Presenilin 1

What is being analysed?
This test looks for mutations in the PS1 gene, which is associated with early-onset familial Alzheimer’s disease (also called Alzheimer’s disease type 3 or AD3). Although most cases of Alzheimer’s disease begin after the age of 65 (late-onset sporadic forms), about 5-10% of cases begin before 65. Many cases of early-onset Alzheimer’s disease are familial. Three genes associated with AD3 have been identified so far: APP, PS1 and PS2. Of these, PS1 is the one most frequently involved in the onset of the disease and is thought to cause about half of AD3 cases.

The PS1 gene is inherited in an autosomal dominant pattern. The molecular mechanism linking PS1 to Alzheimer’s disease type 3 is not yet clear. The role of the gene and the function of presenilin 1 (the protein it produces) are still being studied. Several lines of evidence suggest that it is an enzyme involved in the proteolytic cleavage of the beta-amyloid precursor protein, whose build-up leads to the formation of the plaques typical of Alzheimer’s disease. Mutations in the PS1 gene are rare; about 40 have been identified so far, but only in a few families worldwide.

Genetic testing for PS1 mutations has been introduced recently and its clinical use is not yet fully established. The analysis is easier to perform if the mutation responsible for the disease has already been identified in the family.

How is the sample collected for testing?
The sample is taken from a vein in the arm.

How is it used?
When is it requested?
What does the test mean?
Is there anything else I should know?

How is it used?
PS1 gene analysis is performed in asymptomatic or symptomatic adults with a strong family history of early-onset Alzheimer’s disease, especially when a disease-causing PS1 mutation has already been identified in the family. This test can also help in the differential diagnosis of early-onset familial Alzheimer’s disease from other forms of dementia that also begin early.

When is it requested?
This test is generally requested for asymptomatic or symptomatic adults with a strong family history of early-onset Alzheimer’s disease, especially when cases of the disease are present in the family across up to 3 generations. It should not be used as a screening test in the general population or in people with the sporadic late-onset form of the disease.

What does the test result mean?
If one of the PS1 gene mutations is present, the person is highly likely to develop Alzheimer’s disease, generally at about the same age as affected relatives. The penetrance of the disease (symptoms, severity and progression) can, however, vary from person to person.

It should be remembered that genetic testing for PS1 mutations, in its current form, can only identify 30-60% of cases of Alzheimer’s disease type 3. A negative result therefore does not rule out the presence of a mutation.

Is there anything else I should know?
PS1 gene mutation is not associated with late-onset Alzheimer’s disease. In some cases the mutation may be present even though no cases of the disease have been seen in the family; this may be due to new mutations, or to the fact that the relative carrying the PS1 mutation died before symptoms appeared and therefore before the mutation could be identified.

Genetic testing for PS1 mutations has been introduced recently and its clinical use is not yet fully established, so it is currently rarely requested. The test is not performed in all laboratories, so the sample may be sent to a reference laboratory. Turnaround times for this test can be very long.

1. My father has been diagnosed with early-onset Alzheimer’s disease. Can the doctor tell me whether my father has a genetic mutation without a blood test?
2. What other genes cause Alzheimer’s disease type 3?

1. My father has been diagnosed with early-onset Alzheimer’s disease. Can the doctor tell me whether my father has a genetic mutation without a blood test?
No. The symptoms of Alzheimer’s disease, whether early- or late-onset, are the same except for the age at onset. It is not possible to tell whether a person has a gene mutation from a physical examination alone. However, if there is a strong family history of early-onset Alzheimer’s disease, and especially if a gene mutation has been identified in a relative, the doctor may suspect a familial form and therefore that the mutation is also present in that person. A blood test is needed to confirm the presence of the mutation.

2. What other genes cause Alzheimer’s disease type 3?
The other genes associated with Alzheimer’s disease type 3 are PS2 (presenilin 2) and APP (amyloid precursor protein). These tests are currently performed mainly for research purposes. In addition, PS2 and APP mutations are very rare and have been identified in only a small number of families.