To detect a rare mutation in the PSEN1 gene known to be associated with early onset familial Alzheimer disease (EOFAD)
When you are an adult who has symptoms of dementia and a strong family history of Alzheimer disease that begins before age 60 to 65 or if you are an asymptomatic adult with a family member who has early onset Alzheimer disease and an identified PSEN1 genetic mutation
A blood sample drawn from a vein
No test preparation is usually needed. However, prior to testing, you may wish to receive genetic counseling. This could be a helpful and important step in deciding if testing is right for you and for dealing with the result if you decide to be tested – especially if you currently have no symptoms of dementia.
This test looks for mutations in the PSEN1 gene sequence that have been associated with early onset familial Alzheimer disease (EOFAD).
Although most Alzheimer disease (AD) cases present after the age of 65, about 5-10% of cases present in people younger than 65 years of age. Much of this early onset AD is familial – it runs in family lines and is caused by a genetic mutation. So far, there have been three genes that have been identified as being associated with EOFAD: PSEN1, PSEN2, and amyloid precursor protein (APP).
Of these three genes, PSEN1 is the most commonly involved and is thought to cause about 20% to 70% of early onset AD. Since PSEN1-associated AD is dominantly inherited (autosomal dominant), it only takes one mutated copy, inherited from either the mother or father, to lead to the development of EOFAD.
Why PSEN1 mutations cause EOFAD is not completely understood. Scientists think that the normal role of the PSEN1 gene is to make the presenilin 1, a protein used in the development of the brain and spinal cord. Presenilin 1 also works with other enzymes to cut certain proteins into smaller pieces (amyloid beta peptides). A mutation in PSEN1 produces an abnormal presenilin 1 protein that no longer functions properly, resulting in a breakdown of this process. This can lead to increased production of a longer, stickier configuration of the amyloid beta protein, which is toxic to the nervous system and eventually forms the characteristic amyloid plaques seen in individuals with AD.
A wide variety of PSEN1 mutations have been identified in the families studied to date, and there is no common or high frequency mutation known. Some mutations may be more common in specific populations. Testing is more straightforward if a specific PSEN1 mutation has already been identified in a person's family line. The PSEN1 genetic mutation analysis is a relatively new test and is offered by a limited number of laboratories.
PSEN1 genetic mutation analysis may be performed in adults who have a strong family history of early onset Alzheimer disease (EOFAD), especially when a specific PSEN1 mutation has been identified in other family members. It may be used to aid in the differential diagnosis of EOFAD versus other forms of early onset dementia but usually only in those with a strong family history of disease.
The PSEN1 test is not useful as a screen for the general population or for those who have late onset familial AD or sporadic AD.
This test may be ordered when you develop symptoms associated with Alzheimer disease before 65 years of age. Signs and symptoms may include:
PSEN1 mutation analysis may also be ordered when an asymptomatic adult has a strong family history of early onset Alzheimer disease, especially when there are multiple family members over several generations who have had or were thought to have had EOFAD.
If a person has a disease-causing PSEN1 mutation, it is highly likely that the person will eventually develop AD, usually at a similar age to other affected family members. The symptoms, severity, and rate of progression can vary from individual to individual. Since it is a dominant gene, each child will have a 50% chance of having the PSEN1 mutation passed on to them.
If no PSEN1 mutation is identified, it is still possible that the person has EOFAD because the specific PSEN1 mutation is not able to be identified by the existing testing method or there is a mutation in a different gene.
PSEN1 mutations are not associated with late onset sporadic AD. Some individuals will not have a strong family history because their family is not informative (i.e., key people passed away before they would have developed symptoms or their full medical histories are not known). Other issues that could confound family history are non-paternity and undisclosed adoption.
The PSEN1 test is a relatively new test that has limited use and is still rarely ordered. It is performed in only a few laboratories, so if a healthcare practitioner recommends the test, the blood sample will need to be sent to a reference laboratory.
No, the clinical symptoms of all forms of AD are often the same. They only differ by age of onset. You cannot tell whether someone has an inherited form of AD just by looking examining them. If there is a strong family history of early onset AD, especially if another family member has had positive genetic testing, your doctor may suspect a genetic problem that may be confirmed by a blood test.
The other genes that have mutations associated with EOFAD are PSEN2 and APP (amyloid precursor protein). Testing is available, but these are less frequent causes of EOFAD.
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