Category: Alzheimer’s Disease

Introduction

Alzheimer’s disease is the most common form of dementia, this disease is the fourth leading cause of death in industrialized nations, preceded by cardiovascular disease. Neurodegenerative disease (ND) is an umbrella term for a group of primary diseases of neuron with the defining feature of a progressive loss of functioning neurons, mainly in the cortex and hippocampus, during the process of learning and memory formation brain undergoes a physical and chemical change which called as synaptic plasticity, its shows contribution of various signal transfusion pathway induction of gene expression which result formation of new synapse between nerve cell, this process undergoes remodelling with time the memory of a new experience can we divided by three types- namely short term, long term memory. The process of memory formation involves the binding neurotransmitter to the receptor which triggers the cascade oh molecular events including action of CREB and PKc pathways, resulting in the formation of new protein receptor and some structural proteins, the synaptic connection between two repeatedly communicating neurons which ultimately result developed long term memory. Memory can be classified into declarative and non-declarative, declarative memory affords and capacity for cognizant recollection about fact and event, in declarative memory a heterogeneous collection nonconscious ability in include learning of skills and way of life, in these cases behavioral change, but without according access any memory content, and different kind of memory are supported by different brain system. This disease has provided significant path physiology, it affects all ethnic groups and occurs slightly more in female than males. Disease according to age like brain disorder in create symptoms such as confusion and memory loss and sometime after converted yet normal age in personality and behaviour changed and awareness decision and in creative problem among friends and family members in complete loss, form mental works functions because this disease related to a mutation in most cases of Alzheimer’s disease has mostly with 65 years old people. ApolipoEprotein is major genetic risk factor play the role of increased problem in Alzheimer’s disease, apolipoprotein is a cholesterol carrier for lipid transfer repair damage in brain, cause mutation responsible for amyloid precursor protein apolipoprotein located in chromosome 19 and encodes299 amino acid, extracellular plaques of insoluble beta-amyloid peptide and neurofibrillary tangles remaining hyperphosphorylated tou protein in neuronal cytoplasm is remarkable path physiological cause patients brain.

Glycoprotein and apolipoE single several nucleotide polymorphisms convert result in coding region of apoEprotein, there are three common different of apoE genes are called alleles apoE2, apoE3 , apoE4 this differ from 1 or 2amino acids these are most common Isoform . Every gene has one copy combination determine apoE, ApoE2 is rarest form of apolipoprotein decrease developing risk of Alzheimer’s disease, apoE3 is allele and apoE 4 allele is increase risk of Alzheimer’s disease. Genomicus is graphical browser in which analysis four different type species like as, plant, fungi, vertebrate, non-vertebrates and flowering plants in study development of genes organization. Full genome sequences are available in Gene Databank, without growth in genes visualization and alignment sequences in Bioinformatics tool to possible used in genome starting development time restricted from again a new synteny browser in analysis multiple genome sequences in can seen phylogenetic view and ancestral genome. Most of genome data displayed in Genomicus is already publicly available from the assembled database but without extensive synteny visualization tool, the two main types of information that are required by genomics are positional information in their respective genome and phylogenetic relationships between genes. Genomicus in edits Ensembl phylogenetic trees in three ways – first duplication nodes with a duplication consistency score below a threshold, that optimize increase synteny between extent genomes are selected such cases duplication notes .second added ancestral nodes in existing trees of placental mammals third added extent species that are not currently referenced in Ensembl with their respective ancestral nodes for each of new species.

ApolipoE protein-

ApolipoEprotein plays an important role distribution and metabolism of cholesterol triglyceride, E2, E3, E4 remains 112 and 158 ApoE3 is cyst112, Arg158. ApoE4 is arginine and ApoE2 is cystein, in lipid effect cause properties and three dimensional structures between isoforms. ApoE4 has substituted of amino acid with salt bridge formation between arginine and glutamic acid in arginine position is 61, n-terminal domain and glutamic acid position in 255, c-terminal of apoE4 Bind ApoE3 and ApoE2 protein in high density lipoproteins, anionic carboxylate of gluttamic acid and cationic ammonium of arginine remain with ionizable side chain as histidine, tyrosine and serine can take a part, depend on external factor. Formation of amyloid beta fibrils and oligomers need a conformational change from alpha helix two beta-sheets, which occurs due to formation of a salt bridge. ApolipoEprotein important role is maintenance, repair and reorganization according to neurons, produce cholesterol and improve synapse develop in central nerves system. Apolipoprotein transfer lipid and damage repair in brain and alleles are genetic determinants, allele 4 has increased carry risk for individual but compare to allele 2 and allele 3 decreases the problem. Apolipoprotein bind to lipids in several cell surfaces. Hydrophobic Amoyloid beta peptides lead to synaptic neurodegeneration in Alzheimer disease.

Genomics tool –

Genomicus in genome data stored in available Ensemble Database, comparative genomics in study of evolutionary genes, genomics in new synteny browser can represent and compares a number of genomes rebuilding ancestral in syntenic blocks describe procedures details and comparative genes between available genome sequences, Genomicus database in analysis data of two different genomes of differ species by help of different type tool such as- matrix view, compute synteny block in phyldiag view, can alignment of different comparative genes .

Phyloview-Align view-

In selected apolipoE gene center display in 15 neighbouring genes like paralogs and orthologs on both side are known as about to genes. Gorilla species in orthologs or paralogs are shown by matching colours. Align view in reference genes alignments between Genes are present with genomic region Identify genes are belonging from same family. Genomicus is provided a comparison of pair wise genome interface in karyotype view according to colour of chromosomes cause syntenic, can rebuild of ancestor gene.

Phylodiag view in synteny blocks-

Comparison pairwise whole genomes provide by Genomicus representation with dot plot matrix, between two species in orthologs relationship relies extracted from apolipoE gene. Users allow preservation between two genomes global map in display. In representing segment by the diagonal line in between genomes no quantification degree of synteny. Phildiyag in allows to user compared for select two species as (ancestral and extent), phyldiyag display parameter in present chromosomes displayed gap for permit in synteny blocks. In synteny available, two selected different species in shows result two different colours by plot sinteny blocks. Only display phyldiyag views in genes are belonging from individual synteny blocks. Align view in displayed orthologs between human and gorilla.

Phyldiag view

Karyotype view-

Karyotype is process of pairing and ordering all chromosomes of an organism, thus providing a genome-wide snapshot of an individual’s chromosomes. Karyotypes are prepared using standardized staining procedures that revel characteristic structural features for each chromosome. Clinical cytogeneticistis analysis human Karyotypes to detect gross genetic changes, -anomalies involving several mega bases or more of DNA. Karyotypes can revel changes in chromosome number in associated with aneuploid conditions, such as trisomy 21 (Down syndrome) careful analysis of Karyotypes can also revel more subtle structural changes, such as chromosomal deletions, duplications, translocations or inversions, in fact, as medical genetics become increasingly integrated with clinical medicine, karyotypes are becoming a source of diagnostic information for specific birth defects, genetic disorders.

Karyotype view and multikaryotype view

Experimental Method –

1. Firstly go to homepage of Genomicus Database , in an analysis of data evolution gene sequences alignment Of different species .
2. Then search box in enter the reference ApoE (ENSGGoG0000006377) gene name and species name –gorilla.
3. After search open phylo view can seen phylogenetic tree by help ancestral gene, by differ type colour shows nodes, can known query about genes.
4. Then after can seen in align view in alignment of genes, ancestral chromosomes, duplication, protein similarity, dN/dS ratio, Karyotype view, multi karyotype view in shows between human and gorilla gene, known physical length-100 and number of chromosome-40.
5. Comparisons genes can see matrix view and synteny blocks in phyldiag view, by alignment in genes of reference species.
6. Analysis of comparative genes can see alignment of different species genes by use of genomicus tool.

Author’s comments: Draft in provide outline of topics in discussed proposal for research project. Method section elaborated upon clearing certain doubts on Bioinformatics used. Documents in more aspect timeline will be presented details of document in figures tube added introduction part which describe about to Alzheimer’s disease, ApolipoEprotein, and Genomicus browser. Thanks you. ****

References-

1. Matthieu Muffato,Alexasenderluis,charlesEdouarpoisnelHugesroestcrollius,Genomicus:addatabase and a browser to study gene synteny in modern and Ancestral genome.bioinformatics,volume26,Issue8,15 April-2010,1119 -1121.
2. SinhaAu, Mellerj.cinteny: flaxible Analysis and visualization of synteny and genome rearrangement in multiple Orgnisms, BMC Bioinformatics, 2007 vol8.pg82.
3. Alexandra louis,MatthieuMuffato,Hgesroestcrollius.Genomicus: five genome browser for compretivegenomics in eukaryotaNuclic Acids Research,volume41,Issue D1,1january ,pg.D700-D7
4. Nga ThiThuy Nguyen, pierrevincens,Hugesroestcrollius,Alexandralouis.Genomicus 2018:Karyotype evolutionry trees and on-the-fly synteny computing Nuclid acid Reaserch,volume 46,Issue d1,4January2018,pagesD816-D822.
5. Lucas J.M ,RoestcrolliusH.Highpresions detection of conserved sagments from syntenyblocks.PloS ONE .2017;12:e0180198.
6. Louis A.,Nguyen N.T.T MuffatoM.Roestcrollious 8 genomicus update2015:Karyoview and MatrixView provide agenome – wide praspective to multispaciescomprative genomics. Nuclic Acid Res.2014;43D682-D689.
7. Jongeen lee, Dehwaanlee,Mikangsim,Deahang Kwon Juyeonkim,youneeKo and Jeabumkim, my Synteny portal: an Application Package to construct website for synteny block Analysis.BMC bioinformatics 19,Article number:216(2018).
8. Grabherr MG,Russellp,MeyerM,MauceliE,AlfoldiJ,Di Palma F,Lindblad-tohK.Genome-wide synteny through HighlysenstiveAlignmentSatsuma.Bioinformatics,2010;26(9):114-51.
9. Allen D.Roses* Alzheimer Disease: A Model of Gene Mutation and Suseptibilitypolimorphisms for complepsychiatric Diseases.GlxowellcomeReaserch and Development,Reaserch triangle park,Northcarolina
10. Michael K Lee ,Devit R Borchelt,philip C wongSangramsisodia Donald at price Transgenic Madels of neurodegenerative disease.
11. Allen D.Roses .on the Metabolism of Apilipoprotein E and Alzheimer Diseases.Josephkothleenbrayenalhezeimer disease reaserchcentre, Duke university Medical center ,Durham North corolina 27710.
12. Warren J.Strimatter and Allen D.RosesApolipoprotien E and Alzheimer Disease Department of Medicine andNeourobiology joseph and Kathleen bryan Alzheimer Disease reaserch center.
13. jgsukim. jacobs.Basak, DavidM.Holtzman, The ApolipoproteinE in Alzheimer disease.Department of Neurology, development biology, Hope center for Neurological Disorders, Alzheimer Disease research center, Washington university, school of Medicine St Louis,mo,63110,USA.
14. 1999 K.R Bales,T.verina,R.C.Dodel,y.DulAltestial,MBender,PHyslop,E.MjohstoneSP.LittileDjcummins Lack of ApolipoProteinE is essential for deposition in(V717F) teancgenic mouse Model of Alzheimers disease.proc.Natl.Acad.Sci.USA,96(1999).
15. E.Hcorder,A.MSaunders,W.Jstrittmatter,D.E.Schamachel,P.cGaskell,G.w small AD Roses,J.L.Haines,Maparicakvance Gene Dose of ApolipoproteinE type 4 Allel and Risk of Alzheimerdisease in late on set families.Science261(1993).
16. A.M Fagan,G.Bu,Y.sun,Adaaugherty,D.MHoltazmanApolipoprotein high density Apolipo protein High-density Lipoprotein Promotes nuriet outgrowth and ligand for low density lipoprotein receptor-related protein.Jbiol .chem,271(1996),pp.30125.
17. y..Itoh, M.yamadaApolipoproteinE and neuropathology of dementia.N.Engl.Med,334(1996).
18. m.Landan,c.hesse.p.Fredman,BRegLand,A.Wallin,K.Blennow.Apolipoprotein E in cerebrospinal fluid from petient with Alzehimer disease and other forms of demenatia is reduce but without any correlation to the apoE4 isofarm dementia,7(1996).
19. D.R. Riddell,H.Zhou,K.Atcison,H.K Warwick,p.jAtkinson,j.jeffrson,L.xu,S.Aschmies,y.Kriksey,y.Hu,et aL.Impact of Polipoprotein polymorphism on Brain ApoE lavels.j.Neurosci.,28(2008),pp.11445-11453.
20. Danny M.Hatters,cClareA,Peters-Libeu,KarlH.Weisgraberapolipoprotein E Structure:insights into function.Gladston Institute Nurological Disease and Gladstone Institute ofCardiovascular disease ,San Francisco,CA 94143,U.S.A.

Introduction

Alzheimer’s disease is a progressive neurodegenerative disease that leads to memory deficits and eventually fatality. Around the world, one person is diagnosed with Alzheimer’s every 2 seconds currently affecting around 40 million people worldwide but by 2050 it will be 150 million people. For people older than 85 their chance of having Alzheimer’s is almost 1 in 2. Today of the top ten causes of death worldwide Alzheimer’s is the only one we cannot prevent, cure, or even properly slow down. Though the number of people with Alzheimer’s disease is increasing each year because of extended life expectancy universally, present treatment can only slightly relieve the symptoms of Alzheimer’s disease. There is no established treatment to cure or avert the disease, perhaps owing to a lack of understanding concerning the molecular mechanisms of disease pathogenesis. Recent studies have acknowledged the “amyloid hypothesis,” in which the neuropathogenesis of AD is thought to be activated by the accumulation of the toxic amyloid beta protein in the central nervous system. The knowledge that may be critical to unscrambling the unknown pathogenic pathway of Alzheimer’s disease has remained exposed. This essay focuses on the neurotoxic form of amyloid protein in the brain of people diagnosed with AD and also reviews current advances in the analysis of these accumulation mechanisms alongside the knowledge impact on therapeutic strategies for this disease.

Alzheimer’s disease is a progressive neurodegenerative disease discovered by a German physician called Dr. Alois Alzheimer in 1906. This disease can happen in anybody at any stage in life; Although, it is most frequent among the aging and is rarer in the youthful population. However, Alzheimer’s disease develops differently for each individual, it generally gives similar symptoms; in the premature phases, the most common deficiency is a recollection of recent proceedings or short-term recall mutilation. As the disease develops, Alzheimer’s disease patients progressively lose their aptitude to contemplate and reason distinctly, make decisions, solve complications, interact with people, and self-care. In addition, there are symptoms such as mood swings, irritability, confusion and aggression, vicissitudes in character and behavior, difficulties with attentiveness and spatial coordination, difficulty with language, and long-standing recollection loss, all of which can distress a person’s everyday life. Alzheimer’s disease can reach the stage of the death of the suffering patient in the ultimate stages by causing, brain death, malnutrition, and organ failure due to the number of nerve cells that have decreased. Today, Alzheimer’s disease affects more than 26.6 million globally, and its pervasiveness is escalating radically every year. By 2050, the quantity of Alzheimer’s disease patients is estimated to quadruple to more than 106 million worldwide, and it is projected that 1 in 85 people will be diagnosed with the disease. Following numerous decades of research, Alzheimer’s disease is considered a complex disease that outcomes from both environmental and genetic factors, such as the family history of Alzheimer’s disease age, and gender. Conversely, the definite stimulant of Alzheimer’s disease is still unknown. Moreover, Alzheimer’s disease is not yet fully understood, however, its histopathological features in the brain are well understood. So far, there have been a large number of studies that have conjectured disease mechanisms for Alzheimer’s disease, of which most of which back the amyloid hypothesis. It is believed that the neuropathogenesis of this disease may be activated by the accumulation of toxic amyloid in the central nervous system (CNS). Therefore, a richer awareness of how these toxic proteins accumulate in the brain of Alzheimer’s disease patients is crucial for the development of more effective therapeutic and precautionary approaches. Possible mechanisms linked to overproduction or impaired clearance of these amyloids that may lead to their abnormal deposition in the brain as well as some possible molecular targets for Alzheimer’s disease treatment will be the focus of this review.

Amyloidosis

Amyloidosis is a mass group of proteins in which a specific protein called amyloid is accumulated within several tissues and organs. Recent research has suggested that this is due to the build-up of a protein in the brain called amyloid beta protein. Amyloid beta protein is a sticky protein that has the tendency to clump together and is produced from a large precursor protein. The amyloid precursor protein clumps together the amyloid beta protein and these clumped proteins interact with the surface of our nerve cells and then cause problems that we see in people who have Alzheimer’s disease. If we can understand how amyloid is produced, how it clumped together, and how it is interacting with the nerve cells, then there is potential to disrupt the processes and produce a potential treatment for Alzheimer’s disease. Trying to understand the process that is going on in the brain causing Alzheimer’s disease is not fully understood. If we can understand any weaknesses of Alzheimer’s we could exploit them as therapeutic methods for the future development of drugs.

In amyloidosis, amyloid refers to starch like and it goes back to an observation made by the German scientist Rudolph Virchow who saw mysterious deposits in the tissue that stained blue with iodine just like plant starch. Amyloids are proteins that take on an abnormal shape which makes them stick together and settle in tissues amyloidosis is the name given to the disease that develops from the tissue damage that results from the tissue deposits. Normally our cells produce thousands of proteins every moment and these proteins need to fold into a particular shape to carry out their specific function. If the protein is synthesized incorrectly, normally it is seen as foreign and destroyed by proteases. In amyloidosis there are a few different ways in which protein folding can occur, one way is when normal proteins are produced in large amounts and a small fraction of them fold incorrectly. Secondly, abnormal proteins with incorrect amino acid sequences are produced and they fold incorrectly. The misfolded proteins with amyloids start to build up. Sometimes there are simply too many of them for the proteases to handle and other times the way that they are folded makes them tough to break down. When the amyloid proteins get excreted outside the cell they tend to clump together forming a rigid insoluble structure called the beta-sheet. These beta-sheets then deposit in the extracellular space of the tissues and cause damage. So amyloidosis is a process where there are extra protein deposits, and there are many different proteins and diseases that follow this same underlying process. In general, amyloidosis can be systematic, meaning that those proteins occur in multiple organ systems or it can be localized meaning that they occur in one organ. There are two types of systematic Alzheimer’s, one of the types is AL amyloidosis. The A refers to Amyloidosis and the L refers to the immunoglobin light chain as the protein that gets misfolded and deposited and deposited. In plasma cell disorder, like multiple myeloma plasma cells, the bone marrow produces more light chains than heavy chains and these excess light chains leak out into the blood. Since there are so many light chains some misfold into AL proteins, and build up in various tissues.

Many years before a person becomes forgetful they will build up plaque in the brain composed of this amyloid protein, they are round neurotic plaques also known as senile and amyloid plaques which can only be seen microscopically. Shortly after the build-up of amyloid protein, tangles will build up in the brain with the Tau protein. The Plaques and tangles together mount up over decades and lead to short-circuiting of nerve cells, leading to a failure of the systems in the brain for one nerve to transfer communication to the next. In 1992 Brival Hospital studied that the Amyloid beta protein is made within everyone throughout life. Everyone does not get Alzheimer’s disease because there are genetic risk factors and environmental factors that help people handle the amyloid protein more poorly than other which lead to these people obtaining Alzheimer’s disease. There are two types of amyloidosis, systematic, where amyloid is accumulated throughout the body and localized amyloidosis where amyloid is accumulated in specific areas of a single tissue.

Systematic Amyloidosis

In AA amyloidosis previously known as secondary amyloidosis the misfolded protein comes from serum amyloid A. Under normal circumstances, serum amyloid A is a properly folded protein that’s an acute phase reactant meaning that it is secreted into the bloodstream by the liver whenever there’s inflammation. But when inflammation goes on for too long, like in rheumatoid arthritis, inflammatory bowel disease, and various cancers, or hereditary immune disorder like Familial Mediterranean fever, there is a lot of serum amyloid A in the blood, and a small proportion of the serum spontaneously fold incorrectly into AA amyloids, which end up accumulating within tissues creating Amyloidosis.

In systemic amyloidosis, amyloids deposit in various organs. In the Kidneys, amyloid deposits can damage the podocytes which are the cells that line the glomerulus. When the podocytes are damaged, proteins like albumin spill into the Urine which result in proteinuria, typically if there are greater than 3.5 grams a day hypoglycemia occurs. Over time with less protein in the blood, the oncotic pressure falls and that drives water out of the blood vessels and into the tissues this process is called Edema. Albumin and other proteins normally inhibit the synthesis of lipids, or fat so losing them leads to hyperlipidemia.

In the heart, amyloid deposits can make the heart walls stiff and non-compliant and this can lead to restrictive cardiomyopathy which is when the ventricle is unable to stretch out and fill up with blood. Over time this can lead to congestive heart failure. Amyloid deposits can also interfere with the electrical conduction system of the heart causing arrhythmias, and an irregular heartbeat. In the intestine amyloid deposits can damage the tips of the villi. When the Villi are damaged nutrients are not absorbed and end up in the stool. Amyloid deposits can also build up in the liver, spleen, or tongue, making them enlarge. Amyloid deposits can injure peripheral nerve fibers like the one carrying sensory or motor signals, or autonomic nerves that control things like digestion and blood pressure.

Localized amyloidosis

AL amyloidosis can too act as a localized disease, where amyloid deposition is restricted to a single organ. The area of the body disturbed varies upon the biochemical nature of the amyloid fibril protein and, constant with this, Kourelis demonstrated that IGVL gene usage is different between localized and systemic forms of the disease. Localized AL amyloidosis may initially be noticed based on its location. Standard sites related to localized AL amyloidosis include skin, brain, urinary tract, bladder, larynx, conjunctiva, and the tracheobronchial tree in the non-existence of systemic visceral dysfunction. For patients with localized AL amyloidosis that need life-long monitoring are necessary, whilst these patients have been revealed to have a normal life expectancy.

Potential treatments

The treatments for Alzheimer’s disease are limited. Two drugs in the one class called cholinesterase inhibitors have been around for a long time and their mechanism is that we know in people with AD start to lose a neurotransmitter called Acetylcholine. There is an enzyme that breaks Acetylcholine and this is the cholinesterase inhibitor. They give Cholinesterase inhibitors to make the enzyme less able to break down the Acetylcholine that is in the brain. Early in AD when there are still enough brain cells around to make this chemical it makes sense that this treatment would work. Later in the disease, there are not many brain cells left that are making acetylcholine so we do not know whether to give it or not toward the later stages of AD makes. Too much of a difference. The other class o drugs there is the generic name Memantine commonly known as Namenda. Memantine protects damaged brain cells from further injury from glutamine which is a normal chemical within the brain. Glutamine will attack the injured brain cells in AD and make them die faster so the Memantine will protect the brain cells a little bit longer. Neither acetylcholine nor Memantine is cured, most of the studies with these drugs indicate that they slow down the progression of AD. Some studies look t small changes in memory or function and whilst it does help a little, the drugs are not too effective. When treating a disease that has no known cure there is a tremendous placebo effect that can go along with these drugs because it looks as if they are causing a positive effect.

At the Tsai laboratory at MIT, a team established that the gamma rhythm amplitude at the 40 Hertz range was reduced in mice with AD called 5XFAD mice. More specifically, the gamma rhythm was significantly decreased in a brain region crucial for learning and memory, called the hippocampus. The diminished gamma rhythm in 5XFAD mice occurred with the accumulation of amyloid beta, which eventually becomes toxic and resulted in neuronal death and memory loss within the mice. Researchers in the lab used optogenetics to artificially correct the gamma rhythm in the hippocampus of 5XFAD AD mice. By stimulating neurons in the 40 Hertz range at the optimal gamma rhythm amplitude, they showed that amyloid beta levels were cut nearly in half. They discovered that the 40-hertz optogenetic stimulation to correct the gamma rhythm in Ad mice activated genes in the brain cells called microglia. Microglia are part of the brain’s immune system and function in part to ingest or clear away microorganisms that might cause disease. Optogenetic stimulation at the 40-hertz range activated microglia to promote the clearance of amyloid beta to create an effective treatment in humans with AD, it’s ideal to invent a non-invasive technique. The team created a sensory paradigm that uses flickering light to restore the gamma rhythm and reduce the levels of amyloid beta.

The use of natural elements from plants for medication is can help due to their low cost, availability, and safer. Nonetheless, the efficacy and safety of each natural or plant product must be established before human usage. Many herbs have been described to exhibit a neuroprotective effect in Alzheimer’s disease. Herbal medications have the mechanisms essential to Amyloid beta accumulation, which is now thought to be a principal instrumental pathway in Alzheimer’s disease pathogenesis, which could be the most efficient approach to averting the disease. For example, cerebral blood plants may be beneficial, the ethanolic. part of the Morinda citrifolia fruit, containing its chloroform and ethyl acetate segments, was recently stated to considerably improve cerebral blood flow in a mouse model, signifying that Morinda citrifolia may prevent Amyloid beta buildup. Increased oxidative stress and AChE undertakings, which are common problems in AD, were also diminished by the ethanolic part of Morina citrifolia, which upkeeps its prospective belief to prevent AD. Changing the guideline of the appearance of genes involved in amyloid genesis may be an additional mechanism of neuronal defense by plants.

Conclusion

To conclude, Alzheimer’s disease is a progressive neurodegenerative disease that leads to memory impairment and eventually fatality. Though, there is presently no established medication to stop or cure the development of the disease. This essay fixated on the “amyloid hypothesis,” which believes that the neuropathogenesis of Alzheimer’s disease is activated by the build-up of toxic Amyloid beta in the Central Nervous System. I underlined the significance of the current treatment used to try and tackle Alzheimer’s. In addition to this, I wrote about the possible use of medicinal plants as an alternative to current treatments.

1. Introduction

1.1 Problem Summary

There is this great problem of large amount of data being produced by medical apparatus which becomes too much to handle for a human. Or in some cases, there is la ack of specialist doctor needed to examine that data in order to diagnose a disease. Medical science with the use of information technology and in particular the use of machine learning can benefit from it.

Alzheimer being a neurodegenerative disease, it is hard to manage after certain stage. If in brain scan it is early diagnosed it can be helpful in greatly managing in coming time. But there is large amount of data and very few experts, and so there is the problem of detecting Alzheimer from brain scan images and that we hope to solve.

1.2 Aim and objectives of the project

Our aim is to provide a machine learning-based system that can precisely diagnose the Alzheimer brain patterns from the brain scan data it had been given. Then it can handle large amount of brain scan data and with the accuracy we strive to achieve, it can be really helpful for medical practitioners.

A web-based system which can be helpful in early detection of neuro-degenerative disorder is really helpful. Alzheimer being diagnosed without the help of neurologist and with the less effort and great accuracy is our primary and to help medical system.

1.3 Problem Specifications

A typical brain slice can not be distinguished from the normal brain slice. There are different parameters to check for in the different regions of the brain image. All of these things with the catalogued training data set that we provide are learnt by our model to diagnose Alzheimer from unknown dataset.

1.4 Brief literature review

We have done extensive web research and found many patents of which we have created various PSAR reports. Below image is sample of the search that we have done. Detailed PSAR reports can be found in Appendix.

We also have referred to various articles and papers which are mentioned in reference section.

1.4 Materials / Tools required

Hardware:

• High end GPU based system for to train our model. With the use of GPU we can train our model with images and process those images.

Software:

• Google colab
• VS Code
• Anaconda
• Tensorflow.

2. Design

2.1 AEIOU Summary

In AEIOU summary we have following parts:

2.1 .1 Environment:

The surroundings and the nature of the place we visited.

2.1.2 Interactions:

we visited medical institutions where we found patients and we observed interactions among these patients.

2.1.3 Objects:

The objects we observed during the visit are mentioned in below. The detailed list is shown in Figure 2.1.

2.1.4 Activities:

We found activities like medicines being bought, treatment, diagnosis etc.

2.1.5 Users:

The users we observed were patients being treated and other users which are hospital staff. Further users are shown in figure 2.1.1.

Figure 2.1.1 Canvas of AEIOU

2.2 Empathy Mapping

2.2.1 Users:

Here, we have took a doctor Raj Patel as shown in figure.

2.2.2 Stakeholders:

The stakeholders are depicted in Figure 4.2.

Figure .2.2.1 Stakeholders

2.2.3 Storyboarding:

Figure 2.2.2 Story

Figure 2.2.3 Canvas of Empathy Maping

2.3 Ideation Canvas

In Design ideation: the conceptual sketch in the digital age Ben Johnson defined ideation as ‘a matter of generating, developing and communicating ideas.’ The various aspects of the Ideation canvas prepared by our team are shown in Figure 2.3.1- 2.3.5.

2.3.1 People:

This section can have all the people involved and related to the domain of medicine.

Figure 2.3.1 People

2.3.2 Activities:

This section has activities of all the people mentioned above in the “People” section in the ideation Canvas.

Figure 2.3.2 Activities

2.3.3 Situation/Context/Location:

In this section, we need to find in which situation do they do.

Figure 2.3.3 Situation/Context /Locations

2.3.4 Props/Possible Solutions:

Props are the keywords which may flash in our mind by thinking of some issues which may occur by combining random people, activities and situation/context/location sections in the ideation canvas.

The props for our design project are shown in figure 2.3.4.

Figure 2.3.4 Probes/Tools

Figure 2.3.5 Ideation canvas

2.4 Product Development Canvas

Our aim is to provide diagnosis of Alzheimer using machine learning.

Figure 2.4.1 Canvas of Product Development

3. Implementation

• · Our road map to project is very simple. It can be understood with the use of the following flow diagram. By which, it can be well understood how we are to implement and develop and then in the end deploy our product.

Figure 3.1 Alzheimer Project flow

• · This are some of the Alzheimer patients brain scan slices that we have trained our model with.

Figure 3.2 Brain Slices

• · This is the snippet of the Alzheimer machine learning model code that we have developed. It has accuracy of 70-75%.

Figure 3.3 Machine Learning model

This is the Next step is the pre- processing of the image of the brain slice into grey-scale that we want to check for the Alzheimer.

Figure 3.4 Image Pre-processing

• · We can see the given brain slice is of Alzheimer patient’s or not from our resultant output. This is how our model works with current training of model.

Figure 3.5 Final result

4. Conclusion

4.1 Advantages of our work:

4.2 Unique features of our work:

• · Our work makes the work of medical practitioners easy.
• · It is a unique way to handle and diagnose disease from large amount of data.
• · It provides a web-based interface for processing of a brain slice to know if it is Alzheimer or not which will be very helpful in rural areas.

4.2 Scope of future work

• · Our road map in future includes web-based User Interface which will be helpful in using out product.
• · Machine learning model code that we have developed. It has accuracy of 70-75%. Which we plan to improve to 95% or more with upcoming future work.

References

1. Alvarez, I., Gorriz, J. M., Ramirez, J., Salas-Gonzalez, D., Lopez, M., Puntonet, C. G., et al. (2009a). Alzheimer’s diagnosis using eigenbrains and support vector machines. Electron. Lett. 45, 342–343. doi: 10.1049/el.2009.3415.
2. Anagnostopoulos, C. N., Giannoukos, I., Spenger, C., Simmons, A., Mecocci, P., Soininen, H., et al. (2013). “Classification models for Alzheimer’s disease Detection,” in Engineering Applications of Neural Networks, Vol. 384(Pt II), eds L. Iliadis, H. Papadopoulos, and C. Jayne (Berlin; Heidelberg: Springer), 193–202. doi: 10.1007/978-3-642-41016-1_21.
3. Chaves R, Ramirez J, Gorriz JM, Illan IA, Gomez-Rio M, Carnero C, Alzheimer’s Disease Neuroimaging Initiative. 2012. Effective diagnosis of Alzheimer’s disease by means of large margin-based methodology. BMC Medical Informatics and Decision Making 12:17.
4. Dong Z, Liu A, Wang S, Ji G, Zhang Z, Yang J, Zhang Y. 2015a. Magnetic resonance brain image classification via stationary wavelet transform and generalized eigenvalue proximal support vector machine. Journal of Medical Imaging and Health Informatics 5:1-9
5. Eliasova I, Anderkova L, Marecek R, Rektorova I. 2014. Non-invasive brain stimulation of the right inferior frontal gyrus may improve attention in early Alzheimer’s disease: a pilot study. Journal of the Neurological Sciences 346:318-322
6. Eskildsen, S. F., Coupé, P., Fonov, V. S., Pruessner, J. C., and Collins, D. L. (2015). Structural imaging biomarkers of Alzheimer’s disease: predicting disease progression. Neurobiol. Aging 36(Suppl. 1), S23–S31. doi: 10.1016/j.neurobiolaging.2014.04.034
7. Gomes, T. A. F., Prudêncio, R. B. C., Soares, C., Rossi, A. L. D., and Carvalho, A. (2012). Combining meta-learning and search techniques to select parameters for support vector machines. Neurocomputing 75, 3–13. doi: 10.1016/j.neucom.2011.07.005
8. Kalbkhani, H., Shayesteh, M. G., and Zali-Vargahan, B. (2013). Robust algorithm for brain magnetic resonance image (MRI) classification based on GARCH variances series. Biomed. Signal Process. Control 8, 909–919. doi: 10.1016/j.bspc.2013.09.001
9. Lopez, M., Ramirez, J., Gorriz, J. M., Alvarez, I., Salas-Gonzalez, D., Segovia, F., et al. (2009). “Automatic system for Alzheimer’s disease diagnosis using eigenbrains and bayesian classification rules,” Bio-Inspired Systems: Computational and Ambient Intelligence, Vol. 5517, eds J. Cabestany, A. Prieto, F. Sandoval, and J. M. Corchado (Berlin: Springer-Verlag Berlin), 949–956.
10. Savio, A., and Grana, M. (2013). Deformation based feature selection for computer aided diagnosis of Alzheimer’s Disease. Expert Syst. Appl. 40, 1619–1628. doi: 10.1016/j.eswa.2012.09.009
11. Streitburger, D. P., Möller, H. E., Tittgemeyer, M., Hund-Georgiadis, M., Schroeter, M. L., and Mueller, K. (2012). Investigating structural brain changes of dehydration using voxel-based morphometry. PLoS ONE 7:e44195. doi: 10.1371/journal.pone.0044195.

Alzheimer’s Disease (AD) is amongst the main causes of morbidity and perhaps mortality in the older population1. Alzheimer’s disease pathology has over the years bordered on the deposition of the protein beta- amyloids (Aβ) and the subsequent involvement of tau plaques in the brains of patients. However, there has been evidence to suggest the involvement of vascular and endothelial factors 2 but this association is not clear. Writing in the journal of neuroscience, Bonds et al report that the reduction of Caveolin-1 (CAV-1) in a Type 2 diabetes (DM2) model induces the precursors of AD Pathology 3.

AD usually affects people in their mid-60’s and gradually progresses through life. Typical AD pathology reveals the increased presence of Aβ deposits and tau resulting in the death of brain cells. Typical symptoms include short-term memory loss and cognitive decline4. DM2 is characterized by a rise in blood sugar level due to insulin resistance or the bodies inability to produce properly functioning insulin5. Roberts and colleagues, DM2 significantly increased the risk of developing AD6. CAV-1 is mostly found in endothelial and fat tissues and helps in the trafficking of insulin via the blood-brain barrier into neural tissues7. It interacts with proteins within the lipid rafts and this is interesting since Amyloid Precursor Protein (APP) and BACE-1 processing also occur in the lipid raft8,9. This association with AD is a novel finding and opens a door into understanding the microvascular association.

The authors studied CAV-1’s role in AD. They checked the levels of CAV-1 in the brains of DM2 human patients and their controls and diabetic model mice also with their control group. Results showed significantly reduced CAV-1 levels in both human and mice T2D groups but not in both controls groups. Moving on, the reduced CAV-1 levels coincided with an increased level in APP, BACE-1 and Aβ in both diseased groups but was normal in the controls. Moving on, after CAV-1 reduction, irregularities in tau metabolism was assessed only in db/db mice. Results showed a significant increase in total tau which may have affected the AT8/DA9 ratio (fig 1)3.

With an Alzheimer’s disease model in place, the authors then sought to find out if there was any compromise to the functioning of the hippocampus. This was done by introducing novel and familiar test objects to see if they could remember. Unfortunately, diseased mice had difficulties in identifying the objects but when CAV-1 levels were increased, their performance levels increased significantly3. This meant CAV-1 reduction potentially affected the learning and memory performance of these mice.

Did CAV-1 reduction lead to AD pathology? To answer this question, the CAV-1 levels were increased in the diseased mice which resulted in a significant decrease in BACE-1, APP and tau levels in the brains of these animals. Further testing was carried out to determine if CAV-1 regulates the amyloidogenic pathway. Results showed significantly increased levels of Fl-APP, APP carboxyl-terminal fragments and Aβ when CAV-1 was underexpressed3. More importantly, this CAV-1 reduction resulted in a significant increase in human Aβ but not mice Aβ levels. When

Taking their results together, Bond and colleagues were able to somewhat establish a link between T2D and AD however a few questions linger around their methods and some of their findings.

One inadequacy in this study is the fact that human Aβ cannot be found in the type of mouse strain (db/db) used. Thus, it makes it difficult to fully compare both parties since the expression of AD pathology in humans will be different from these mice. But the question remains, is there any other diabetic mouse strain that harbours human Aβ? Certainly not. Till another mice strain is found, it will be much appreciated if human organoids can be made from stem cells from AD individuals as this will certainly harbour the human Aβ and create a brain microenvironment that can be used to better understand the disease pathology. Also, this organoid model will afford the opportunity to easily manipulate genes and other proteins all in a bid to develop therapies to overcome the debilitating effects this condition comes with.

Secondly, the author’s use of the word depletion/ reduction was misleading. This is important because we do not know by how much CAV-1 was reduced. Was it by two folds, 30% or even 80%? Knowing to what level CAV-1 was depleted to or by how much will help in determining a threshold for future studies. This will help in the creation of a protocol and help in repeatability of these results. Lastly, the diseased test subjects used were all-male db/db mice and it is not clear why the author did not use female mice also or perhaps only female mice since it is known that there is not a statistical difference in gender relating to this strain of mice10.

In a paper by Chang et al, deletion of CAV-1 in an intracerebral haemorrhage (ICH) model resulted in a reduced brain injury11. This is different from the findings in this study which shows CAV-1 reduction rather increasing the AD pathology. The diseases might be different but shows that there might be a lot more happening behind the scene.

All in all, this paper certainly provides evidence for how these vascular and endothelial factors might induce AD pathology through DM2. Nevertheless, more work will need to be done to come up with a robust theory.

References

1. Qiu, C., Kivipelto, M. and von Strauss, E., 2009. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues in clinical neuroscience, 11(2), p.111.
2. Sweeney, M.D., Montagne, A., Sagare, A.P., Nation, D.A., Schneider, L.S., Chui, H.C., Harrington, M.G., Pa, J., Law, M., Wang, D.J. and Jacobs, R.E., 2019. Vascular dysfunction—The disregarded partner of Alzheimer’s disease. Alzheimer’s & Dementia, 15(1), pp.158-167.
3. Bonds, J.A., Shetti, A., Bheri, A., Chen, Z., Disouky, A., Tai, L., Mao, M., Head, B.P., Bonini, M.G., Haus, J.M. and Minshall, R.D., 2019. Depletion of Caveolin-1 in Type 2 Diabetes Model Induces Alzheimer’s Disease Pathology Precursors. Journal of Neuroscience, 39(43), pp.8576-8583.
4. Jack Jr, C.R., Bennett, D.A., Blennow, K., Carrillo, M.C., Dunn, B., Haeberlein, S.B., Holtzman, D.M., Jagust, W., Jessen, F., Karlawish, J. and Liu, E., 2018. NIA‐AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia, 14(4), pp.535-562.
5. Xu, W., Qiu, C., Winblad, B. and Fratiglioni, L., 2007. The effect of borderline diabetes on the risk of dementia and Alzheimer’s disease. Clinical Diabetology, 8(5), pp.188-195.
6. Roberts, R.O., Geda, Y.E., Knopman, D.S., Christianson, T.J., Pankratz, V.S., Boeve, B.F., Vella, A., Rocca, W.A. and Petersen, R.C., 2008. Association of duration and severity of diabetes mellitus with mild cognitive impairment. Archives of neurology, 65(8), pp.1066-1073.
7. Fridolfsson, H.N., Roth, D.M., Insel, P.A. and Patel, H.H., 2014. Regulation of intracellular signaling and function by caveolin. The FASEB Journal, 28(9), pp.3823-3831.
8. Okamoto, T., Schlegel, A., Scherer, P.E. and Lisanti, M.P., 1998. Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. Journal of Biological Chemistry, 273(10), pp.5419-5422.
9. Vetrivel, K.S., Cheng, H., Lin, W., Sakurai, T., Li, T., Nukina, N., Wong, P.C., Xu, H. and Thinakaran, G., 2004. Association of γ-secretase with lipid rafts in post-Golgi and endosome membranes. Journal of Biological Chemistry, 279(43), pp.44945-44954.
10. Ma, Y., Li, W., Yazdizadeh Shotorbani, P., Dubansky, B.H., Huang, L., Chaudhari, S., Wu, P., Wang, L.A., Ryou, M.G., Zhou, Z. and Ma, R., 2019. Comparison of diabetic nephropathy between male and female eNOS−/− db/db mice. American Journal of Physiology-Renal Physiology, 316(5), pp.F889-F897.
11. Chang, C.F., Chen, S.F., Lee, T.S., Lee, H.F., Chen, S.F. and Shyue, S.K., 2011. Caveolin-1 deletion reduces early brain injury after experimental intracerebral hemorrhage. The American journal of pathology, 178(4), pp.1749-1761.

Alzheimer’s disease (AD) is an age-dependent neurodegenerative disorder marked by declining cognitive and, in late stages, physical functioning that is ultimately fatal. As AD progresses, patients experience deficits in memory, language, and problem-solving abilities as well as behavioral changes resulting in obstruction of daily activities. Most cases occur past the age of 65 and are on the rise due to improvements in life expectancy. In the coming years, the prevalence of AD is expected to skyrocket with the aging Baby Boomer population. It is for this reason that the need for more knowledge of the pathology of AD as well as novel therapies are becoming increasingly necessary. (‘2015 Alzheimer’s disease facts and figures,’ 2015)

AD is a chronic disease with a pathology that is complex and has yet to be well-characterized. However, the hallmarks of AD progression are the accumulation and aggregation of amyloid beta (Aβ) and the hyperphosphorylation of tau (Talarico, Trebbastoni, Bruno, & de Lena, 2019). Aβ is derived from the cleavage of β-amyloid precursor protein (APP). Aggregation of Aβ results in the formation of neuritic plaques which, along with soluble Aβ and its oligomers, have toxic effects on neurons (Talarico et al., 2019). The hyperphosphorylation of tau results in the formation of neurofibrillary tangles that impair interneuronal communication (Campbell & Gowran, 2009). The formation of both are localized at the start of the disease with neuritic plaque formation beginning in the cortex, hippocampus, and amygdala (Campbell & Gowran, 2009) and neurofibrillary tangles beginning in brainstem nuclei, entorhinal and transentorhinal cortices and later moving to the hippocampus (Aso & Ferrer, 2016).

Current therapies have been primarily targeted at acetylcholine neurotransmission and particularly the inhibition of acetylcholinesterase which breaks down acetylcholine in the synaptic cleft. This is based on the observation of degeneration of basal forebrain cholinergic neurons. Other therapies have been aimed at decreasing excitotoxicity through inhibition of NMDA receptors as well as targeting the formation of neuritic plaques and neurofibrillary tangles directly. These approaches have had little or very temporary success in preventing symptoms of the disease and slowing progreession. Therefore, it is imperative that new approaches are taken. (Talarico et al., 2019)

One new approach to AD has involved the endocannabinoid system (ECS). The ECS consists of CB1 and CB2 receptors, the endogenous ligands which they bind, and the enzymes involved in the production and degradation of endocannabinoids (Talarico et al., 2019). CB1 receptors are primarily located in the central nervous system and are involved in learning and memory whereas CB2 receptors are primarily localized with immune cells including astrocytes and glia in the central nervous system (CNS). Recent studies have shown many neuroprotective effects associated with the administration of exogenous cannabinoids through both CBR-dependent and -independent mechanisms. In addition, some studies have shown that activation of CB1Rs has been associated with reduced cognitive decline. This has brought obvious attention to the ECS as a potential target for future AD therapies. (Patricio-Martínez et al., 2019)

In this paper, I will review the efficacy of therapies involving CB1 and CB2 receptors primarily in mouse and rat models. This is primarily due to the fact that human studies are much less prevalent and tend to be less conclusive due to confounding variables. Mouse and rat models provide cheaper, more efficient, and more precise ways to manipulate and control variables allowing for better and more ample data. Through the coverage of studies involving drugs and genetic manipulations targeting CB1 and CB2 receptors, I will explore how the ECS may be implicated in AD as well as how it can be used to alleviate its symptoms.

Although these topics were briefly discussed in the introduction, it is important to take a closer, more in-depth look at the pathology of AD and further introduce the purpose and make-up of the ECS. This will provide a better understanding of where the AD progression and the ECS overlap and how we can manipulate one to effect the other.

As discussed previously in the introduction, the hallmarks of AD are the presence of Aβ senile plaques due to the aggregation of Aβ monomers and neurofibrillary tangles composed of hyperphosphorylated and truncated forms of tau protein (Talarico et al., 2019). Other factors key to the progression of AD are inflammation, oxidative stress, decreased mitochondrial function, and improper functioning of degradation pathways.

Neuroinflammation associated with AD is commonly thought to be brought on by Aβ aggregation as the inflammatory response works to break down and/or remove the senile plaques. This process is characterized by microglial activation, astrocyte reactivity, and the presence of inflammatory mediators like cytokines. Microglial activation is a key part of this response as these cells work to remove senile plaques. It is important to note that there are two main types of microglia: one that is detrimental (M1) and one that is beneficial (M2). This makes the inflammatory response a two-edged sword: not all good or bad. Astrocytes also play a role as they internalize Aβ, release inflammatory mediators, (Aso & Ferrer, 2016) and increase expression of inducible nitric oxide synthase (iNOS) which produces NO, a reactive nitrogen species that can have toxic effects (Patricio-Martínez et al., 2019). Another thing that complicates the effects of the inflammatory response is the stage of AD and the length of inflammation. In early stages of the disease, the inflammatory response is favorable as it removes accumulated Aβ. However, chronic inflammation triggered by continuous Aβ aggregation can cause more harm than good due to the system’s prolonged exposure to inflammatory mediators which can have toxic effects. Therefore, in determining the effects of neuroinflammation, it is important to note the stage of the disease, the length of inflammation, the specific brain region involved and which type of microglia is most prevalent.

Overactive neurons in specific regions of the brain are thought to be early disturbances of Alzheimer’s disease. In a new study, researchers from the Technical University of Munich, Germany, were the first to explain the causes and mechanisms of this early important neurological dysfunction. They found that the excitatory neurotransmitter glutamate persisted for too long in the vicinity of active neurons. This causes these neurons to suffer from pathological over-stimulation, which is likely to be a key factor in learning and memory loss in patients with Alzheimer’s disease. The results of the study were published in the August 9th, 2019 issue of Science, entitled ‘A vicious cycle of β amyloid–dependent neuronal hyperactivation.’

The brains of patients with Alzheimer’s disease who have developed clinical symptoms contain large β-amyloid masses (ie, plaques). Many treatments focus on the removal of plaques, but so far this attempt has only met with limited success.

Arthur Konnerth, author of the paper and professor of neuroscience at the Technical University of Munich, explains, “We are critical to detecting and treating this disease earlier. Therefore, we focus on overactive neurons, which are more common in this disease. It occurs early, and it occurs long before the patient has memory loss.’ Because of hyperactivity, neurons connected together in the neural circuit constantly receive false signals, which leads to damage to signal processing.

Konnerth, his PhD student Benedikt Zott, and his team succeeded in identifying the causes and triggers that triggered this early disturbance in the brain. This discovery may open the way for new treatments.

Neurons communicate with each other using chemicals called neurotransmitters. As one of the most important chemicals, glutamate plays a role in activating neurons that are connected together. Glutamate is released at a junction site called a synapse between two neurons and is quickly removed to allow propagation of the next signal. This removal involves the so-called active pump molecules and the passive transport of glutamate along nearby cell membranes.

These researchers found that high concentrations of glutamate persisted for too long in the synaptic cleft of highly active neurons. This is due to the action of beta-amyloid molecules: they prevent glutamate from transporting out of the synaptic cleft. They tested this mechanism using beta-amyloid molecules from patient samples and tested them using various mouse models, all with similar results.

he researchers also found that this neurotransmitter blockade is mediated by early soluble beta-amyloid rather than plaque. Beta-amyloid is initially present in a single molecule form (monomer) and then aggregates into a bimolecular form (dimer) and a larger β-amyloid chain, eventually forming plaques. They found that glutamate blockade is caused by soluble beta-amyloid dimers.

As the first author of the paper, Benedict Zott, outlined, “Our data provide clear evidence for the rapid and direct toxic effects of a specific β-amyloid (ie, dimer). We can even explain this. mechanism.’ These researchers now want to use this knowledge to further enhance their understanding of the cellular mechanisms of Alzheimer’s disease and support the development of treatment strategies for the early stages of the disease.

Alzheimer’s disease (AD) is a progressive, degenerative neurological disease whose onset can hardly be observed. AD is clinically characterized by symptoms such as memory impairment, aphasia, impaired visual spatial skills, executive dysfunction, and personality and behavior changes. The underlying cause hasn’t been specified yet. Numerous efforts have been made to find effective medicinal treatment for AD, but the majority of them only turned out to be failure.

It is an admitted fact that the battle against Alzheimer’s is rather difficult and hard to be conquered. This is largely because aging is the number one risk factor for this disease, and we cannot stop aging at this time. After intensive research for several decades, scientists have discovered a few factors that are most likely to be the leading cause of AD. Most researchers believe that Alzheimer’s is caused by two proteins, one called tau and the other called beta-amyloid. As we age, most scientists believe that these proteins will disrupt signals between neurons or simply kill them, thus causing the cognitive degradation.

Amyloid Hypothesis

The amyloid hypothesis, which began in the 1980s, is the most important theory to explain the causes of AD. The presence of amyloid (β-Amyloid, Aβ) in the brain of patients is one of the important signs of AD. The amyloid hypothesis believes that the level of Aβ in AD patients is abnormally increased due to the imbalance between the production and degradation processes, leading to the deposition of Aβ in the brain, which leads to damage and death of brain neurons, and declines in patients’ memory and cognition.

Based on this theory, different therapies that target Aβ have been developed. Some therapies try to target Aβ-producing proteases to prevent Aβ production; while some therapies hope to combine free Aβ monomers in the blood to prevent them from entering the brain. The results of current trials indicate that these therapies have not been effective in preventing a decline in patients’ cognitive levels.

Tau Hypothesis

In 1986, Kosik et al. discovered that NFTs are composed of phosphorylated tau protein. Microtubule-binding protein Tau (MAPT) stabilizes microtubules and can withstand a range of post-translational modifications, including phosphorylation. When tau protein is hyperphosphorylated, it detaches from the microtubules and aggregates to form double helix filaments (PHFs) and NFTs. The Tau protein hypothesis suggests that tau tangles occur before Aβ plaque formation, and that tau phosphorylation and aggregation are the main causes of AD neuronal decline.

Phosphorylation of the Tau protein reduces its ability to promote microtubule assembly, leading to abnormal synaptic function and neuronal loss resulting in neurodegeneration. Nerve fiber tangles can also cause neuronal dysfunction and death. Although the amyloid peptide hypothesis suggests that tau aggregation occurs downstream of Aβ aggregation, tau protein tangles can be seen in the brains of very mild dementia patients without Aβ. Tau protein is also more closely related to the pathological process and severity of AD than Aβ. However, although tau-based treatment research has shown promising results, and seven tau-related treatments are currently undergoing phase II clinical trials, unfortunately, many anti-tau treatments have failed in clinical trials. Glycogen synthase kinase 3 beta (GSK-3β) is a protein kinase that promotes tau phosphorylation, making it an attractive target for anti-tau treatment options. However, Tideglusib, a GSK-3β inhibitor, has not shown significant therapeutic effects in phase II clinical trials.

Brain iron accumulation

Now, a new study from the University of California, Los Angeles suggests a third possible cause: iron accumulation. Professor George Bartzokis and his colleagues analyzed two regions in the brain of Alzheimer’s patients. They compared the hippocampus (which is a well-known area that is damaged early in the disease) and the thalamus (this area is generally not damaged until the end of the disease). Using sophisticated brain imaging techniques, they found that the amount of iron was increased in the hippocampal region and that this was related to tissue damage in that region. But there was no increase in iron in the thalamus.

The destruction of the myelin sheath (adipose tissue covering nerve fibers in the brain) can affect the communication between neurons and promote the accumulation of plaque. These amyloid plaques in turn destroy more and more myelin sheaths, disrupt brain signals, and cause cell death and classic Alzheimer’s clinical symptoms. Long-term research has supported that iron levels in the brain may be a risk factor for aging diseases such as Alzheimer’s. Although iron is essential for cell function, too much of it may promote oxidative damage.

Studies have found that the amount of iron increases in the hippocampus and is associated with tissue damage in patients with Alzheimer’s disease, but in healthy elderly individuals or in the thalamus, the amount of iron was not found to increase. Therefore, the results of the study suggest that the accumulation of iron may indeed contribute to Alzheimer’s disease.

In addition to the three possible causes mentioned above, there are other suspects that are to be blame such as lifestyle, exercise, diet, etc. It may take longer time to crystalize the real culprit of AD.

ABSTRACT

Alzheimer’s Disease has been around for over 100 years and has no cure. It is a neurogenerative disease that leads to dementia in patients, where the episodic memory is impaired, along with a decline in cognitive skills. A report in the 2019 Alzheimer’s Disease Facts and Figures consisted a graph and table which indicated the number of annual Alzheimer’s Disease death rates in the United States per 100,000 people by age and year. The death rates increased as the age and years increased. The purpose of this research paper was to answer the question of why there was a change in rates over the years. It was hypothesized that people who had Alzheimer’s Disease also had other health problems arising from old age such as strokes, which is assumed to play a role in the increase in death rates over the years. The results of this research showed that with age, the chances of acquiring other health problems increased as well. The results also showed that Alzheimer’s Disease and strokes had similar effects in the brain, which indicated a correlation between the two but not necessarily the primary reason for the increase in rates.

INTRODUCTION

Alzheimer’s Disease was first discovered in 1906 by German psychiatrist and neuroanatomist, Alois Alzheimer (Ryan et al. 2015). It is a neurogenerative disease which causes dementia in patients. This disease impairs the episodic memory, along with other cognitive skills, and specific neuropathological changes that usually include neurofibrillary tangles and senile plaques which are often supplemented by synaptic loss and deposits (Bouwman et al. 2010). It is one of the leading causes of death and is usually diagnosed in people over sixty-five years but can also be diagnosed earlier on in life. The help of medication can prolong a person’s life to four to eight years and at times, twenty years and more. The number of people who are impacted by Alzheimer’s Disease is rapidly increasing. In the United States, more than five million people are affected by this disease and this number is expected to triple by 2050 (Mielke et al. 2014). With age, symptoms worsen and the chances of developing further health problems increases as well.

Alzheimer’s Disease and stroke are known to increase at equivalent rates with age. A stroke is a brain injury caused by a sudden disruption in blood supply to the brain (Gund et al. 2013). Symptoms of stroke include the speech impairment, movement and memory problems and at times, death. Stroke is the third common cause of death in the United States. One in every ten deaths is caused by a stroke (Gund et al. 2013). In the year 2013, it was estimated that over 160,00 elderly Americans died of a stroke yearly in the United States (Gund et al. 2013). A stroke is typically seen in adults over the age of sixty-five and usually doubles after the age of fifty-five. Cerebral ischemia, a type of stroke, is common in elderly patients with Alzheimer’s Disease which drastically increases the rate of cognitive decline. 30% of patients with Alzheimer’s Disease contain evidence of blockage of arteries in autopsies, which may be the result of ischemic strokes (Kalaria 2000). Obstructions of blood supply, lesions, and white-matter can be seen on magnetic resonance imaging scans in patients with Alzheimer’s Disease and with patients who suffered from a stroke. Cerebral plaques can also be found in these images

(Qui et al. 2009). These are indications that both are correlated to one another. Each may be the cause of one another but there is not enough research to prove that stroke is the cause of increase in death rates with patients suffering from Alzheimer’s Disease.

The number of deaths of people with this disease has significantly increased over the last nine years. It is often assumed that with the advancement of technology and the discovery of new medicine, the number of diseases can be controlled and at times eradicated but on the contrary, the death rates have considerably increased. There must be a credible reason for the increase in this rate. This sparked an interest in this research to understand what the issue was. The purpose of this research paper is to answer the question of why there was a change in rates over the years. People who have Alzheimer’s Disease also have other health problems arising from old age such as strokes. Hence, it can be hypothesized that strokes play a role in the increase of death rates over the years. The importance of this research is to understand why there was an increase in the rates, especially for the people over sixty-five. There is insufficient evidence to prove that the increase in death rates of people with Alzheimer’s Disease is caused by strokes but there is enough evidence to conclude that Alzheimer’s Disease is interrelated with stroke. With more studies done it can be helpful to find reliable answers.

MATERIALS AND METHODS

The data was obtained through the Google search engine by searching “2019 Alzheimer’s Disease Facts and Data.” The first link opened the Alzheimer’s Association website where a report on the 2019 Alzheimer’s Disease Facts and Figures could be downloaded. Multiple studies done on Alzheimer’s Disease were combined and summarized in this report. The report consisted of a section titled “Mortality and Morbidity.” This section contained a graph and table which indicated the number of annual Alzheimer’s Disease deaths in the United States per 100,000 people by age and year. The death rate increased as the age and years increased. The death rate for middle-aged people progressed slowly but there was a significant increase in the rate for people age seventy-five and older.

A graph consisted of the death rates for different age groups of people through the years 2000-2017 will be observed. This data will be analyzed through the search for other reasons that impacted the increase in the death rates of people who have Alzheimer’s disease throughout the years. This study would specifically focus on the correlation between heart problems, such as stroke, and Alzheimer’s Disease. The data found on individuals who have strokes and the percentage of those individuals who also have Alzheimer’s disease will be reviewed and then determined whether there is a correlation between the two.

RESULTS

Data was collected from studies of people who had Alzheimer’s Disease and as a result died from it. Additionally, data was also collected from people who suffered from strokes. The results of this research showed there was an association between Alzheimer’s Disease and strokes. However, the findings of the studies did not state that the reason the rates had changed over the years was primarily because of strokes. The data showed how one had an effect on one another but not the cause of the death of the other. The causes for the increase in the rates of people with this disease were because of other health issues, genetics, and aging.

Figure 1 demonstrated how as age increased, the death rates of people who had Alzheimer’s Disease increased as well. Figure 2 provided a table for the rates seen in Figure 1. For ages 45-54 the death rate, per 100,000, stayed at a steady rate of 0.2 from 2000-2017. The death rates for ages 55-64 increased from 2.0 to 2.8. For ages 65-74, the rates increased from 18.7 to 24.5. The death rates for ages 75-84 increased from 139.6 to 219.7. Lastly, for ages 85 and older the death rates significantly increased from a rate of 667.7 to 1,244.7. There was not much of an increase for people aged 65-74. However, the death rates of people aged 75 and older, increased drastically.

This disease can be genetic and be passed down from generation to generation. A mutation in genes can cause a person to develop Alzheimer’s Disease. However, this disease also has a hereditary component to it. If people’s parents or siblings have the gene for the disease, the chances of developing this disease increases. It can also be inherited from supplementary health issues, such as heart diseases or cerebral vascular diseases, such as strokes. Figure 4 shows a chart of the leading causes of death in the United States, which includes heart diseases as the leading cause of death. Figure 4 also shows that about 31.7 people, per 100,000, died due to Alzheimer’s Disease and about 30.1, per 100,000 died due to strokes.

As people age, the chances of dying increase. According to Figure 3, the average life expectancy is about 78.7. The symptoms of Alzheimer’s Disease are usually first seen at the age of sixty-five. As people age, the symptoms worsen. The results indicated that people who suffered from strokes had higher chances of developing Alzheimer’s Disease as the effects of strokes are detrimental. According to this research, MRI images of the brains of people who had Alzheimer’s Disease showed similar plaques and lesions in the brain that were also found in people who suffered from strokes. This is evidence that there is a correlation between this disease and strokes.

DISCUSSION

The importance of this research was to find why the death rates of people who had Alzheimer’s Disease increased over the years. The death rates increased with age and it was hypothesized that the reason for this was due to strokes. Strokes were not necessarily the reason for the increase in death rate but played a part in the cause of this disease. As people age, the risk of having additional health issues increase, such as strokes, high blood pressure and cholesterol (Ballard et al. 2011). Along with these health issues, elderly people tend to suffer with depression and anxiety as well. According to the results, suffering from a stroke can lead to developing Alzheimer’s Disease.

The significance of this research was to understand that the rates of people who have Alzheimer’s Disease are increasing and are projected to double in the next 20-30 years. Many studies on the deaths of Alzheimer’s Disease do not focus on stroke being the primary reason of death. However, with this completed research it is apparent as to why there was in increase in the death rates. This research showed that the lives of people who suffer from this disease can be prolonged, with the help of medication and therapy, up to age 85 but plateaus at approximately age 90 (Bondi et al. 2017). The chances of suffering from a stroke are extremely high at this age. People who are diagnosed with Alzheimer’s Disease forget how to complete daily tasks, they are unable to recognize common things, disoriented and frequently experience confusion. At the age of 90, their immune system weakens and their ability to fight infections is extremely low, which can lead to death.

The greatest risk factor of Alzheimer’s Disease is age. The symptoms of Alzheimer’s Disease worsen with age. The symptoms are not noticed at an early age but at the age of 65, the symptoms become more apparent. The effects of this disease lead to dementia, which is the decline of cognitive ability. Memory loss is one of the first alarming symptoms. Over the years, people who are diagnosed with Alzheimer’s Disease forget how to complete daily tasks, they are unable to recognize common things, disoriented and frequently experience confusion (Vijayan and Reddy 2016). Additionally, at the later stages, their ability to fight infections get impaired which ultimately leads to death.

Strokes can affect a person’s mobility, speech, memory, and at times, lead to death. Alzheimer’s Disease has a similar effect as it is a degenerative disease that causes dementia. The MRI images of people who suffer from Alzheimer’s Disease and strokes had similar features. Alzheimer’s Disease is associated with synaptic loss and dysfunction, plaques, and neurofibrillary tangles (Vijayan and Reddy 2016). The images of people who suffered from strokes also consisted of plaques, synaptic dysfunction, and intracellular tangles. These images were important because there was a correlation between the two. Both had similar effects on the brain. Since they have similar effects, the studies of strokes can be used to further expand our knowledge on Alzheimer’s Disease and help develop treatment to better control this disease.

Although Alzheimer’s Disease is mostly genetic, certain steps that can help prolong the symptoms of this disease. There is not a specific plan that one needs to follow but simple daily tasks can help such as walking. Walking while having conversations tends to improve posture and motor abilities. Easy word puzzles improve mental functions and can possibly improve memory. Small and tolerable muscle and strength exercises can be done to improve strength and balance. These will prevent falling in the later stages of the disease (Paillard 2016). Taking appropriate medication and vitamins will certainly assist in elongating one’s life. Alzheimer’s Disease is a growing challenge and has a significant impact on individuals and those around them.

REFERENCES

1. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland Dag, Jones E. 2011. Alzheimer’s disease. Lancet. 377:1019-1031.
2. Bondi MW, Edmonds EC, Salmon DP. 2017. Alzheimer’s disease: past, present, and future. Journal of the International Neuropsychological Society. 23(9-10):818-831.
3. Bouwman FH, Verwey NA, Klein M, Kok A, Blankenstein MA, Sluimer JD, Barkhof F,Van Der
4. Flier VM, Scheltens P. 2010. New research criteria for the diagnosis of Alzheimer’s disease applied in a memory clinic population. Dementia and Geriatric Cognitive Disorders. 30:1-7.
5. Gund BM, Jagtap PN, Ingale VB, Patil RY. 2013. Stroke: A Brain Attack. IOSR Journal of Pharmacy. 3(8):1-23.
6. Kalaria RN. 2000. The role of cerebral ischemia in Alzheimer’s disease. Neurobiology of Aging 21. 21(2):321-330.
7. Mielke MM, Vemuri P, Rocca WA. 2014. Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clinical epidemiology. 6:37–48.
8. Paillard T, Rolland Y, de Souto Barreto P. 2015. Protective effects of physical exercise in Alzheimer’s disease and Parkinson’s disease: a narrative review. Journal of clinical neurology. 11(3):212-219.
9. Qiu C, Kivipelto M, Von Strauss E. 2009. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues in clinical neuroscience. 11(2):111-128.
10. Ryan NS., Rossor MN, Fox .C. 2015. Alzheimer’s disease in the 100 years since Alzheimer’s death. Brain. 138(12):3816-3821.
11. Vijayan M, Reddy PH. 2016. Stroke, vascular dementia, and Alzheimer’s disease: molecular links. Journal of Alzheimer’s Disease. 54(2):427-443.)

A German psychiatrist Alois Alzheimer first observed some strange behavioral symptoms, including short-term memory loss in his patient Auguste Deter. Upon her death, he carefully studied her brain and found some anomalies, of what later became known pathological hallmarks of Alzheimer’s disease. Alzheimer’s disease (AD) is a common form of dementia that is associated with progressive decline in memory, cognition and loss of thinking ability. Upon progression of the disease, it can be serious enough to interfere with activities of our daily life. AD accounts for up to 60-80% of total dementia cases. Patients diagnosed with AD lose their ability to be self-reliant, thereby needing support of their family as a care-taker or from healthcare providers. While the financial burden of providing a caretaker is significant, what affects the most is the emotional burden to the patient and their immediate family members of the deterioration of memories.

It is very stressful to know that someone in the world develops dementia every 3 seconds. There were an estimated 46.8 million people worldwide living with dementia in 2015, while it is believed to have touched 50 million in 2017 (Prince et al. 2015). In America alone, there were 5.7 million people diagnosed with Alzheimer’s dementia. By 2020, this number is projected to rise to nearly 14 million (Alzheimer Association 2018). The magnitude of the disease can be imagined when we think that between 2000 and 2015, the deaths from heart diseases have reduced by 11%, while the death from Alzheimer’s have increased by 123%. Currently, the caregivers provide an estimated 18.4 billion hours of care valued at over $232 billion. Early and accurate detection of this disease could save the taxpayers up to $7.9 trillion in medical care and costs (Alzheimer Association 2018). However, the current treatments available for Alzheimer’s type dementia cannot reverse the damage that has already been caused but is more focused on merely treating the symptoms. More about the current therapeutic strategy for Alzheimer’s will be mentioned in detail in the next section.

Currently, there are 5 therapies that have been approved for treatment of Alzheimer’s disease. Four of these, namely – tacrine, donepezil, rivastigmine and galantamine are classified as Cholinesterase inhibitors, while memantine is a N-methyl-D-Aspartate receptor (NMDARs) antagonist.

Acetyl choline is a chemical neurotransmitter released into the synaptic space by the pre-synaptic neurons. These neurotransmitters then bind to acetyl choline receptors on the post-synaptic neuron and is believed to help in cognition. To regulate this process, there is presence of acetylcholinesterase in the synaptic space, which degrades acetyl choline to acetyl CoA and Choline (Figure 1). The cholinergic hypothesis of AD states that in memory loss and deterioration of other cognitive and noncognitive functions can be attributed to impairment of cholinergic systems in the basal forebrain. This is due to the loss of acetylcholine neurons, loss of enzymatic function for acetylcholine synthesis, and degradation by the action of acetyl cholinesterase. Hence, using inhibitors of acetyl cholinesterase would enhance the cholinergic transmission by binding to acetyl cholinesterase in the synaptic space and blocking degradation of acetyl choline. This would lead to increase the availability of acetyl choline in the synaptic space, thereby helping neuronal transmission (Figure 1). These inhibitors have been approved by the FDA for mild to moderate AD and have been regarded as standard and first-line treatment for Alzheimer’s.

The only available medication for AD that affects the function of NMDA receptor (NMDAR) is Memantine. While excitotoxicity in mid-stage Alzheimer’s is believed to contribute to neurodegeneration, the exact role of glutamate in AD remains unclear. Memantine opposes the effect of glutamate in the brain and believed to halt the progression of neurodegeneration. Memantine binds to open channel of NMDAR’s and blocks the influx of Ca2+ into the cell. Memantine is believed to bind to the Mg2+ pore of NMDAR and is hence called trapping channel blockers of NMDARs (Figure 2). These inhibitors result in slight improvement in cognition and memory. Note, memantine has been approved by FDA only for severe AD.

It’s often quoted that no drug comes without its own limitations. Using acetylcholinesterase inhibitors increases acetyl choline signaling in CNS. However, note that acetyl choline not just acts on the central nervous system (CNS), but also activates the peripheral nervous system (PNS). These medications can hence cause common side effects like nausea, gastrointestinal (GI) upset, and diarrhea. Some of the other less common side effects include muscular weakness, syncope, and significant weight loss on occasion. A drug with most adverse side effects is rivastigmine, where only a limited number of patients can tolerate the full dose of 6mg twice daily. (Refer paper for more limitations)

While memantine’s action on NMDAR is believed to halt the progression of neurodegeneration, we also know that NMDARs play a key role in controlling synaptic plasticity and memory function. Depending on specific NR2 sub-unit type of NMDAR is present (NR2A or NR2B), blocking NMDARs impair synaptic plasticity, and compromises learning and memory. Hence, it is important for memantine to not block all NMDARs and memantine meets this criterion since it only blocks NMDARs which are in open state or is overstimulated. The clinical significance is only seen in case of severe AD and the cost is also considerably high for this drug. Note that there are other trapping channel blockers like ketamine, which has strikingly similar channel blocking properties to memantine, but exhibit dissimilar clinical effects and hence not been approved for clinical use. Recent phase III trials have shown Memantine’s efficacy in moderate to severe AD.

Basic question for any family whose dear ones are diagnosed with Alzheimer’s in its early stage is how clinicians decide on the prognosis. It should be noted that there are no established guidelines on the prognosis for Alzheimer’s. If the patient is diagnosed with Alzheimer’s early enough, then they are put on acetyl cholinesterase inhibitors (ACheIs). Synergistic effect of ACheIs with Memantine has been observed in moderate to severe AD. In early stage AD, synergistic effect of drugs has not been observed.

To summarize, the existing drugs do not treat the underlying cause of the disease and only slow its progression modestly. Hence, many research groups have now been focused on finding a more efficient drug for treatment of Alzheimer’s that could treat the underlying symptoms. We know that neuroinflammation plays a key role in progression of Alzheimer’s disease, and molecular targeting of microglial proteins involved in neuroinflammation is crucial. To understand this, we need to carefully evaluate the signaling pathway involved in neuroinflammation, which is precisely what my project will be focused on.

Abstract

Alzheimer’s is a progressive degenerative disease that ultimately leads to death due to the degeneration and plaque build up within the brain. Memory is an important aspect of daily life and for performing every day activities and when that is hindered it could be detrimental to the individual and how they are able to function throughout their life. Alzheimer’s may be hard to initially diagnose due to some believing that it is just due to older age but after performing tests and detecting specific biomarkers the provider is able to diagnose Alzheimer’s. Some genetic and environmental influences increase the risk in getting Alzheimer’s disease. Since Alzheimer’s is a progressive degenerative disease the patients will pass away within a few years of being diagnosed. Although the lifespan is not as long as one would generally hope, it can always be ensured that their life quality and care is the best that they deserve. A study was conducted for this research project on an Alzheimer’s patient and how many times she would forget that she just made a statement and would repeat herself. This research used a qualitative experimental design and also includes a small interview with the patient’s primary caregiver.

Alzheimer’s Disease

Memory is what allows one to complete small tasks throughout the day that generally does not require much thought to complete it. Short-term and long-term memory both plays part in day-to-day life and when one is hindered it could cause many issues for an individual. Alzheimer’s disease (AD) is a progressive neurodegenerative disease that accounts for most individuals who suffer with dementia after the age of 65 (Amoroso, 2018). Neurodegenerative symptoms such as dementia and cognitive impairment precede the diagnosis of Alzheimer’s. Life for individuals who suffer from Alzheimer’s may notice that daily tasks become more difficult, they may misplace things, have difficulty with time and place, and much more. Memory is an important aspect when it comes to Alzheimer’s disease and after some time individuals who suffer may not have the capabilities to form new memories. By identifying and understanding the early stages of AD can aid in future disease-modifying treatments (Amoroso, 2018). The purpose of this research aims to bring awareness to AD and the effects that it has on one the affected every day life.

Literature Review

Alzheimer’s starts at small memory changes then progresses to dementia then eventually death. Diagnosis is generally occurs in individuals after the age of 65 (Ulep, Saraon, & Mclea, 2018). The diagnosis generally starts off with analyzing any changes in memory, then doing a full medical, psychiatric, and substance abuse history. If a patient suffers from HIV, Lyme disease, and Syphilis it has been shown to increase ones chances of dementia (Neugroschl & Wang, 2011). A physical and neurological exam must me done to also rule out any other possible diseases or disorders that one may suffer from. Some screenings such as the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA) may be done as well the MoCA is more sensitive and useful for diagnosing moderate and severe dementia (Neugroschl & Wang, 2011). In order to have a definite diagnosis of AD specific biomarkers must be obtained such as structural and functional imaging, cerebrospinal fluid analysis (CSF), and amyloid positron emission tomography (PET Scan) (Ulep, et al., 2018). By performing more in depth procedures allow more accuracy in diagnosis. By analyzing CSF fluid, biomarkers are detectable 15-20 years before the initial symptoms present themselves (Ulep, et al., 2018). Depending on when one gets diagnosed and how early they get diagnosed for example, Mild AD (early stage), moderate AD (middle stage), and severe AD (late stage), will determine the next steps for that patient and the care that is needed for them in following.

By analyzing imaging of the brain it allows providers to see any dysfunction that may be going on with the brain. If one suffers from AD their brain will show amyloid plaques and neurofibrillary tangles. Alzheimer’s characteristics are the degeneration and death of neurons. When one views a brain scan there may be atrophy of certain region and appear to be shrunken and damaged. According to, Foundations of Behavioral Neuroscience (2014), by Neil R. Carson, “Amyloid plaques are extracellular deposits that consist of a dense core of protein known as β-amyloid, surrounded by degenerating axons and dendrites, along with activated microglia and reactive astrocytes, cells that are involved in destruction of damaged cells” and “Neurofibrillary tangles consist of dying neurons that contain intracellular accumulations of twisted filaments of hyperphosphorylated atu protein”. AD causes excessive amounts of phosphate ions to attach to the strand of the tau protein, which change its molecular structure. In a normal brain, amyloid is found in the extracellular space around neurons, but during Alzheimer’s irregular forms of amyloid clump together and deposit and plaque. Accumulation of plaque can be seen within the cerebral cortex of patients (Carson, 2014). Plaques within the brain disrupt normal cell function, which eventually results in a disruption of communication with neurons, loss of function, and cell death.

Familial history and genetics have shown play roles within Alzheimer’s, studies have shown that numerous mutations of two presenilin genes found on chromosomes 1 and 14 also produce AD (Carson, 2014). One gene that consistently is shown to be associated with onset AD is apolipoprotein E gene (Bekris, Yu, Bird, & Tsuang, 2010). For example, if a parent is a carrier of apolipoprotein E gene it puts their child at higher risk for having Alzheimer’s. Family members with apolipoprotein E comes in many different variations and depending on the variation that one has will determine the percentage of risk they have for developing AD. Females who carry the apolipoprotein E gene are at a higher risk of developing AD versus men who carry the disease (Bekris, et al., 2010). Through studies and by analyzing genetics within individuals it is evident that genetics play a role and may increase risk in developing AD.

The environment that one lives in can influence certain organisms within their body and the body adapts to its external environment. Many environmental factors have been linked in increasing the risk of AD such as, metals, air pollution, pesticides, chronic psychological stress, starvation, hyperthermia/hypothermia, and brain trauma (Wainaina, Chen, & Zhong, 2014). Depending on the environment that one grew up in the brain will adapt and release different hormones from the hypothalamus to better adapt to the situations surrounding them. If an individual suffers from a stroke or a traumatic brain injury (TBI) it increases their chances of having some type of dementia due to the damage that has been done. External factors also affect neuronal mechanisms and activate the autonomic system, cerebrovascular dysfunction, glial activation, metals malmetabolism, kinase/phosphatase imbalance, and much more are the main mechanisms involved in the effects of environmental factors for AD (Wainaina, et al., 2014). If one is predisposed to a higher risk of AD due to genetic factors, by avoiding some environmental factors it could possible decrease their risk of getting AD.

Due to AD being a progressive deteriorating disease there is no cure but only symptomatic treatments. The symptomatic treatments attempt to counterbalance the neurotransmitter disturbance that occurs. Some treatments include, cholinesterase inhibitors for mild to moderate AD and memantine for severe AD (Yinnapoulou & Papageorgiou, 2013). According to Taber’s Medical Dictionary (2017), cholinesterase inhibitors prevent the degradation of the neurotransmitter acetylcholine that is involved in memory and learning and memantine is used to slow the decline in cognitive function. As reviewed previously, a related factor of AD is degradation of acetylcholine and by inhibiting it allows a slower breakdown and slower memory and learning loss. The delirium and constant confusion often can cause frustration and depression on the patients so some antipsychotic and antidepressant treatments can be used along with the other pharmacologic treatments (Yinnapoulou & Papageorgiou, 2013). By decreasing the frustration and depression within the patients is highly beneficial for patient along for the caregivers of that patient. Studies have shown that systolic and diastolic hypertension is associated with cognitive impairment, so by administering antihypertensive it can decrease the incidence of cognitive impairment (Massoud & Gauthier, 2010). Although it is not possible to be completely cured from AD, the treatments that are available can decrease the symptoms and even slow down the progression of AD.

Discussion

This research study has shown that Alzheimer’s is a complex disease that affects the one who suffers with the disease along with the caretakers. When Alzheimer’s initially occurs, the onset could be missed or confused for another disease. The brain structure and function of one who has Alzheimer’s can be distinguished by observing scans for specific biomarkers specifically within the cerebral cortex. Many studies have been conducted and have shown that genetic and environmental factors increase the risk for one to have Alzheimer’s disease. Although for many there is no treatment and pass away a few years after diagnosis the way of living does not always have to be viewed negatively. Through caring for a patient who suffers from Alzheimer’s it is evident that the quality of living in the beginning is not very different but after time more deterioration occurs. Many of those who care for individuals who suffer from Alzheimer’s view it as a burden (Riepe, et al., 2009). Regardless of what a individual may be going through their life should never be considered a burden in my opinion, they did not ask to have the disease. Usually patients have impaired awareness and are unable to make decisions or make right judgments in certain situations (Riepe, et al., 2009). With the patient that was studied it was evident that many times she would forget what was discussed or stated just shortly before. A couple of times the patient got confused and would speak about her family and worrying about when she needs to return to then, she often worried about packing up her items to go “home”, and many times she would forget that she was in California and would be unaware of where she was and how she was going to return to California. The way that I approached responding to her whenever she got confused was just by softly remind her where she was and that she was at home already. I found that by reminding her that her son is coming home would quickly put her to ease. Although the Alzheimer’s is slowly going to get worse, her life that she has and her life that she lived will always remembered for her loved ones and everyone who cares for her would continue to present her with patience and love.

Relevance to the Bible

Alzheimer’s affects ones memory and recall but there is no scientific study where anyone has been able to prove that it affects their relationship with God. However with that being said, in the book of Daniel 5:21 with the story of what happened to King Nebuchadnezzar, “He was driven away from people and given the mind of an animal; he lived with the wild donkeys and ate grass like the ox; and his body was drenched with the dew of heaven, until he acknowledged that the Most High God is sovereign over all kingdoms on earth and sets over them anyone he wishes (NIV).”That verse of scripture one could arguably say that it could prove that though you could loose your mind you can still be mentally aware that God exist. Although if one had a relationship with Christ prior to being affected by Alzheimer’s and after decline in memory one may completely forget Deuteronomy 31:8 states, “ The Lord himself goes before you and will be with you; he will never leave you nor forsake you. Do not be afraid; do not be discouraged (NIV).” With that being said, the Lord knows what is ahead and what he has planned for ones live. If one receives Alzheimer’s the Lord knew previous to the diagnosis and the Lord knew the heart of the individual prior to the memory loss. He will not leave nor forsake one and although there may be no progression of the relationship it will always be there.

Conclusion

Alzheimer’s disease is a progressive degenerative disease that when initially diagnosed can be concerning for what is expected in the future. Progressively the ability to perform daily activities, ability to remember names when introduced to new people, the ability to remember what was done that day, and much more disappears. Diagnosis of the disease involves identifying specific biomarkers through structural and functional imaging, CSF analysis, and PET Scans. Some specific biomarkers that would be viewed include amyloid plaques and neurofibrillary tangles. There are studies that have been conducted to show risk factors that are related to AD along with genetic and environmental factors are related to AD. Although there are no treatments for AD there are certain medications that will slow the degeneration and decrease the dementia. When patients have AD it may be scary to the family and patient due to the unknown, but by remembering the life that the patient lived and by knowing that God is in control can aid the family in coping with Alzheimer’s disease.

References

1. Alzheimer, Alois. (2017). In Venes, D. (Ed.), Taber’s Medical Dictionary. Available from https://nursing.unboundmedicine.com/nursingcentral/view/Tabers-Dictionary/754160/all/Alzheimer_Alois
2. Amoroso, N., Rocca, M. L., Bruno, S., Maggipinto, T., Monaco, A., Bellotti, R., & Tangaro, S. (2018). Multiplex networks for early diagnosis of alzheimers disease. Frontiers in Aging Neuroscience,10. doi:10.3389/fnagi.2018.00365
3. Bekris, L. M., Yu, C., Bird, T. D., & Tsuang, D. W. (2010). Review Article: Genetics of Alzheimer Disease. Journal of Geriatric Psychiatry and Neurology,23(4), 213-227. doi:10.1177/0891988710383571
4. Carlson, N. R. (2014). Foundations of behavioral neuroscience. Boston: Pearson.
5. Holy Bible: New International Version. (2005). Grand Rapids, MI: Zondervan.
6. Massoud, F., & Gauthier, S. (2010). Update on the pharmacological treatment of alzheimer’s disease. Current Neuropharmacology,8(1), 69-80. doi:10.2174/157015910790909520
7. Neugroschl, J., & Wang, S. (2011). Alzheimers disease: diagnosis and treatment across the spectrum of disease severity. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine,78(4), 596-612. doi:10.1002/msj.20279
8. Riepe, M. W., Mittendorf, T., Förstl, H., Frölich, L., Haupt, M., Leidl, R., . . . Schulenburg, M. G. (2009). Quality of life as an outcome in alzheimers disease and other dementias- obstacles and goals. BMC Neurology,9(1). doi:10.1186/1471-2377-9-47
9. Ulep, M. G., Saraon, S. K., & Mclea, S. (2018). Alzheimer disease. The Journal for Nurse Practitioners,14(3), 129-135. doi:10.1016/j.nurpra.2017.10.014
10. Wainaina, M. N., Chen, Z., & Zhong, C. (2014). Environmental factors in the development and progression of late-onset alzheimer’s disease. Neuroscience Bulletin,30(2), 253-270. doi:10.1007/s12264-013-1425-9
11. Yiannopoulou, K. G., & Papageorgiou, S. G. (2012). Current and future treatments for alzheimer’s disease. Therapeutic Advances in Neurological Disorders,6(1), 19-33. doi:10.1177/1756285612461679