How is Alzheimer Disease inherited?
Around 75% of the time, Alzheimer Disease (AD) is not inherited. 25% of the time Alzheimer's disease can be inherited. This is called familial AD. There are at least four known genes that can cause familial, or inherited Alzheimer Disease.
We all have two copies of every gene, including two of the PSEN1 and PSEN2 genes that can cause familial AD. We inherit half of our genetic information from our mom and half from our dad; so one copy of each gene is inherited from our mother and the other from our father. If a parent has familial AD caused by PSEN1 or PSEN2, there is a 50% chance that any of their children will also have AD. This is called autosomal dominant inheritance. Only one copy of the gene needs to be not working (mutated) to lead to symptoms of Alzheimer Disease.
We also have two copies of the APP gene. One of our APP genes is inherited from our mother, and the other is inherited from our father. Sometimes AD caused by APP gene changes is inherited in a dominant fashion like PSEN1 and PSEN2.
Other times, both copies of the APP gene must have genetic changes (mutations) for someone to have symptoms of AD. In this case, if both parents have 1 APP gene mutation, there is a 25% that any child will have symptoms of AD. There is also a 25% chance that any child will inherit neither parent's APP mutation. There is a 50% chance that any child will only inherit one APP gene mutation and be a "carrier" like their parents. Someone with AD caused by APP gene mutations cannot have a child with Alzheimer Disease unless their partner also has at least one APP gene mutation.
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What does it mean to have a "variant of uncertain significance" in Alzheimer disease?
Some genetic changes are called "variants of uncertain significance". This means that we found a genetic change that we do not fully understand. We are not quite sure how this genetic change affects the body at this time. It may cause familial Alzheimer Disease and it may not. We need more data and research to make a conclusion about whether or not this change is disease causing. A genetic counselor or geneticist may be able to help explain what this result means for your particular situation. As we learn more, variants of uncertain significance are typically re-classified as either "disease causing" or "not disease causing." It will be important to check in every year with your healthcare provider to see if more has been learned about your variant of uncertain significance. A medical geneticist can be found by asking your doctor for a referral or looking on the American College of Medical Geneticists website. Genetic counselors can be found on the National Society of Genetic Counselors website.
If someone has a child with Down syndrome, are they at increased risk to have Alzheimer Disease?
People who have Down syndrome have an increased risk to develop Alzheimer Disease in their lifetime, but it is not believed that their relatives without Down syndrome are at any increased risk. Researchers believe that people who have Down syndrome are at increased risk because they have three copies of the APP gene instead of two. Most people have 23 pairs of chromosomes resulting in 46 total chromosomes. People who have Down Syndrome have 47 total chromosomes because they have an extra copy of chromosome 21. The APP gene is found on chromosome 21. People who have Down Syndrome have 3 copies of the APP gene instead of 2. Their relatives do not have this extra copy of the APP gene so they are not believed to be at increased risk.
What is the risk to develop Alzheimer Disease if there is no or limited family history of the disease?
The general population lifetime risk to develop dementia symptoms is around 10% to 12%. If a person has a parent, sibling, or child with Alzheimer Disease and no other family history, the risk for that person to develop Alzheimer Disease is around 20% to 25%. The risk value is higher if there is a stronger family history of Alzheimer Disease. Also, if there is a known genetic change in the family that causes Alzheimer Disease, the risk is possibly greater than 25% as well. Each family is different and unique. A genetic counselor or geneticist can help review your family history and determine a more accurate risk for members of your family. Genetic counselors can be found on the National Society of Genetic Counselors website.
What's my risk to develop Alzheimer Disease if my parent had the disease?
The answer to this question depends on many factors. If a person has a parent with Alzheimer Disease (AD) and no other relatives with AD, the risk for that person to develop AD is around 20% to 25%. Someone with many relatives with AD may have a greater chance to develop Alzheimer Disease. Also, if your parent was found to have a genetic change in PSEN1, PSEN2, or APP that is causing their Alzheimer Disease your risk could be as high as 50%. If you are concerned about your risk and you have a family history of AD, a genetic counselor may be able to help you better understand your risk. Genetic counselors can be found on the National Society of Genetic Counselors website.