If you are an adult who has symptoms of dementia and a strong family history of early onset Alzheimer’s Disease (AD that begins before age 60-65) or if you are an adult with no symptoms but with an identified PSEN1 genetic mutation (and EOFAD) in your family
A blood sample taken from a vein in your arm
This test looks for mutations in the PSEN1 gene, which have been associated with Early Onset Familial Alzheimer’s Disease (EOFAD). Although most AD starts after the age of 65 (late onset), about 5-10% of cases of the disease begin in people under 65 years of age. Much of this early onset AD is inherited - it runs in families and is caused by a genetic mutation. There have been three genes identified so far that are associated with EOFAD; all are very rare - accounting for less than one in 1000 cases of Alzheimer's disease. Of these, PSEN1 is the most common and is thought to cause about half the cases of EOFAD. Since PSEN1 is a dominant gene, it only takes one mutated copy, inherited from either your mother or father, to cause EOFAD. Why PSEN1 is associated with EOFAD is not yet known. It is thought that the normal role of the PSEN1 gene is to make the protein presenilin 1, a protein used in the development of the brain and spinal cord. It also works with other enzymes to cut certain proteins into smaller pieces (amyloid beta peptide). A mutation of PSEN1 produces an abnormal presenilin 1 protein that no longer functions properly, resulting in a breakdown of this process. This breakdown lends itself to increased production of the longer, stickier configuration of the amyloid beta protein, which is toxic to the nervous system and eventually forms the characteristic amyloid plaques of AD.. PSEN1 is a rare mutation. So far, about 40 mutations of the PSEN1 gene have been identified but only in about 50 different families worldwide.
The PSEN1 genetic mutation analysis is new and not widely accepted yet. In its present form, it is only capable of identifying about 30-60% of patients who have EOFAD caused by a PSEN1 mutation. The analysis is made easier if a patient already has an identified PSEN1 mutation in their families.
How is the sample collected for testing?
This test is not readily available in the UK however, if required under special circumstances a blood sample is obtained by inserting a needle into a vein in your arm.
Is any test preparation needed to ensure the quality of the sample?
No test preparation is needed.
How is it used?
PSEN1 genetic mutation analysis is not readily available in the UK. It has the potential to be used to screen asymptomatic (without symptoms) or symptomatic adults (with symptoms) who have a strong family history of early onset familial Alzheimer’s Disease (EOFAD), especially when a PSEN1 mutation has been identified in other family members. It may be used to aid in the diagnosis of early onset Alzheimer’s Disease (versus some other form of early onset dementia) but usually only in those with a family history of EOFAD. PSEN1 is also occasionally used with genetic counselling to assess the risk of having and passing on a PSEN1 mutation to your unborn child.
When is it requested?
The test can be used in asymptomatic or symptomatic adults with a strong family history of early onset Alzheimer’s Disease, especially when there are multiple family members in multiple generations (preferably three generations) who have had EOFAD. It is NOT useful as a screen for the general population or for those who have late onset AD.
What does the test result mean?
If you have one of the PSEN1 mutations, it is highly likely that you will eventually develop EOFAD, usually at a similar age to other affected family members. The 'penetrance' of the gene (symptoms, severity, and rate of progression), however, can vary from individual to individual. Since it is a dominant gene, if you have a PSEN1 mutation, each of your children will have a 50% chance of having the PSEN1 mutation passed on to them.
It should be remembered that the PSEN1 genetic mutation analysis, in its current form, is only capable of picking up 30-60% of PSEN1-caused EOFAD. If your test is negative, there is still a chance that you have an unidentified PSEN1 mutation.
Is there anything else I should know?
PSEN1 genetic mutation is almost exclusively family-related and is not associated with late onset AD. A few cases of PSEN1 genetic mutation will show up without a strong family history because of 'alternate' paternity, new mutations, or because a parent died before symptoms developed so this element of the family history was unknown.
The PSEN1 test is a new, relatively expensive test that has limited use and is still very rarely used. It is performed in only a few laboratories in the world, so if your doctor recommends the test, your blood sample will need to be sent to a reference lab and results may take a while to return.
My father has been diagnosed with early onset AD. Can my doctor tell if my father has a genetic mutation without a blood test?
No, the symptoms for EOFAD, sporadic early onset AD, and late onset AD are the same except for the age of onset. You cannot tell whether someone has a genetic mutation just by looking at them. If there is a strong family history of early onset AD, and especially if another family member has been diagnosed with a genetic mutation, your doctor may suspect a genetic problem, but a blood test is the only way to confirm this suspicion.
What other genes cause EOFAD and is testing available for them?
The other genes that have mutations associated with EOFAD are PSEN2 and APP (amyloid precursor protein). PSEN2 testing is available, but APP is still being researched. It should be noted that PSEN2 and APP mutations are very rare. They have only been identified in a very small number of specific family lines.