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Alzheimer's Disease

Vicky Zhang

Introduction

Alzheimer’s Disease (AD) is a neurodegenerative disease caused by the degeneration in the function of neurons. It is currently the most common cause of dementia, making up for more than 60% cases of dementia worldwide. Clinical symptoms of AD include memory loss, weight loss, delirium, and personality changes. In the late stage of AD, patients usually have lost their self-care ability and rely on the care of others for living. However, people know so little about such a common disease that they will not start to search about it flusteredly until someone around them got diagnosed. This article will discuss AD from the following three aspects: pathogenesis, risk factors, and treatments.

Pathogenesis


So far, scientists’ understanding about AD is not sufficient enough to provide an exact conclusion about its pathogenesis. All theories related to its pathogenesis are nothing but hypotheses.

The most studied hypotheses include the cholinergic hypothesis, family inheritance, amyloid protein hypothesis, and tau protein hypothesis. Cholinergic hypothesis is the earliest hypothesis about the pathogenesis of AD and has laid the foundation for many current researches and drug developments. Through studying the brain of AD patients, researchers discovered a close relationship between cholinergic neurons and the synthesis of acetylcholine (ACh). As a type of neurotransmitter, ACh can be found in both the central nervous system and peripheral nervous system, and it plays a significant role in the cardiovascular system, digestive system, respiratory system and nervous system. In tissues, ACh is broken by AChE within a short time. The decrease of ACh level will affect the transfer of information between neurons. Therefore, medications developed based on this hypothesis emphasize on decreasing the rate of ACh being hydrolyzed by AChE, controlling the progression of the disease.

In addition, family inheritance is also an important research field of AD pathogenesis. According to a series of family studies, individual genes have been confirmed to be directly related to the onset of AD, including APP gene, PSEN1, and PSEN2. Expression of all three genes affects amyloid precursor protein, leading to increased production of Aβ24 and accumulation of amyloid plaques. Amyloid plaque is the core of the amyloid hypothesis and is believed to be the trigger of a cascade of reactions, such as oxidative stress and hyperphosphorylation of tau protein, leading to nerve damage and death. Studies on AD patients with Down syndrome (DS) seem to provide evidence for this hypothesis. The APP gene mentioned earlier, which can have an effect on amyloid accumulation, is expressed on chromosome 21 in human DNA. While DS patients have an extra copy of chromosome 21, the APP gene is overexpressed, leading to excessive production of amyloid. Nearly all neurogenic fiber tangles in DS patients over the age of 40 are sufficient to be diagnosed as AD based on pathology. Meanwhile, the intracellular amyloid accumulation in neurons of DS patients happens much earlier than normal people. Therefore, drug development based on the beta amyloid hypothesis has identified clearing and reducing production of beta amyloid plaques as the major therapeutic target.


Another pathological mechanism of AD that has been studied extensively is the Tau protein hypothesis. This hypothesis revolves around the abnormal phosphorylation of Tau proteins. Tau protein molecules in the healthy adult brain 2-3 phosphate groups; however, AD patients’ brains usually contain 5-9 phosphate groups. The increase in each phosphate group adds a net charge of -1 to the protein. The aggregation of phosphate groups causes large local charge effects that alter molecular interactions. Overphosphorylated Tau proteins bind to microtubule proteins at only one-tenth the strength of normal Tau proteins, resulting in the disruption of neuronal microtubule structure and causing prominent loss of neuronal function impairment and neurodegenerative lesions. Some drug development targets on reducing overall Tau phosphorylation by modulating Tau activating enzyme activity and enhancing Tau lectures using small molecule medications.


Complex as the human brain, there are as many mysteries in simply one organ as the number of celestial bodies in the universe, and AD is just one star in this vast universe of neuroscience. Scientists may still have a long way to go before they can really unveil the pathogenesis of the disease and find out the truth behind it.

Risk Factors


There are many risks that could potentially lead to the development of AD, including aging, family history, DS, head injury, and cardiovascular diseases. Among them, age is certainly the most crucial risk factor. Statistics show that the likelihood of developing AD doubles every five years after age 65. However, due to family genetics and other factors, the AD patient population also includes a proportion of patients under the age of 65. This condition, known as early- onset Alzheimer’s disease, mostly affects people around the age of 40. Genetics is part of the risk factors for AD, but not a major one. For most people, genes inherited from parents increase the risk of developing AD, but only a small percentage of cases of diagnosis are actually due to this factor. Unless there is a history of dementia or AD over several generations of family members, most people do not need to worry about genetic factors. In addition to the family inheritance of genes at high risk for AD, trisomy 21 also increases the risk of developing AD. In addition, there are a range of acquired risk factors due to acquired causes. Lifestyle and health conditions associated with cardiovascular disease increase the risk of AD, including smoking, obesity, diabetes, hypertension, and high cholesterol. Other unidentified acquired risk factors include a history of depression, brain damage, stroke, social isolation, and cardiovascular disease- related lifestyle and health conditions.

Treatments


There are not many medications approved by FDA for the treatment of AD; the most common ones belong to the group of acetylcholinesterase inhibitors (AChE inhibitors). These drugs reduce the hydrolysis of ACh by binding to AChE binding sites, slowing the progression of AD. Specifically, this group of medications include donepezil, galantamine, and rivastigmine.


Donepezil is a selective AChE inhibitor that basically works only on the AChE n the central nervous system and has little effect on peripheral AChE. Donepezil is indicated for the treatment of mild to moderate AD and can improve dementia symptoms. Many experimental results have demonstrated that donepezil is effective in slowing down the progression of the disease and improving blood flow in the prefrontal cortex and parietal lobes. A cross-sectional trial comparing different medications for AD treatment compared donepezil, galantamine, memantine and rivastigmine, and it has found that donepezil was the most cost-effective of the four commonly used drugs for mild to moderate AD. However, since the ACh level in the brain of AD patients is still continuously declining, donepezil will eventually lose its effectiveness when ACh level becomes too low. Furthermore, due to the presence of ACh in different systems in the human body, donepezil can have various degrees of side effects, such as seizures, ataxia, and cardiac conduction abnormalities.


Galantamine also can increase ACh concentration and the activity of ACh in the brain by inhibiting AChE. The medication is able to bind to nicotinic ACh receptors and increase ACh release while keeping AChE inhibited. In addition to its use in treatment for AD, galantamine has also been used in organophosphate poisoning and autism treatment. The side effects of galantamine are similar to those of other AChE inhibitors, with common symptoms of nausea and vomiting. Studies using dose-escalation therapy have observed significant improvements in the incidence of these two side effects. On April 27, 2006, FDA warned the risk of bradycardia after using this medication.




Moreover, a drug called aducanumab was approved by the FDA as an AD treatment recently. This drug claims to reverse the progression of AD, achieving unprecedented effects that AChE inhibitors could not achieve, and it has seemingly opened a new chapter in AD therapy. However, two years after its official approval, the drug is still under many debates. Some take this as the dawn of AD patients after almost twenty years of darkness with no medication invented successfully; others believe that the efficacy of aducanumab is still unclear and that the use of this drug may not be beneficial or may even delay proper treatment

Conclusion



AD is known as undead cancer. Behind this worrying name is the helplessness of countless families and the suffering of patients. We may not be able to do much about the disease; but until then, we can raise awareness of AD prevention for ourselves and our families. For example, we can encourage social interaction and hobbies for the elderly in our families, keep them active in their brains, seek medical attention when early clinical symptoms such as progressive cognitive decline are noticed, avoid head injuries, and maintain a healthy lifestyle. As the sixth cause of death in the world, perhaps when the medical challenge of AD is overcome, human life expectancy and quality will be improved once again.

Reference


Alzheimer’s: Drugs help manage symptoms. (2022, October 12). Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers/art-20048103

Head, E., Lott, I., Wilcock, D., & Lemere, C. (2016, July 18). Aging in down syndrome and the development of alzheimer’s disease neuropathology. NIH. Retrieved December 20, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948181/

Lott, I., & Head, E. (2005, March). Alzheimer disease and down syndrome: Factors in pathogenesis. Elsevier. https://www.sciencedirect.com/science/article/abs/pii/S0197458004002672?via=ihub

Medications for Alzheimer’s disease. (2017, September 12). Stanford Health Care. https://stanfordhealthcare.org/medical-conditions/brain-and-nerves/alzheimers-disease/treatments/medications.html

Memantine as a treatment for dementia. (n.d.). Cochrane. https://www.cochrane.org/CD003154/DEMENTIA_memantine-treatment-dementia

NHS website. (2022, May 30). Causes. nhs.uk. https://www.nhs.uk/conditions/alzheimers-disease/causes/

Silva, M. V. F., Loures, C. D. M. G., Alves, L. C. V., de Souza, L. C., Borges, K. B. G., & Carvalho, M. D. G. (2019). Alzheimer’s disease: risk factors and potentially protective measures. Journal of Biomedical Science, 26(1). https://doi.org/10.1186/s12929-019-0524-y


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