Diseases and Disorders

Genetic Mechanisms Involved in Alzheimer's Disease

Fatemeh sana Vasebi


Introduction

Neurodegenerative Diseases are a group of disorders which cause progressive and irreversible degeneration of the Nervous system. Alzheimer's Disease is one of the most common Neurodegenerative Diseases which is widely observed among the elderly. Thus, identifying and studying the factors causing this fatal disease are essential. Additionally, Neurodegenerative Diseases involve progressive destruction of nerve cells and cause dementia and aim cognitive functions. [1]  AD is a type of progressive dementia that eventually causes death. Although researchers demonstrate that there are remarkable genetic and molecular mechanisms leading to AD, certain reasons for this disease's outbreak are not well-known yet. 

 

Genetics of Alzheimer's Disease

Causes of Alzheimer's Disease usually depend on an individual's genetics, environment, and lifestyle. In late-onset AD, environmental and lifestyle factors are usually involved, although in some cases, genetic mutations can predispose an individual. The most common genetic mutation in people with late-onset AD is a mutation in the ApoE gene on chromosome 19 [2].   This gene has four variants, each of which has mutations that can reduce or increase the risk of being afflicted [3].  Mutations in variant 4 of this gene increase the risk of affliction. 25% of people have only one copy of the mutation of this variant; however, AD can appear at young ages and before the age of 65 for these people [3].  On the other hand, 2% of people have two copies of variant 4's mutation, which increases the risk of infection by 75% [3].   Mutation in variant 3 has a moderate risk of infection. About 60% of people have two copies of the mutation in variant 3, and only 25% of these people develop AD over the age of 80. Mutation in variant 2 can reduce the risk of infection. 11% of people have a copy of the mutation in variant 2 and a copy of the mutation in variant 3. However, only 0.5% of people have two copies of variant 2's mutation, which significantly reduces their risk of developing AD. Additionally, 20 other types of genes have been discovered in which mutations could be linked to  AD. These 20 genes are generally involved in activities such as inflammation, immunity, fat metabolism, and intracellular transportation [3]. 

In early-onset or familial AD, a person shows symptoms before the age of 65. One of the genes involved in AD is the PSEN-1 gene, which is on chromosome 14 [5].  Mutation in this gene is the most common cause of early-onset AD. 80% of people with early-onset AD show a mutation in this gene. These people develop AD symptoms around the age of 30 or 40 [5].  Another gene is PSEN-2. This gene is carried on chromosome 1, and if a mutation occurs, the person shows symptoms later than the mutation in the PSEN-1 [5].  Mutation in these genes is associated with the protein presenilin. The protein presenilin is a subunit of the enzyme gamma-secretase, which has been implicated in the cleavage of the apolipoprotein precursor. A mutation in the APP gene, which is carried on chromosome 21, can cause AD [5]. Because patients with Down syndrome have 3 copies of chromosome 21, they will develop this disease in the future if there is a mutation in the APP gene. Because of this, people with Down syndrome are also more likely to develop AD. If one parent has a mutation in any of the genes mentioned, the probability of the child being infected is 50% [5].  If the child is not infected, it will no longer be carried and will not pass on to the next generation [5]. However, a small number of families do not show any mutations in these genes. These people probably have mutations in genes whose effects on AD are unknown.

Tables 1,2,3: The relation between genotype and the average age of affected sporadic case subjects [7]

In cases where there is no genetic background in the family, the average age of developing AD in females and males is approximately equal (71). Table 3 clearly shows that in all cases, genotype e4/e4 causes infection at a younger age than the other two genotypes. However, the age of developing AD is almost equal in genotypes e3/e3 and e3/e4. Although Table 3 confirms that allele e4 is more dangerous than other alleles, this is not right about tables 1 and 2. For instance, in table 1, the average age of developing AD in people with genotype e4/e4 is higher than the genotype e3/e3. The reason for this discrepancy is most likely due to these cases being sporadic and that no one else in their family has the disease or gender may play a relatively important role in the average age of AD. As women with genotype e4/e4 are more prone to infection than men with the same genotype.

Tables 4,5,6:The relation between genotype and the average age of affected members of AD families [7]

Table 6 clearly shows that people with e4/e4 genotype have a lower incidence. This confirms that in people with familial history, allele e4 reduces the age of onset. On the other hand, it can be concluded that cases with genotype e3/e3 and familial history in males have lower age of incidence compared to females. This principle can be easily understood by comparing Tables 4 and 5. It can also be inferred that in cases with familial history the Disease occurs earlier in men than women, especially men with genotype e3/e3.

 

Conclusion

Alzheimer's is one of the Diseases for which the key to understanding and comprehending the processes involved in its development has not yet been fully understood. Therefore, it is difficult to discover a cure for this disease, especially considering the genetic deficits involved. Among genes causing the disease, ApoE (e4) has a significant role and strengthens the possibility of being infected [5]. 


References


  1. (2019). Brain facts. Retrieved: 26/12/2020

  2. Ridge, Perry G. Mark T. W. Ebbert and John S. K. Kauwe (25/7/2013). Hindawi. Genetics of Alzheimer’s Disease. https://www.hindawi.com/journals/bmri/2013/254954/. Retrieved: 26/12/2020

  3. Alzheimer's Association. Is Alzheimer's genetic?. https://www.alz.org/alzheimers-dementia/what-is-alzheimers/causes-and-risk-factors/genetics. Retrieved: 26/12/2020

  4. Banks Nutrition Center. https://banksnutrition.com/2018/05/25/apoe4-and-genetic-mediated-risk-of-alzheimers/. Retrieved: 20/1/2020

  5. National Institute on aging. Alzheimer's disease genetics fact sheet. https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet. Retrieved: 27/12/2020

  6. Nature https://www.nature.com/news/alzheimer-s-disease-the-forgetting-gene-1.15342 Retrieved: 20/1/2020

  7. Corder, E.H. et al (1995). Apolipoprotein E, survival in Alzheimer's disease patients, and the competing risk of death and Alzheimer's disease. Retrieved: 27/12/2020

Fatemeh sana Vasebi

Fatemeh sana Vasebi


Sana is a student, studying in Farzanehgan high school, and is interested in neuroscience and genetics. Thus, she likes venturing into infinite and astounding world of neurogenetic diseases. She hopes for a world full of happiness and health, both mentally and physically.