EXPLORING THE ROLE OF GENETICS IN DEMENTIA.

Understanding the role of genetics in Alzheimer’s disease and other forms of dementia can help determine whether these conditions can be inherited.

Understanding genes

Our genetic material is packaged into structures called chromosomes, which contain thousands of genes. Genes are the blueprints for making proteins and are responsible for passing specific characteristics, such as hair colour, height, and the tendency to develop certain diseases, from one generation to the next. Each person inherits two copies of every gene, one from each parent.

A mutation is a permanent change in a gene. Some mutations cause diseases, meaning that if a person inherits a mutated gene for a particular disease, they will develop that illness. However, the vast majority of dementia cases are not caused by inherited genetic mutations. Dementia is common enough that having one or two close relatives with dementia does not necessarily indicate a genetic link.

There are also susceptibility or risk genes, which do not guarantee the development of a disease but increase the risk. Some susceptibility genes associated with dementia have been identified.

Genetics of Alzheimer’s disease

Familial Alzheimer’s disease

Familial Alzheimer’s disease (FAD) refers to the small number of families with a genetic mutation that directly causes the disease. FAD usually affects younger individuals, sometimes as early as their 30s or 40s. On average, half of the children of a person with FAD will inherit the faulty gene, and all who inherit it will develop Alzheimer’s disease. People who do not inherit the faulty gene cannot pass it on to their children.

Three genes are known to cause FAD if mutated: presenilin 1, presenilin 2, and the amyloid precursor protein (APP) gene. These mutations result in increased production of beta-amyloid plaques, which damage the brain in Alzheimer’s disease. However, these mutations are rare and account for less than 5% of all Alzheimer’s cases.

Genetic testing can identify mutations that cause FAD, determining whether a person has the disease and if a child has inherited the gene. However, it cannot predict when symptoms will begin, though the onset age is typically similar to that of the parent.

Sporadic Alzheimer’s disease

Most cases of Alzheimer’s disease are sporadic, meaning they are not caused by known gene mutations. The cause is often unknown, with many factors, including genetic and environmental, influencing the risk. Having a close relative with Alzheimer’s slightly increases the risk, but this is not solely due to genetics.

About 10 susceptibility genes that increase the risk of Alzheimer’s have been identified. The most significant is the apolipoprotein E (ApoE) gene, which has three forms: ApoE2, ApoE3, and ApoE4. Having one or two copies of ApoE4 increases the chance of developing Alzheimer’s but does not make it certain. Some people with ApoE4 never develop Alzheimer’s, and others without it do.

ApoE3 is associated with an average risk, while ApoE2 is linked to a reduced risk. A blood test can identify which forms of ApoE a person has, but it cannot predict who will or will not develop Alzheimer’s disease, so ApoE testing is generally only available as part of research studies.

Other susceptibility genes also play a role in increasing Alzheimer's risk, but their impact is smaller compared to ApoE4. Carrying ApoE4 is also linked to a higher risk of cardiovascular disease and vascular dementia.

Genetics of frontotemporal dementia

Frontotemporal dementia (FTD) involves the degeneration of the frontal and/or temporal lobes of the brain, affecting behaviour and language abilities. Some forms of FTD are inherited, caused by specific gene mutations. Two genes, MAPT (tau gene) and progranulin, account for about 50% of familial FTD cases. Several other rare gene mutations can also cause FTD.

In familial FTD, half of the children of an affected person will inherit the faulty gene and develop the disease. Genetic testing is available for these families. However, familial FTD only accounts for about 10-15% of all cases, with the majority being sporadic.

Other genetic forms of dementia

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy): This rare inherited form of vascular dementia is caused by mutations in the NOTCH3 gene on chromosome 19. It is characterised by recurrent mini-strokes, brain lesions, migraines, psychiatric symptoms, and progressive dementia.

  • Familial Lewy Body Disease: Very rare, but some gene mutations, such as those in the SCNA gene, can cause Lewy body disease, which may manifest as dementia, Parkinson’s disease, or related disorders.

  • Creutzfeldt-Jakob Disease: Familial forms, caused by mutations in the PRNP gene, account for 5-10% of cases and lead to rapidly progressing dementia.

  • Huntington’s Disease: This inherited condition causes motor, psychiatric, and cognitive symptoms, often including dementia. It is caused by mutations in the huntingtin gene.

For these familial dementias, children of an affected person have a 50% chance of inheriting the gene and developing the disease

Genetic testing

Due to the rarity of inherited dementias, genetic testing is not relevant for most families. However, it is available for those affected by familial dementia. For individuals with symptoms and a family history suggestive of a genetic cause, genetic testing can confirm the diagnosis. It can also predict the development of the disease in family members, especially children, of a person with a known genetic mutation.

The decision to undergo genetic testing is complex and should be carefully considered. The test requires informed consent and should never be done under pressure. Knowing one carries the gene can help with future planning, lifestyle choices, and reproductive decisions. However, since no cure exists, individuals must consider whether they want to know if they will develop dementia in the future.

For those concerned about passing on a faulty gene, prenatal genetic testing or IVF procedures can offer additional options. Specialised genetic counselling, available through state-based genetics services, is essential for those considering these issues. Your doctor can provide details and referrals.

For more information, the Centre for Genetics Education offers current genetics information for people affected by genetic conditions.