The PSEN1 test is used to detect a rare genetic mutation, also called a variant, in the PSEN1 gene known to be associated with early onset familial Alzheimer’s disease (EOFAD) or Alzheimer's disease type 3 (AD3). Although most Alzheimer's disease starts after the age of 65 and is termed late onset, about five to 10 per cent of cases begin in people who are younger.

What is being tested?

This test looks for genetic faults (pathogenetic variants) in the PSEN1 gene, which have been associated with early onset familial Alzheimer's disease (EOFAD). Although most Alzheimer's disease (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 variant. There have been pathogenetic variants identified in three genes so far that are associated with EOFAD; all are very rare. Of these, PSEN1 is the most common and is thought to cause about 30-70% of the cases of EOFAD. The other two genes are APP (amyloid precursor protein ), accounting for 1-15% of EOFAD and PSEN2 (presenilin 2) accounting for less than 5% of EOFAD.

Since PSEN1 is a dominant gene, it only takes one faulty copy, inherited from either your mother or father, to cause EOFAD. Why genetic variants in PSEN1 are associated with EOFAD is not completely understood. 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 (including amyloid beta protein).

A faulty copy of PSEN1 produces an abnormal presenilin 1 protein that no longer functions properly, resulting in a breakdown of this process. This leads 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. A wide variety of pathogenic PSEN1 variants have been identified in the families studied to date.

How is it used?

PSEN1 genetic testing may be performed in symptomatic adults (with dementia-related symptoms) who have a strong family history of early onset familial Alzheimer's disease (EOFAD). This is known as diagnostic testing.

Testing may also be offered for asymptomatic adults where a PSEN1 gene fault (pathogenetic variant) has been identified in other family members, to determine the likelihood of developing early onset dementia (predictive testing). Appropriate professional genetic counselling should be pursued before testing, especially for predictive testing, and when assessing the risk of a patient having and passing on a PSEN1 variant to his/her offspring. 

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, for diagnostic or predictive testing as discussed above.

It is NOT useful as a screen for the general population or for those who have late onset Alzheimer's disease.

What does the result mean?

If a person has a genetic fault (pathogenic variant) in the PSEN1 gene,  it is highly likely that the person will eventually develop EOFAD, and usually at a similar age to other affected family members. However the symptoms, severity, and rate of progression, can vary from individual to individual. Since pathgenetic PSEN1 variants are dominant, if someone has a PSEN1 variant, each of their children will have a 50% chance of inheriting the variant and developing EOFAD.

Is there anything else I should know?

Genetic testing of PSEN1 cannot detect 100% of pathogenic variants; thus, even with a negative result there is still a chance that there is a PSEN1 variant present that was not identified by the testing method utilised. A negative PSEN1 result in a person with early onset Alzheimer’s disease may also mean that the person has a variant in a different gene instead (e.g. APP, PSEN2 or another gene yet to be identified).

Pathogenic variants in PSEN1 are almost exclusively family-related. Occasionally, a strong family history of EOFAD may not be apparent e.g. because certain family members passed away before symptoms developed or because there is occurrence of a new variant. Other issues that could confound family history are non-paternity and undisclosed adoption.

There is currently no Medicare rebate for PSEN1 testing

Common questions

• 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 are known to be associated with EOFAD are PSEN2 and APP. Clinical testing for these genes is available in Australia but is not Medicare rebated. It should be noted that genetic faults (pathogenetic variants) in PSEN2 and APP mutations are very rare. 

More information

RCPA Catalogue of Genetic Tests and Laboratories