Ask a neuroscientist…

‘How do genes influence the risk of Alzheimer’s disease?’

Simon Maksour

Simon Maksour is a PhD candidate at the Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong (UOW), studying the molecular changes in Alzheimer’s disease.

Rachelle Balez

Rachelle Balez is a PhD candidate at the IHMRI, UOW, who uses patient-derived stem cells to model neurodegenerative diseases.

Professor Lezanne Ooi

Professor Lezanne Ooi is a cellular neuroscientist and Group Leader of the Neurodevelopment and Neurodegeneration Laboratory at the Illawarra Health and Medical Research Institute, the School of Chemistry and Molecular Bioscience and Molecular Horizons, University of Wollongong. Professor Ooi is also an AJDC Editorial Adviser.

Have you ever wondered why your eyes are the colour they are, or why you have curly hair? Genes are responsible for making us who we are and making us unique. Genes are inherited from our parents and are the reason why family members may look alike. In some cases, the genes that we inherit can be faulty and can sometimes cause disease.

In the case of Alzheimer’s disease (AD), and other types of dementia, like Parkinson’s disease, in addition to the interplay of lifestyle choices, we can inherit certain genes that can increase our risk of developing that disease. In this article, we will investigate how genes influence the risk of AD, the most common form of dementia.

How do genes work?

Genes are the blueprint of our body. Our genome – the complete set of genetic material we all have – consists of approximately 21,000 genes. Every person has two copies of each gene, one inherited from each parent. The DNA in a gene contains the instructions for making proteins, which play many critical roles in how our body develops and in keeping us healthy.

Sometimes the instructions in a gene may be altered – this is called a mutation – and the gene produces a protein that may not function properly (loss of function) or that functions in a different way (gain of function). Sometimes these changes in the protein may result in little to no changes to how the body works; but other times they are more serious and result in disease.

What is the genetic difference between ‘early- onset’ and ‘late-onset’ Alzheimer’s disease?

A small proportion of the people who develop AD (approximately 5%) have what is known as ‘early- onset’ or familial AD. This rare form of AD usually develops between the ages of 30 and 60 years and is the result of an inherited genetic mutation. A mutated version of any of these genes contributes to the production of a small protein fragment called amyloid-ß, which clumps together in the brain to form amyloid-ß plaques, a hallmark of AD.

By comparison, for most people with what is known as ‘late-onset’ or sporadic AD (around 95%), the cause is more complex. It is influenced by many genetic risk factors, which alter a person’s chance of developing the disease, with additional factors, such as ageing and lifestyle also playing a part. Therefore, from a genetic perspective, a mutated gene is the cause of the rare, early onset form of disease. In the more common, late-onset form of AD however, variations of many genes affect the person’s risk, but do not guarantee they will develop the disease.

What are the common risk factor genes in late-onset Alzheimer’s disease?

The most common gene associated with the development of late-onset AD is called the APOE gene. There are three versions of the APOE gene. Depending on which version of the gene is inherited, there can be an increased risk of developing late-onset AD.^1,2 However, it is also possible to inherit a version of APOE that is protective against AD.

Evidence suggests that the APOE gene is indeed a ‘genetic risk factor’ for AD – meaning that having a particular version of the APOE gene can give you an increased risk of developing AD. However, the APOE gene does not directly or necessarily cause AD and many people have the gene without developing it.

A better understanding of genetic risk factors is providing clues as to the causes of late-onset AD. The genome sequencing of tens of thousands of people with AD have implicated many different genes and pathways – such as amyloid-ß build up, chronic inflammation and oxidative stress – and they can all contribute.^3,4

The future of genetic research in Alzheimer’s disease

With dementia currently the second leading cause of death in Australia⁵ – and AD being the most common type of dementia – it is a clear research priority. To date, research has shown us just how complex AD is, with several different mechanisms and factors implicated in the development of the disease.

Future research is focused on understanding how the interplay of risk genes, protective factors and lifestyle influences affect a person’s risk of developing AD. By identifying more genes that may influence the risk of AD, researchers will help to uncover target pathways for developing new treatments.

Your genes and risk factors in perspective

Importantly, having a close relative with late-onset AD does not mean you will definitely develop it too. People carrying those risk factor genes are only at a slightly increased risk of developing the disease compared to the general population. Fortunately, there are many things we can do (eg. exercise, diet and mental stimulation^6,7) to protect our brain health and reduce our risk of developing AD.