Genetic mutations behind familial Alzheimer’s disease
Last Reviewed: Jul 2, 2025Genes control how every cell in the body works. Some genes decide basic traits, such as the color of the eyes and hair. Other genes can increase or decrease the risk of certain diseases.
What mutations cause FAD?
Familial Alzheimer’s disease (FAD) is caused by specific mutations (also called pathogenic variants) in three genes:
APP (the amyloid precursor protein gene) has between 32 and 69 mutations reported to cause FAD.
PSEN1 (the presenilin 1 gene, also known as PS1) has between 176 and 326 mutations reported to cause FAD.
PSEN2 (the presenilin 2 gene, also known as PS2) gene has between 14 and 68 mutations reported to cause FAD.
There are also people who develop early-onset Alzheimer's disease without an FAD mutation. Scientists are working to identify the causes and other potential genetic factors that impact a person’s risk of getting early-onset Alzheimer’s disease.
For more information about how genetics factor into Alzheimer’s disease in general, explore this Alzheimer's Disease Genetics Fact Sheet from the US National Institute of Health (NIH).
If you’re dealing with a non-familial form of early-onset Alzheimer's disease, these resources might help.
How do FAD genetic mutations cause Alzheimer’s?
The APP, PSEN1, and PSEN2 genes provide blueprints for proteins that play a critical role in how the brain makes and processes amyloid-β (pronounced “amyloid-beta”, also referred to as β-amyloid or Aβ).
Mutations in the APP, PSEN1, and PSEN2 genes can lead to an increased amount of Aβ and/or change the types of Aβ fragments that are produced. Scientists believe that these altered Aβ fragments are longer, stickier, or more toxic, making them more prone to stick together. As these fragments buildup in the brain, they form clumps of Aβ called amyloid plaques.
Scientists believe that the buildup of toxic forms of Aβ and amyloid plaques damages neurons and eventually drives changes in the brain that lead to Alzheimer’s disease. Scientists are still learning about the precise ways this occurs.
Learn more about how genetic mutations cause FAD.
How are genetic mutations passed down?
If a parent carries a mutated gene associated with FAD, each of their children has a 50% chance of inheriting that gene.
This is because the condition is passed down in an autosomal dominant manner.
In autosomal dominant diseases, only one copy of the mutated gene (from one parent) is needed to inherit the disease or condition.
Learn more about autosomal dominance.
Does it matter which mutation my family has?
Yes. Although all FAD genetic mutations cause the disease, scientists have found that mutations have different characteristics. A specific mutation may be associated with a specific:
Age of symptom onset (i.e., when a family members starts showing signs of disease)
Disease duration
Range of disease symptoms
Where amyloid accumulates in the brain
Our understanding of each mutation is constantly developing. Learning exactly what FAD mutations do helps scientists better understand how Alzheimer’s disease works.
Scientists use terms like pathogenicity, penetrance, and de novo to describe what is known about different mutations. Learn more about these terms.
What are the most prevalent FAD mutations?
PSEN1 E280A ⧉ - known as the Paisa mutation, found in a large family that lives in Antioquia, Colombia
PSEN2 N141I ⧉ - known as the Volga German mutation
PSEN1 A431E ⧉ - known as the Jalisco mutation, found in many families with descendants from Jalisco, Mexico
APP V717APP ⧉ - known as the London mutation
PSEN1 G206A ⧉ - found in many families from Puerto Rico and the Dominican Republic
What is APOE4?
Aside from FAD mutations, researchers have found genetic variants that change a person’s likelihood of developing late-onset Alzheimer’s disease (LOAD). These variants are sometimes called “Alzheimer’s risk genes.”
The most well-known risk gene is apolipoprotein E (APOE), which provides the blueprint for the APOE protein. This protein is involved in carrying cholesterol and other fats in the bloodstream. Problems in this process are thought to lead to Alzheimer’s.
The APOE gene comes in 3 main forms (or alleles).
APOE ε2: Reduces one’s risk for Alzheimer’s disease and may provide some protection against the disease.
APOE ε3: The most common allele, thought to be neutral - it doesn’t change one’s risk of Alzheimer’s.
APOE ε4: Increases a person’s risk of Alzheimer’s disease and is also associated with an earlier age of onset. Some people inherit 2 copies of APOE ε4, which causes a unique genetic form of Alzheimer’s disease.
Unlike APOE, FAD genetic mutations are not “risk genes.” Without intervention, FAD mutations cause FAD for nearly everyone who carries them.
What’s the difference between a genetic variant and a genetic mutation?
How can I find out my family’s specific genetic mutation?
In order to know if one is at risk for an FAD mutation, the affected family member has to undergo genetic testing to demonstrate which, if any, FAD mutation runs in the family.
When someone tests positive for an FAD mutation, the doctor or genetic counselor will often provide information about the details of your family’s mutation in a genetic testing report.
The report will provide details about the gene that the mutation is on, such as PSEN1, as well as the specific mutation detected, which is expressed as a series of letters and numbers such as A79V or p.a79v. It may refer to the mutation as a “pathogenic variant.”
Where can I learn about my family’s specific mutation?
If you’re interested in learning about the specific age of disease onset and disease duration that is typical for your specific mutation, one of the best points of reference is the article, The landscape of autosomal-dominant Alzheimer’s disease: global distribution and age of onset ⧉ , by Liu H, Marsh TW, Shi X, et al.
This supplemental table ⧉ from this paper lists identified genetic mutations with their specific position on the gene, the genetic change, the classification, countries they’ve been found in, the average age at onset (AAO), and the standard error associated with the age of onset. If you have trouble accessing or understanding this information, contact us and we can help.
Another great resource is the Alzforum.org mutation database ⧉. Here, you can search for a specific mutation and find out about previous scientific findings, including what families/countries it has been found in.
Finally, it is helpful to talk to physicians with specific expertise on FAD. These physicians can typically be found at Alzheimer’s Disease Research Centers (also known as ADRCs) ⧉ or other specialized dementia clinics.