Early-onset familial Alzheimer’s disease (EOFAD) is a rare form of Alzheimer’s disease that causes symptoms like memory loss much earlier than usual, often before the age of 65. It is caused by specific gene mutations (also called variants) passed down in families. Variants have been identified in three main genes that are associated with EOFAD, all of them are rare.
PSEN1 is the most common genetic cause of EOFAD, accounting for up to 70 per cent of cases. Variants in APP and PSEN2 account for a smaller proportion.
Variants that cause EOFAD are very rare. They are inherited and are usually found in families where Alzheimer’s disease has affected several generations, often at relatively young ages.
These variants in the PSEN1, PSEN2 and APP genes directly cause Alzheimer’s disease. This is different from the APOE ε4 genetic variant. APOE ε4 does not directly cause Alzheimer’s disease but increases your risk of developing it. PSEN1, PSEN2 and APP are therefore described as causal genes, whereas APOE is termed a risk gene.
Genetic testing can help diagnose EOFAD if you have symptoms and a strong family history. It can also be used in relatives without symptoms if a specific variant that causes EOFAD has already been found in a family.
Genetic counselling is essential because the results can have significant implications for you and other members of your family.
How do variants in PSEN1, PSEN2 and APP cause EOFAD?
Amyloid plaques are one of the characteristic features of Alzheimer’s disease. These plaques are made from a protein called amyloid beta which builds up between brain cells and eventually damages and destroys them.
APP stands for amyloid precursor protein. This is the material from which amyloid beta is made. APP is cut up into smaller pieces, some of which are amyloid beta.
Genes are short sections of DNA. Genes give the instructions that tell the body how to grow, work and react to its surroundings. If you inherit a variant or alteration in a gene, it can change the instructions.
The APP gene provides the instructions for making APP protein. Inherited variants in the APP gene can affect how APP is made.
PSEN1 and PSEN2 are genes that provide instructions for the enzymes that cut APP into smaller pieces including amyloid beta. If you inherit a variant copy of one of these genes it can alter the way APP is cut. This can lead to forms of amyloid beta that are more likely to build up and eventually form the amyloid plaques of Alzheimer's disease.
Many different disease-causing variants have been identified in the PSEN1, PSEN2 and APP genes, with most occurring in PSEN1 and thought to account for up to 70 per cent of cases. APP accounts for about 15 per cent, and PSEN2 represents less than five per cent of EOFAD.
Testing is ordered for PSEN1, PSEN2 and APP genes:
EOFAD is inherited in an autosomal dominant way, meaning a child only needs to inherit one faulty gene from one parent to be at risk of developing EOFAD. This means, any child born from a parent who has the gene fault has a 1 in 2 chance of inheriting the mutation and a 1 in 2 chance of not inheriting it.
Variants in PSEN1, PSEN2 and APP are almost exclusively family related. However, there can also be what is called a de novo variant. This refers to a genetic alteration that appears for the first time in a family and develops for the first time in that person.
A de novo genetic alteration can occur when the mother’s egg or father’s sperm is being made or shortly after conception as the embryo begins to develop. A de novo variant in the PSEN1, PSEN2 or APP genes is rare.
There is currently no Medicare rebate for PSEN1, PSEN2 and APP genetic testing. However, testing may be provided through a public genetics service free of charge if you meet their eligibility criteria. If publicly funded testing is not available, you may need to pay for the test privately.
It is essential to have professional genetic counselling before deciding whether to go ahead with testing. This is especially important if you are having predictive testing, to assess the risk of you having a PSEN1, PSEN2 and APP variants and passing them on to your children.
Genetic counselling is a helpful step in deciding if testing is the right course of action and for dealing with the result. Occasionally, a strong family history of EOFAD may not be apparent because family members have passed away before symptoms developed. Other issues that can confound family history are non-paternity and undisclosed adoption.
Sample
Blood.
Any preparation?
None.
For genetic testing of PSEN1, PSEN2 and APP, the pathology report will usually state the variant found and how it has been classified.
The variants identified may be called pathogenic or disease-causing variants. The variants of strong or potential clinical significance are highlighted. Genetic testing reports are highly complex. They typically present the most important and relevant information first followed by supplementary information.
| Result | What this may mean |
| Pathogenic variant Likely pathogenic variant | A genetic change known to cause early-onset familial Alzheimer’s disease (EOFAD) has been found. A pathogenic variant is a genetic change with strong, well-established evidence that it causes disease. A likely pathogenic variant is a genetic change that is very likely to cause disease, but where the evidence is not yet conclusive. If either of these are found in PSEN1, PSEN2 or APP in someone with symptoms and an appropriate family history, it can support or confirm a diagnosis of autosomal dominant Alzheimer’s disease. |
| Variant of uncertain significance (VUS) | A genetic change has been found, but there is not enough evidence to know whether it causes EOFAD. It should not be used to diagnose or predict the disease. |
| No pathogenic or likely pathogenic variant detected | No disease-causing variant was found in the genes tested. This does not completely rule out a genetic cause, because some variants may not be detected and other genes can be involved. |
A positive result means that there is a pathogenic or likely pathogenic variant in the gene. This means that it is likely a person will eventually develop EOFAD, and for PSEN1 usually at a similar age to other family members but the age of onset varies more for PSEN2. However, the symptoms, severity and rate of progression, can vary from person to person. A negative result means PSEN1, PSEN2 or APP-related Alzheimer’s disease is unlikely. However, someone with symptoms of EOFAD may have a variant in a different gene. Genetic testing cannot detect all disease-causing variants, so even with a negative result there is still a chance that there is a variant present that was not identified by the testing method. | |
Pathology and diagnostic imaging reports can be added to your My Health Record. You and your healthcare provider can now access your results whenever and wherever needed.
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