele never develop the disease. Routine genetic testing for late-onset Alzheimer’s risk in healthy individuals is not advised without thorough consideration.
Genetic counseling is recommended for anyone considering Alzheimer’s genetic testing or those with a family history of the disease. A genetic counselor can assess family history, explain what genetic testing can and cannot reveal about risk, and discuss potential social or economic impacts of the results. This guidance helps individuals make informed decisions about genetic testing and understand what the genetic information means for their health and future planning.