To what extent do Genetics contribute to the onset of Alzheimer’s and other forms of dementia?

Someone across the world develops dementia every 3 seconds. There were an estimated 46.8 million people worldwide living with dementia in 2015. This number is continuing to grow with an ever-ageing population. It is predicted that numbers will almost double every 20 years, reaching 75 million in 2030. Dementia is one of the biggest health-related problems around the world and it is important for us to put in efforts in towards stopping this.

What is Dementia?

Dementia itself is not one disease. In reality it is a group of diseases and is an umbrella term for the symptoms caused such as memory loss, confusion and personality change. It is a progressive disease of the brain that slowly causes impairment in memory and cognitive function. The exact cause of the neurodegenerative disease is unknown, but is usually linked to the excessive build-up of proteins in the brain, which reduce functionality of nerve cells and later cause them to die. The death of cells in certain areas is what causes the thinning/shrinking of parts of the brain. Currently, there is no cure or treatment available to slow or stop the progression of this disease.

Overall, there are around 7 stages of dementia which scale from very mild signs of cognitive decline, which is associated to normal memory loss with aging, to Very Severe Cognitive Decline where communication is limited, physical systems decline and most memory has been lost. As mentioned before, Dementia is an umbrella term for a group of diseases, each having different effects on different parts of the brain. Some of the most common ones are: Alzheimer’s Disease; Vascular Dementia; Dementia with Lewy Bodies; Frontotemporal Dementia; Posterior Cortical Atrophy; Primary Progressive Aphasia; Huntington Disease and Familial Prion Disease.

Risk Factors – Genetic Factors vs Environmental and Social Factors

The single biggest risk factor for dementia is age. Once you hit the age of 65, your risk of developing Alzheimer’s disease (the most common type of Dementia) doubles every five years, according to the Centres for Disease Control and Prevention. Ageing manifests itself in a variety of age-associated diseases and occurs at different rates in different people. Scientists have previously attributed ageing to cell damage accumulated throughout one’s lifetime, but have not closely considered how aging rates might be inherited. However recently, a group of researchers at the Karolinska Institute (Sweden) and the Max Planck Institute (Germany) have found that damaged DNA in the mitochondria partly control the rate of ageing. Although damage to this Mitochondrial DNA happens over a lifetime, some damage is present at birth and has been passed from the Mother to the child. Since Mitochondrial DNA contains gene from only your mother it gives evidence towards higher rates of ageing being inherited and therefore may affect at how early on you may get dementia in your lifetime.

Linking to your age and the onset of Alzheimer’s there are 2 types of Alzheimer’s: Early-Onset Alzheimer’s (EoA) and Late-Onset Alzheimer’s (LoA), which work in different ways. As the name suggests, Late-Onset Alzheimer’s is where symptoms begin after the age of 65. On the other hand, the rarer Early-Onset Alzheimer’s is used to classify where symptoms begin before the Age of 65.

LoA follows a much more complex pattern of inheritance. Although having a relative, with this form of disease does increase the chance of you getting LoA, it doesn’t increase them in a predictable way. Thus, it is seen that environmental factors have a larger effect on the onset of LoA. For example, there is a strong link between any form of head injuries and the future onset of Alzheimer’s (and other forms of dementia). People aged 55 and older who sustained traumatic brain injury were at significantly increased risk of developing dementia, while even mild brain injury increased dementia risk in the 65 and older group. It also goes without saying, that maintaining a health brain is important in reducing your chances in developing LoA. So therefore, things like Smoking or Heavy Alcohol Consumption can also lead to a higher chance of you developing risk factors. However even though one may try to live a healthy lifestyle, genetics still play a role and could lead one to developing LoA. Recently, a small but growing number of genes have been identified to affect your chances of developing Late Onset Alzheimer’s. The effects of the genes are very subtle but could increase or decrease your chance of developing dementia.

The gene with the greatest risk of getting Late-Onset Alzheimer’s is apolipoprotein E (APOE), which is found on chromosome 19. There are 3 different alleles: APOE 2; APOE 3; APOE 4. The APOE 4 form of the gene is what leads to a higher risk of dementia. Our body cells are diploid which means we have 2 copies of each gene, one from our mother and one from our father. There are in total, 6 different combinations that can be present in your genes: (2-2; 2-3; 2-4; 3-3; 3-4; 4-4).  APOE 4 has the greatest risk of causing dementia and 25% of the population inherits one copy of the gene, which leads to it increasing their risk of getting dementia by 4 times. 2% of population get 2 copies of APOE 4 genes. This increases risk by 10x more. On the other hand, the APOE 2 gene is known to be mildly protective and means people with this gene are less likely to develop LoA. Recently, more and more genes are also being found to increase the risk of developing LoA. For example: CLU, PICALM, CR1, BIN1, ABCA7, are just some of the known genes. On the other hand, even though LoA is only slightly affected by genes and mainly depends of lifestyle choice; the risk of developing Early-Onset Alzheimer’s has been found to be heavily affected by genes. Early-Onset Alzheimer’s (EoA) tends to cluster within families, where several generations of one family have seen to be infected. (EoA is also commonly referred to as eFAD – Early onset familial Alzheimer Disease). If you have eFAD there is a 50-50 chance that one of your children will also have develop eFAD as well. There are currently three known genes that cause familial Alzheimer’s Disease. These are amyloid precursor protein gene (APP) and 2 presenilin genes (PSEN-1 and PSEN-2). Any mutation in even one of these genes guarantees that you will develop eFAD.

The mutations in the PSEN genes result in the production of an abnormal presenilin 1 protein. Presenilin 1 protein is part of the gamma-secretase complex and its function is to cleave (break up) proteins into peptides. The cleaving/breaking up of proteins into peptides (shorter chain proteins) is a step in several chemical signalling pathways that transmit signals from outside the cell into the nucleus. Mutated presenilin 1 interferes with the function of the gamma-secretase complex, which alters the processing of APP (Amyloid Precursor Protein – function not known) and leads to the overproduction of a longer, toxic version of amyloid-β peptide. Copies of this protein fragment stick together and build up in the brain, forming clumps called amyloid plaques that are a characteristic feature of Alzheimer disease. Formation of the plaques likely lead to the death of neurones and lead to other symptoms of Alzheimer’s.

What affects onset of Alzheimer’s?
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Scientists do not fully understand the relative contributions of genetics and the environment to Alzheimer’s Disease (AD), but they believe that there is a spectrum. The later the onset of AD, the more aging and environmental factors are thought to dominate and the smaller a person’s genetic predisposition appears to affect the onset of AD. The earlier the age of onset, the more likely AD is to be driven by a mutation in a single gene that gets passed on through generations.

One of the biggest environmental factors affecting onset of dementia are cardiovascular factors, such as high cholesterol or blood pressure. These are especially prevalent in the onset of vascular dementia, which is caused by a reduced flow of blood to the brain. For Brain cells to function properly and well, they need a constant supply of blood which carries things like Oxygen and other essential nutrients. If the vascular system (blood vessels system that carries blood to the heart) is damaged or affected in any way, the brain cells will eventually start dying and this will therefore lead to the common dementia symptoms like memory loss, impaired thinking and other things. For example, eating a unhealthy diet, high in things like fats and cholesterol is very detrimental to increasing your chance of developing vascular dementia. Cholesterol is a fatty substance found across our body and can be made both naturally and be found in certain foods we consume. If we look specifically in terms of Vascular Dementia, we can see that cholesterol builds up in blood vessels and forms plaques (risk of plaque formation is increased with smoking). The plaques mean that blood flow is decreased to the brain and thus the brain cells may not get enough oxygen and nutrients to survive and therefore will end up dying. In other types of dementia such as Alzheimer’s Diseases, cholesterol also plays an interesting role inside the brain. Researchers are interested in the way that its processed and how it affects the health of brain cells. For example, the APOE 4 gene (mentioned before in risk for onset of Late-Onset Alzheimer’s Disease) encodes one of several proteins involved in cholesterol transport between the different parts of the body and they are the main form of cholesterol transport in the brain. Group studies that measured total blood cholesterol in middle-aged patients found that participants with higher levels of total cholesterol had an increased risk of developing dementia in late-life compared with the participants who had normal or low cholesterol levels.

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General Mental Health is also something that affects the onset of dementia. For example, depression and Alzheimer’s has a complex relationship. Although Depression can be early signs of Alzheimer’s, it has found that depression stemming from isolation and lack of social contact is something that drives mental deterioration and thus can lead to dementia. One study found that depression doubled dementia risk. Being depressed and having a stroke increased dementia risk more than five-fold. Furthermore, people with depression who got a new diagnosis of high blood pressure were at triple the risk of dementia. As seen here pairing of many of these environmental risk factors can lead to a very high chance of developing this disease. Another factor that determines the health of someone’s brain is sleep. Studies have found that a lack of rest and not getting enough sleep can increase cognitive impairment which is again a symptom of dementia.

In Conclusion we can see that even though genetics does have an impact on the onset of dementia, it is not balanced across all types of dementia. It can heavily impact familial diseases but on the other hand for the less rare types of dementia such as Alzheimer’s, genetics only play a small role, however in certain types of Alzheimer’s can guarantee the onset of dementia. Often these genes rarely occur in populations so aren’t very influential. Environmental and Social factors, such as living a healthy lifestyle i.e. healthy eating, sleeping well, leading a healthy social life all can dramatically reduce one’s risk of developing dementia. When a combination of unfavourable environmental and social factors and genetics comes into play it often becomes certain that one will develop dementia. Still, enough research has not been done into dementia. Scientist still do not know what drives dementia and still do not understand the deeper mechanisms that occur in our body which lead to cognitive impairment and loss of brain function. Overall, I think that genetics does have a strong affect on onset of dementia to a certain extent but further research may be able to conclusively prove how strong of a risk factor genetics is.

References:

https://alishawallace97.wordpress.com/2014/08/21/the-genetics-of-dementia/

https://www.alzheimers.org.uk/about-dementia/risk-factors-and-prevention/is-dementia-hereditary

https://www.everydayhealth.com/news/dementia-risk-facto                      rs/

https://www.medicalnewstoday.com/articles/142214.php

https://www.alzforum.org/early-onset-familial-ad/overview/what-early-onset-familial-alzheimer-disease-efad

https://www.hopkinsmedicine.org/health/conditions-and-diseases/prion-diseases

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107296/

https://www.alzheimers.org.uk/about-dementia/risk-factors-and-prevention/cholesterol-and-dementia

Photo Credits due to: https://www.newscientist.com/article/2191814-we-may-finally-know-what-causes-alzheimers-and-how-to-stop-it/

Pratham Upadhyay