Genetics of dementia

2. Alzheimer's disease

Alzheimer's disease is the most common form of dementia and the genetics of Alzheimer's is the best understood of all the common dementias. Studies of how Alzheimer's disease appears in families show that there can be both simple (single-gene mutation) and complex (multi-gene variant) inheritance patterns. The genes involved in each kind of inheritance are different.

Familial Alzheimer's disease

In just over 600 families worldwide, studies reveal many close family members who are affected by Alzheimer's disease across successive generations. This pattern of 'familial clustering' of Alzheimer's disease suggests there is a mutation within a single gene that causes the disease. In these cases, the mutation is being passed down in the DNA from parent to child, across several generations.

People with one of these extremely rare mutations tend to develop Alzheimer's disease early, in their 30s, 40s or 50s. This is much younger than in the majority of people who develop the disease. (Dementia that starts before the age of 65 is known as young-onset or early-onset dementia, whereas dementia that starts after 65 is called late-onset.)

Studies of the affected families show that their Alzheimer's disease is usually caused by a mutation in one of just three genes. (In a few families no mutation is found. They probably have a different but unknown, even rarer, mutation.)

These three genes are the amyloid precursor protein (APP) gene and two presenilin genes (PSEN-1 and PSEN-2):

More than 450 known families worldwide carry a mutation in the PSEN-1 gene on chromosome 14. This causes up to 80 per cent of all familial Alzheimer's disease, with symptoms appearing as early as 30 years of age.

More than 100 known families worldwide have a mutation in the APP gene on chromosome 21, which affects production of the protein beta-amyloid. A build-up of beta-amyloid in the brain is thought to be a major factor in the development of Alzheimer's disease.

More than 30 known families have a mutation in the PSEN-2 gene on chromosome 1, causing familial Alzheimer's disease that can start later than for PSEN-1.

It is important to note that these mutations are extremely rare. Among people with early-onset Alzheimer's disease - which is itself uncommon - only about 1 in 10 has a very strong family pattern of inheritance. However, when symptoms start very early, for example in a person's 30s, the chance that the disease has been inherited is higher than 1 in 10. When all Alzheimer's disease starting at any age is considered, fewer than 1 in 100 cases are thought to be caused by mutations in these three genes.

It is likely that if you inherit a mutation in one of these genes you will develop Alzheimer's disease at a comparatively early age. Unfortunately, in these cases adopting a healthy lifestyle is not likely to reduce your chances of getting the disease.

A child of someone with one of these mutations has a 50 per cent (or 1 in 2) chance of inheriting the mutation.Just like tossing a coin, each child has an equal chance of inheriting or not inheriting the mutation. If you have a full brother or sister with a mutation, you will also have a 50 per cent chance of having it. People who do not inherit the mutation cannot pass it on to their children.

Family tree of gene inheritance

A family tree showing strong inheritance of a mutation (dark figures) across three generations. The affected grandfather had three children. Two of these three inherited the mutation. Of these two, the daughter has one affected male child and the affected son has no children. The two (and any future) children of the unaffected son are free of the mutation.

Risk genes for Alzheimer's disease

The vast majority of people with Alzheimer's disease do not inherit it from a parent as a single-gene mutation with a simple inheritance pattern. Instead, the inheritance follows a more complex pattern. The disease might skip a generation, affect people on both sides of the family, appear seemingly from nowhere or not be passed on at all.

More than 20 gene variants (or regions within the DNA) have now been identified which affect - to different degrees - the chances of a person developing Alzheimer's disease. The effects of these genes are subtle. Different variants act to slightly increase or decrease the risk of a person developing Alzheimer's disease, but do not directly cause it. These 'risk genes' interact with each other and with other factors, such as age and lifestyle, to influence someone's overall risk of getting the disease.

Unlike familial Alzheimer's disease, this multi-gene form generally affects older people, with symptoms starting after the age of 65. The gene with the greatest known effect on the risk of developing late-onset Alzheimer's disease is called apolipoprotein E (APOE). This gene is found on chromosome 19 and the APOE protein plays a role in handling fats in the body, including cholesterol. The APOE gene comes in three variants, which are named with the Greek letter epsilon (e): APOE e2, APOE e3 and APOE e4.

We each have two copies of the APOE gene, and these may be the same as each other or different. Therefore everyone is born with one of the six possible combinations: e2/e2, e2/e3, e3/e3, e2/e4, e3/e4 or e4/e4. The combination we have affects our risk of Alzheimer's disease, as follows:

  • APOE e4 is associated with a higher risk of Alzheimer's disease. About 25 per cent of the general population inherits one copy of APOE e4. This increases their lifetime risk of developing Alzheimer's disease by a little more than two times, on average. People with APOE e4 also tend to develop Alzheimer's at a younger age.
  • About 2 per cent of the population gets a 'double dose' of the APOE e4 gene - one from each parent. This increases their risk of developing Alzheimer's disease by about three to five times, on average. However, they are still not certain to develop Alzheimer's disease.
  • About 60 per cent of the population has a 'double dose' of the APOE e3 gene and is at average risk. Up to a quarter of this group develops Alzheimer's disease by their late 80s.
  • The APOE e2 variant of the gene is associated with a lower risk of Alzheimer's - people with it are slightly less likely to develop the disease. In the general population, 11 per cent have one copy of APOE e2 and one copy of APOE e3, while 0.5 per cent (1 in 200) have two copies of APOE e2.

For a long time, APOE was the only gene to be consistently linked to the risk of late-onset Alzheimer's disease. However, recent scientific advances have allowed researchers to test many more genes to see whether there are other gene variants linked to Alzheimer's disease.

This has revealed several other genes that have variants linked to increased or decreased risk of Alzheimer's. These include genes known as CLU, CR1, PICALM, BIN1, ABCA7, MS4A, CD33, EPHA1 and CD2AP. These are thought to have roles in inflammation and immunity, fat metabolism or transport within cells. The variants of these genes affect a person's risk of developing Alzheimer's disease much less than APOE. Researchers suspect that there are many more risk genes that have not yet been discovered.

If a birth relative has been diagnosed with Alzheimer's disease, it is natural for you to wonder whether you are at increased risk. If you have a close relative (parent or sibling) who has been diagnosed with late-onset Alzheimer's disease, your chances of developing the disease rise slightly compared to someone with no family history of the disease. However, it does not mean that dementia is inevitable for you. Everyone can reduce their overall risk by adopting a healthy lifestyle.