ALZHEIMER’S DISEASE: FACTORS AND BIO-MARKERS

ALZHEIMER’S DISEASE: FACTORS AND BIO-MARKERS

by Abdul Mueed Butt (BS Hons.)

                    Image: https://www.news-medical.net/health/Alzheimers-Disease-Definition-Causes-Diagnosis-Treatment.aspx

How’s great it would be if we discuss the dynamic factors behind the Alzheimer’s disease, that cause a huge death rate in each year? How’s beneficial is that if we reveal the bio-markers that can be used to identify the onset of that disease that express over 60 age and lessen the life-span of the patient? Scientists are so far unable to understand what causes Alzheimer’s disease. There is probably not a single cause, but multiple factors that affect each person in a different way.

According to the report generated by centre for disease control and prevention, the death rate due to Alzheimer’s disease has been increased in every race and ethnicity category over the past 16 years. Almost 5 million people are living with Alzheimer’s disease in the USA. This disease is the six leading cause of death and 4% death occur in 2014 in America.

Highlights of Alzheimer Disease

Alzheimer is an irreversible disease that leads to memory loss and decreases in cognitive functions as well. It disrupts communication among neurons, resulting in the loss of function and cell death. It is the hallmark of Amyloid plaques and neurofibrillary tangles. It has three stages but the most fatal and life-threatening is the last stage. The first stage is Mild Alzheimer in which people experience memory loss, repeating questions, behavioural changes and other cognitive difficulties etc. The second one is Moderate Alzheimer which occur in the area of the brain which controls sensory processing, conscious thoughts and reasoning. The third one is Severe Alzheimer in which Amyloid plaques and Neurofibrillary tangles spread throughout the brain and shrinks the brain completely. People with that stage are unable to communicate and completely depends upon others for care.

Contribution to  Alzheimer’s disease

According to researchers at the University of California, the progressively decline in the quality of sleep among aged people is due to the formation of Amyloid and Tau protein tangles in the brain that leads the person towards Alzheimer’s disease. Amyloid protein clumps together to form plaques between neurons and it comes from the breakdown of the amyloid precursor protein. The coagulation of this protein to abnormal level disrupts the neuron function and in subsequent loss of communication and cognitive functions occurs. The accumulation of Tau protein responsible for neurofibrillary tangles formation inside the neuron. Chronic inflammation and further disruption in the function of neurons comes from the loss of function of microglia and astrocytes. These cells are involved to remove debris from the neuron and plaque formation but the gene TREM2 which control the regulation of this function does not express normally and resultantly more damage happens to neuron.

Image: https://www.news-medical.net/news/20190628/Sleep-quality-could-be-indicator-for-later-Alzheimers-disease-finds-study.aspx

How factors play a role in the occurrence of Alzheimer’s disease?

1- Matthew Macaulay, assistant professor (University of Alberta) suggested  CD33 receptor protein which is bind to the surface of microglial cells, regulate their activity and helps them to remove the waste material from the neurons. Although less than 10% of the population of this protein makes the neurons susceptible to plaques formation and ultimately gets Alzheimer’s disease.

                                   Image:https://www.karger.com/Article/FullText/492596

2- Research has revealed MicroRNAs (tiny sequence of nucleotide) play a vital role in growth, development and regulate human genes as well. MicroRNAs is responsible to block the activity of genes that control the activities of the cell and also involved in the build-up of sticky tangles of protein in the brain that causes neural disruption.

3- The non-modifiable risk factor responsible for Alzheimer’s disease is age. The genomic study revealed a locus on chromosome 17 associated with CCL11 (a protein associated with age-associated cognitive decline) its concentration increased in the brain and cerebrospinal fluid with the age. In the same way, many cardiovascular disorders like high blood pressure, high cholesterol level and heart disease problems arise at high age and lead to the occurrence of Alzheimer Disease.

4- APOE gene is present on chromosome 19, it makes a protein that helps to carry cholesterol and fats in the bloodstream. It comes in different forms and each person inherits two APOE alleles, one from each parent. Not all forms are responsible for this disease except APOE ε4. Having one or two alleles of this gene responsible for AD. About 35% of people carry one copy of this allele, while 5% having two copy of this allele.

Image: https://www.drugtargetreview.com/news/32082/apoe4-gene-variant-alzheimers/

How biological biomarkers indicate the presence of Alzheimer's disease?

In Alzheimer's disease patients, there is increased expression of Ube2h gene in the blood. As our body maintain homeostasis, it synthesize and degrades the protein. Once the protein reaches the end of their life-span it is marked by ubiquitination (a process in which a ubiquitin (protein consisting of 76 amino acids) is attached to another protein) and degraded by cell organelle known as proteasome (large protein complex that breaks down proteins in cells). In the same way, a person with AD has a high accumulation of Amyloid and Tau protein in the brain. To degrade them there is need to high expression of Ube2h gene. The way to analyze this elevation in gene expression is Transcriptome Analysis.

2.      Further study revealed the thickness of retina can also be used as a biomarker for AD patient.  AD patient has thinner retinal layer comparatively to the normal person. Because the retina nerve comes from the brain and because of plaque and tau accumulation this nerve gets thinner. So by analyzing the thickness of the retina layer one can identify the AD patient.

3.      Naturally, Amyloid-beta 42 protein is synthesized in the same amount by each organ of the body. In the brain, this protein gets precipitate and starts damage to the brain a decade before other cognitive problems appear. So, if soon we measure the high level of Amyloid protein in the saliva then we can prevent the onset of this disease in future. So, the Saliva test is used as biomarkers to determine the level of Amyloid protein in the person.

4. Neurofilament light chain is another blood-based bio-markers to determine Alzheimer and neurogenerative diseases. The person with brain disorders has a high level of NFL in cerebral spinal fluid and in blood.

Conclusion

Overall, this study provides us with the novel framework to get an insight into multiple factors responsible for AD and biomarkers used to reveal AD before the onset of this happening. So, if we used all mentioned biomarkers properly then we can not only diagnose this disease but can make it treatment within the possible time that temporarily slow the symptoms of dementia and improve the quality of life. This article provides the landmark for revealing more biomarkers and factors that still are unknown.

Author’s Information

Abdul Mueed Butt (BS Biochemistry), has written this article under the guidance of Miss Iqra (MPhil  Biochemistry) Lecturer at UMT Sialkot, who always motivate her students. 

Reviewer & Editor

Muhammad Numan has reviewed and edited this article.

References

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Dr. Ananya Mandal, M. (2020). Sleep quality could be indicator for later Alzheimer’s disease finds study. Retrieved 14 June 2020, from https://www.news-medical.net/news/20190628/Sleep-quality-could-be-indicator-for-later-Alzheimers-disease-finds-study.aspx

Zhao, L. (2018). CD33 in Alzheimer’s disease – Biology, Pathogenesis, and Therapeutics: A Mini-Review. Gerontology, 65(4), 323-331. doi: 10.1159/000492596

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Lim, K., & Joo, J. (2020). Predictive Potential of Circulating Ube2h mRNA as an E2 Ubiquitin-Conjugating Enzyme for Diagnosis or Treatment of Alzheimer’s disease. International Journal Of Molecular Sciences, 21(9), 3398. doi: 10.3390/ijms21093398

Haan, J., Kreeke, J., Konijnenberg, E., Kate, M., Braber, A., & Barkhof, F. et al. (2019). Retinal thickness as a potential biomarker in patients with amyloid‐proven early‐ and late‐onset Alzheimer's disease. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 11(1), 463-471. doi: 10.1016/j.dadm.2019.05.002

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Dhiman, K., Gupta, V., Villemagne, V., Eratne, D., Graham, P., & Fowler, C. et al. (2020). Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer's disease. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 12(1). doi: 10.1002/dad2.12005