Research Paper on Alzheimer's Disease: 3.65M Affected in US, Projected to Grow to 5.7M by 2060

Introduction

Alzheimer's disease (AD) is the most prevalent dementia, predominantly affecting older adults. Brookmeyer, Abdalla, Kawas, and Corrada (2018) reported that in 2017, 3.65 million people were clinically diagnosed with AD. Out of the 3.65 million Americans with AD, 2.43 million of them had mild cognitive impairment associated with AD, which is projected to grow to 5.70 million by 2060 (Brookmeyer et al., 2018). About 27% of those with mild cognitive impairment had neurodegeneration, while 73% of them had both neurodegeneration and amyloidosis (Brookmeyer et al., 2018). The researchers further estimated that 42% of the 3.65 million AD cases had late-stage clinical AD (Brookmeyer et al., 2018). Estimates also revealed that by 2060, 9.30 million people would have clinical AD (Brookmeyer et al., 2018).

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Causes and Manifestations of ADAD is manifested through the selective death of neurons and two pathologic hallmarks. The first pathological hallmark is abnormal intracellular accumulations of a hyperphosphorylated protein called tau, also known as neurofibrillary tangles (Wang et al., 2014). Another hallmark of AD is senile plaques resulting from extracellular amyloid-beta deposition. Most of the AD cases are spontaneous. It has been established that less than 10% of AD cases are linked to mutations in three genes; presenilin-1 mutations, presenilin-2 mutations, and amyloid-beta protein precursor mutations (Wang et al., 2014). AD has also been found to develop inpatients with Down's syndrome. In this case, AD is linked to an extra copy of the amyloid-v protein precursor found on an extra copy of chromosome 21 (Wang et al., 2014).Oxidative stress and mitochondrial dysfunction are also crucial to the pathogenesis of AD. There is the presence of oxidative damage to macromolecules present in neurons and the initiation of oxidative stress at early stages of the AD before the development of the pathology. Wang et al. (2014) further established that early and prominent symptom of AD is structural and functional damages to mitochondria, which are efficient in the production of reactive oxygen species but less efficient in producing adenosine triphosphate. Because mitochondria have also been found to be susceptible to oxidative stress, the pathogenesis of AD is also attributable to interactions between oxidative stress and mitochondrial dysfunction which initiate and amplify reactive oxygen species (Wang et al., 2014).

AD pathogenesis has also been linked to neuroinflammation. According to Heneka et al. (2015), AD pathogenesis is not only restricted to neuronal damages but interactions between the neuronal compartment and brain immunological mechanisms. In this case, the innate immune response is triggered by misfolded protein aggregates bound to pattern recognition receptors leading to the secretion of inflammatory mediators, which are critical in the severity and progression of AD. Moreover, autosomal dominant AD has been found to result from the decreased concentration of amyloid-beta 25 years before signs and symptoms of the disease are manifested (Bateman et al., 2012). It has also been established that AD is caused by elevated concentrations of tau protein in the cerebrospinal fluid and increased cerebral atrophy, which occurs 15 years before expected symptom onset. Lastly, autosomal dominant AD is caused by episodic memory impairment and cerebral hypometabolism (Bateman et al., 2012).

People AD-related symptoms and relatives of AD patients think that researchers and scientists are doing their best to slow down, stop, or reverse the AD progression. Conversely, some of the relatives of people with AD, researchers, and scientists may not be convinced that enough efforts are being made to slow down, stop, or reverse the AD progression. Because of this, it is important to explore whether researchers are doing enough to slow down, stop, or reverse the AD progression.

Treatment Approaches and Effectiveness

Efforts to stop the progression of AD have focused on the causes of AD. Because beta-amyloid play a key role in AD, scientists have made pharmacological efforts to reduce the formation of beta-amyloid peptides. To this effect, several anti-amyloid treatments have been developed to stop the progress of AD by modifying the course of the disease more effectively. Different anti-amyloid strategies are focused on acting on various steps of amyloid precursor protein metabolism. First, research efforts have been directed towards modulating enzymatic pathways associated with abnormal amyloid precursor protein to decrease the production of amyloid-beta (Folch et al., 2018). This is a prove that scientists and researchers are doing their best to block symptoms of AD by disrupting the action of a problem protein, called beta-amyloid.

Scientists efforts to treat AD by preventing or reversing the formation of beta-amyloid in AD patients is also linked to the fact that like tau proteins, clumps of beta-amyloid aggregate in the brains of AD patients, thus it is suspected cause AD. Upon the formation of sticky plaques of beta-amyloid, there is also a risk of modification of tau proteins, thus increasing their toxicity and forming tangles. In this case, scientists have reported that AD can be prevented through the use of p38gh kinase - an enzyme which is crucial in regulating how tau proteins behave in the brain. Specifically, p38gh kinase is useful in keeping tau untangled and healthy, thus crucial in deterring the onset of memory loss associated with AD pathologies. In AD patients, p38gh kinase reduces significantly as AD progresses. Consequently, scientists have established that increasing the levels of this enzyme is key in prevention and treatment of the disease. This is another confirmation that scientists are making breakthroughs in the treatment of AD and its symptoms.

One of the approaches towards decreasing amyloid-beta is the use of inhibitors of beta-secretase (Folch et al., 2018). Currently, there are two inhibitors of beta-secretase, E2609 and MK-8931. The beta-secretase enzyme initiates the amyloidogenic pathway needed to process amyloid precursor protein. E2609 and MK-8931 have been reported to have 80%-90% efficacy levels in reducing amyloid-beta levels in human cerebrospinal fluid. Scientists have also made progress in developing inhibitors and modulators of gamma-secretase. Specifically, LY450139 (sema-gacestat) is a drug which is currently used as an inhibitor of functional gamma-secretase. LY450139 has been reported to be effective in lowering amyloid-beta levels in both blood and cerebrospinal fluids in human studies. Another drug which has been shown to have high efficacy slowing the progress of AD in animal models and clinical trials is NIC5-15, which acts as an insulin sensitizer. Specifically, clinical trials have shown that high doses of NIC5-15 interfere with amyloid-beta deposition. The high efficacy of NIC5 in the treatment of AD has been attributed to two reasons: its insulin-sensitizing nature and its ability to spare the Notch gamma-secretase inhibitor. High-efficacy of NIC5 is a manifestation that scientists' and researchers' efforts towards treatment of AD is worthwhile.

Another approach that scientists have found to be effective in slowing down the progression of AD is activation of the alpha-secretase enzyme, leading to amyloid precursor protein being processed through the non-amyloidogenic pathway. Through this pathway, a soluble amyloid-beta peptide, which has a neuroprotective role and ability to stimulate synaptogenesis, is formed. Because of this, alpha-secretase activation is crucial in the production of AD-modifying drugs. There are various compounds which have been found to have high efficacy in stimulating the non-amyloidogenic pathway. They include protein kinase C activators, serotonergic agonists, glutamatergic, and acetylcholine muscarinic receptor. One of the recent advancements in the treatment of AD through alpha-secretase enzyme involves epigallocatechin gallate, a flavonoid that is obtained from green tea leaves. Epigallocatechin gallate has been reported to be clinical importance, such as neuroprotective, anti-inflammatory, and antineoplastic properties (Obregon et al., 2006). Moreover, epigallocatechin gallate could have a beneficial impact on cognitive functioning (Obregon et al., 2006). Epigallocatechin gallate is also believed to be effective in inhibiting the production of toxic misfolding of oligomeric proteins of beta-amyloid, in addition to its role in the activation of alpha-secretase (Obregon et al., 2006). All these treatment techniques further confirm that there is hope for patients with AD.

Scientists' and researchers' interest in the treatment of AD has also been proven in the development of tau-aggregation inhibitor therapy for AD (Wischik, Harrington, & Storey, 2014). Methylthioninium chloride (MTC) is the first compound that has been found to have high efficacy in inhibiting tau aggregation, hence its potential use in preventing and treating AD. One of the ways in which MTC helps in the treatment of AD is that it reduces endogenous production of tau protein. MTC is also helpful in reversing AD progression because it enhances mitochondrial b-oxidation, inhibits aggregation of TAR DNA binding protein 43 (TDP-43), and inhibits monoamine oxidase A. In a clinical study, MTC has been established to stabilize mild and moderate AD progression. To further improve its efficacy, scientists have developed a reduced version of MTC (leucomethylthioninium with a suitable counter-ion, LMTX), which is more tolerable and absorbable than MTC and orally administered (Wischik, Harrington, & Storey, 2014). LMTX treats AD by decreasing levels of misfolded and aggregated tau proteins, which are linked to progressive neurodegeneration - a distinctive characteristic of AD.

Coman and Nemes (2017) have further reported that two anti-Tau strategies are vital in the treatment of AD. One of these strategies involves phosphorylation of tau and inhibition of its aggregation. The formation of neurofibrillary tangles in AD, which leads to the death of neurons, has been linked to aggregation of tau proteins and their excessive phosphorylation. Coman and Nemes (2017) reported that progression of AD could be slowed down through inhibition of glycogen synthase kinase 3, an enzyme involved in tau hyperphosphorylation. The inhibition of glycogen synthase kinase 3 and subsequent decrease in Tau phosphorylation and aggregation is achieved through protein kinase C, which is stimulated by acetylcholine and other M1 receptor agonists. The second strategy is the anti-tau immunotherapy. One of the vaccines which are promising is AADvac1. This vaccine targets structural determinants on tau protein. This is another welcomed breakthrough in the treatment of AD.

AD patients and their relatives also have hopes that AD can be treated through anti-amyloid immunotherapy (Coman & Nemes, 2017). Empirical clinical studies have led to the development of two types of anti-amyloid immunizations; active immunization and passive immunization. Active immunization, which has been carried out on animal models, is effective in the prevention of formation of new amyloid aggregates and removal of the existing ones. AD patients who have received active immunization have been reported to show improved cognitive performance, decreased cerebral volume, and reduced cerebrospinal fluid Tau level. Decreased cerebral volume is a key indicator of amyloid-beta 42 destructions, the primary component of AD plaques. Consequently, it shows that active immunization is crucial in reversing the progression of AD. Similarly, reduced cerebrospinal fluid Tau level also shows progress towards the treatment of AD because it is a manifestation of reduced neuronal d...