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Presenilin 1 genetic analysis (PSEN1)

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.

Most early onset AD is inherited and caused by a genetic variant. There have been variants identified in three genes that are associated with EOFAD, all of them rare. Of these, PSEN1 is the most common and thought to account for up to about 70 per cent of EOFAD cases. The other two genes are APP – amyloid precursor protein, accounting about 15 per cent of EOFAD and PSEN2 – presenilin 2, accounting for less than five per cent of EOFAD.

The association between genetic variants in PSEN1 and 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 the PSEN1 gene 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 Alzheimer's disease. A wide variety of PSEN1 variants have been identified in research on families with EOFAD.

 

There are two types of testing:

  1. Diagnostic testing
    PSEN1 genetic testing is ordered for an adult who has dementia-related symptoms and a strong family history EOFAD.
  2. Predictive testing 
    Testing may also be offered to adults who don’t have symptoms but where a PSEN1 gene fault has been identified in other family members. This is to assess the likelihood of them developing early onset dementia.
    PSEN1 genetic testing is NOT useful as a screen for the general population or for those who have late onset Alzheimer's disease.


Genetic counselling
Appropriate professional genetic counselling is important to have before deciding whether to proceed with testing, especially for predictive testing, and when assessing the risk of someone having and passing on a PSEN1 variant to their offspring.

Genetic counselling is a helpful step in deciding if testing is the right course of action and for dealing with the result if testing proceeds. This is especially important for people who do not have symptoms of Alzheimer’s disease.
 

Sample 
Blood 

Any preparation?
None
 

If someone has a genetic variant in the PSEN1 gene, it is highly likely they will eventually develop EOFAD, and usually at a similar age to other family members. However, the symptoms, severity, and rate of progression, can vary from person to person.
Although many genetic disorders require faulty genes to be inherited from both parents, this is not the case with PSEN1. Since PSEN1 is a dominant gene, it only takes one faulty copy, inherited from either a mother or father, to cause EOFAD. 
If one of a couple has a faulty PSEN1 gene, each child they have will have a 50 per cent chance of inheriting the variant and developing EOFAD.

Genetic testing of PSEN1 cannot detect 100 per cent of variants, so 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. 
A negative PSEN1 result in a person with early onset Alzheimer’s disease may also mean they have a variant in a different gene such as APP, PSEN2 or another gene yet to be identified.
There is no Medicare rebate for PSEN1 testing. Similarly, testing for PSEN2 and APP, the other genes  known to be associated with EOFAD, although available in Australia, are also not covered by Medicare.  It should be noted that genetic faults in PSEN2 and APP are very rare. 

Variants in PSEN1 are almost exclusively family related. Occasionally, a strong family history of EOFAD may not be apparent 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.