Prediction Of Alzheimers Disease
- 1College of Computer and Information Science, Northeastern University, Boston, MA, United States
- 2Department of Neurosurgery, Heilongjiang Province Land Reclamation Headquarters General Hospital, Harbin, China
- 3College of Electronic Engineering, Heilongjiang University, Harbin, China
Alzheimers disease is the most common cause of dementia. It is the fifth leading cause of death among elderly people. With high genetic heritability , finding the diseases causal genes is a crucial step in finding a treatment for AD. Following the International Genomics of Alzheimers Project , many disease-associated genes have been identified however, we do not have enough knowledge about how those disease-associated genes affect gene expression and disease-related pathways. We integrated GWAS summary data from IGAP and five different expression-level data by using the transcriptome-wide association study method and identified 15 disease-causal genes under strict multiple testing , and four genes are newly identified. We identified an additional 29 potential disease-causal genes under a false discovery rate , and 21 of them are newly identified. Many genes we identified are also associated with an autoimmune disorder.
How Is Alzheimers Disease Treated
Medical management can improve quality of life for individuals living with Alzheimers disease and for their caregivers. There is currently no known cure for Alzheimers disease. Treatment addresses several areas:
- Helping people maintain brain health.
- Managing behavioral symptoms.
- Slowing or delaying symptoms of the disease.
Specific Cytokine Signaling In Ad
4.3.1. Pro-inflammatory signaling: TNF-
TNF- is one of the more important proinflammatory cytokines in AD, playing a central role in both initiation and regulation of the cytokine cascade during a response to an inflammatory challenge , . TNF- increases vascular endothelial adhesion molecules, allowing leukocytes and immune cells to migrate into areas under duress .
TNF- exerts its biological functions by binding to two main receptors, TNFR1 and TNFR2 . The overexpression of TNFR1 in mouse hippocampal tissue was necessary for the activation of NFB- and A-induced neuronal apoptosis . Conversely, mice lacking TNFR1 crossed with the APP23 transgenic AD model exhibit reduced plaque deposition, mitigated hippocampal microglial activation, and improved performance in cognitive tasks . High levels of soluble TNFR1 and TNFR2 can be detected in cerebrospinal fluid of patients diagnosed with MCI who progress to AD on a 6-year follow-up .
Increased levels of TNF- have been reported in both the brains and plasma of patients with AD . A can directly stimulate microglia production of TNF- through activation of the transcription factor NFB . In addition, TNF- can increase A burden through the upregulation of -secretase production and increased -secretase activity , .
4.3.2. Pro-inflammatory signaling: IL-1
4.3.3. Pro-inflammatory signaling: IL-6
4.3.4. Pro-inflammatory signaling: NFB
4.3.5. Anti-inflammatory signaling: IL-10
4.3.6. Anti-inflammatory signaling: TGF-1
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New Study Suggests Link Between Autoimmune Diseases And Dementia
01 March 2017
BMJ: Associations between specific autoimmune diseases and subsequent dementia: retrospective record-linkage cohort study, UK
Researchers from the University of Oxford have found that people admitted to hospital for autoimmune diseases are more likely to later be admitted for dementia, supporting the growing association between the immune system and dementia. The study is published today in the BMJ.
Autoimmune diseases are caused by unusual activity of the bodys own immune system. In these diseases the immune system, which usually protects the body from disease, attacks healthy cells in the body by mistake. Previous research has shown that the immune system can behave unusually in dementia and contribute to damage to the brain. The researchers in this study set out to see if there might be a link between the two conditions.
Using hospital admission records in England from 1998 to 2012, the researchers analysed how many people admitted to hospital with an autoimmune disease were later admitted with dementia. During this period, they found that 1.8 million people were admitted with an autoimmune disease and that 81,502 of those people were later admitted for dementia. Compared with a group of 7 million people who went into hospital with other conditions, they found that the people admitted with an autoimmune disease were 20% more like to later be admitted with dementia.
Dr Rosa Sancho, Head of Research at Alzheimers Research UK, said:
Boston Hospital Launches First Human Trial Of Nasal Vaccine For Alzheimers Disease
Researchers hope vaccine could offer a safe and effective way to prevent or slow down progression of AD.
Brigham and Womens Hospital in Boston is set to begin a clinical trial that will test the safety and efficacy of a new vaccine delivered nasally that has been developed to prevent and slow the progression of Alzheimers disease .
The launch is a remarkable milestone, said Howard L. Weiner, MD, codirector of the Ann Romney Center for Neurologic Diseases at the Brigham, in a press release. Over the last two decades, weve amassed preclinical evidence suggesting the potential of this nasal vaccine for AD. If clinical trials in humans show that the vaccine is safe and effective, this could represent a nontoxic treatment for people with Alzheimers, and it could also be given early to help prevent Alzheimers in people at risk, he said.
An estimated 55 million people live with dementia, which is a general term for impaired ability to remember, think or make decisions beyond what might be expected from the usual consequences of growing old, according to the World Health Organization . Alzheimers disease is the most common form of dementia, and may account for 60 to 70 percent of cases.
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Vaccine Designed To Trigger An Immune Response To Fight Disease Process
The vaccine uses the immune modulator Protollin, an intranasal agent thats made of proteins derived from bacteria and has been used safely in humans as an adjuvant for other vaccines. An adjuvant is an ingredient used to make vaccines work better by creating a stronger immune response, according to the Centers for Disease Control and Prevention .
According to researchers, Protollin is designed to activate white blood cells found in the lymph nodes on the sides and back of the neck to go to the brain and trigger clearance of beta amyloid plaques which is one of the hallmarks of AD, according to researchers.
In the brain of someone with Alzheimers, there are abnormal levels of the protein amyloid that clump together and form plaques. These collect between neurons and disrupt cell function, according to the National Institute on Aging. Many experts believe that reducing amyloids would reduce memory loss and cognitive decline.
Is Alzheimers An Autoimmune Disease
Some scientists have recently begun to consider the possibility that Alzheimers disease is, in fact, an autoimmune disease. The Amyloid plaques and neurofibrillary tangles associated with Alzheimers are present to some degree even in healthy brains, and likely perform necessary functions. Our immune system produces antibodies to rid the brain of the plaques when they degrade and become harmful. They also clear the brain of neurons destroyed by the tangles . These researchers suspect that an overproduction of these antibodies may be responsible for the onset of Alzheimers, and may hasten the disease process. In the article A New Look at Brain Inflammation in Alzheimers, Jim Schnabel notes:
Wherever it occurs in the body, chronic inflammation is a double-edged sword. The initial inflammatory response is meant to defend tissues against molecular foes such as viruses, cancerous cells, and harmful amyloid protein aggregates. But the longer it lasts, the more this inflammation stresses and kills healthy, innocent bystander cells. Over timeas in rheumatoid arthritis, for examplethe inflammation can become self-sustaining.
Mr. Schnabel goes on to say that this out-of-control process that causes rheumatoid arthritis is also conspicuous in Alzheimers disease. Instead of just clearing the brain of amyloid plaques the antibodies begin to attack healthy brain cells.
Inflammation and Alzheimers disease
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Alzheimers Immune Response Interactions Revealed
Alzheimers disease is a progressive form of dementia. When toxic proteins like beta-amyloid and tau accumulate in the brain, they form plaques and tangles. Researchers have been focusing on how brain plaque contributes to Alzheimers disease and what role they play in disease progression.
Recent studies have found that beta-amyloid has antiviral and antimicrobial properties, suggesting a potential link between the immune response against infections and the development of Alzheimers disease.
Now researchers at Sloan Kettering Institute have uncovered clues to this potential link by identifying a protein called IFITM3. The protein which is involved in the immune response to pathogens has been discovered to play a key role in the accumulation of beta-amyloid in plaques.
Their findings, The innate immunity protein IFITM3 modulates -secretase in Alzheimers disease, is published in the journal Nature.
Innate immunity is associated with Alzheimers disease, but the influence of immune activation on the production of amyloid- is unknown. Here we identify interferon-induced transmembrane protein 3 as a -secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-, the researchers wrote.
The researchers observed that removing IFITM3 decreased the activity of the gamma-secretase enzyme and, in turn, reduced the number of amyloid plaques that formed in a mouse model of the disease.
Mechanistic Insight From Animal Studies
Collectively, clinical studies of immune regulation in AD in humans suggest that peripheral and central immune systems are dysregulated and dynamically change in a non-linear manner over time, innate and adaptive immune processes are associated with presentation and course of the disease, and crosstalk between the central and peripheral systems is likely. However, how this communication occurs and at what stages it is beneficial or deleterious are unclear. Possible routes of communication between the peripheral and central compartments include circumventricular organs, direct transport across the bloodbrain barrier and stimulation of vagal afferents . Current technology limits in vivo study of the mechanisms behind the clinical findings in humans, but animal studies of immune dysregulation provide critical insight into possible mechanisms of centralperipheral immune crosstalk and its temporal dynamics in AD. Of note, in the discussion of animal models, we have used the common nomenclature APP/PS1 as an umbrella term for several types of double-transgenic APP and PS1 strains.
Peripheral inflammatory markers, neuroinflammation and cognition
Peripheral innate immune cell infiltration
Innate immune mechanisms of AD pathogenesis
Adaptive immune mechanisms of AD pathogenesis
The gut microbiome, amyloidosis and peripheral cell infiltration
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An Overactive Immune Response Could Play A Role In The Onset Of Alzheimers
A research study conducted by researchersat Mount Sinai Hospital in Toronto and published in The Journal of Applied Laboratory Medicine foundevidence that Alzheimers disease may not be a cognitive condition alone. This groundbreaking study may haveuncovered a link between certain autoimmune markers and Alzheimers meaning that this disease may actually be an autoimmune disorder.
In individuals who have autoimmune disorders, the immune system attacks healthy cells instead of foreign or harmful cells within the body. The immune system produces antibodies, or autoantibodies, in its effort to fight healthy cells and tissue. This triggers conditions and illnesses like rheumatoid arthritis, lupus and psoriasis.
Over the course of their study, researchers at Mount Sinai Hospital studied the cerebrospinal fluid of individuals who had Alzheimers or Parkinsons, along with healthy individuals who suffered from headaches. They found evidencethat the individuals with Alzheimers had several specific autoantibodies that were attacking brain proteinspresent in their cerebrospinal fluid. Those autoantibodies actually targeted the bodys very own brain proteins just like antibodies attack healthy tissues in individuals with autoimmune disorders.
Autoantibodies that appeared to target specific brain proteins were notfound in the participants with Parkinsons or headaches. They were only seen in the Alzheimers group.
Loss Of Neuronal Connections And Cell Death
In Alzheimers disease, as neurons are injured and die throughout the brain, connections between networks of neurons may break down, and many brain regions begin to shrink. By the final stages of Alzheimers, this processcalled brain atrophyis widespread, causing significant loss of brain volume.
Learn more about Alzheimer’s disease from MedlinePlus.
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Vascular Contributions To Alzheimers Disease
People with dementia seldom have only Alzheimers-related changes in their brains. Any number of vascular issuesproblems that affect blood vessels, such as beta-amyloid deposits in brain arteries, atherosclerosis , and mini-strokesmay also be at play.
Vascular problems may lead to reduced blood flow and oxygen to the brain, as well as a breakdown of the blood-brain barrier, which usually protects the brain from harmful agents while allowing in glucose and other necessary factors. In a person with Alzheimers, a faulty blood-brain barrier prevents glucose from reaching the brain and prevents the clearing away of toxic beta-amyloid and tau proteins. This results in inflammation, which adds to vascular problems in the brain. Because it appears that Alzheimers is both a cause and consequence of vascular problems in the brain, researchers are seeking interventions to disrupt this complicated and destructive cycle.
What Is Alzheimers Disease
- Alzheimers disease is the most common type of dementia.
- It is a progressive disease beginning with mild memory loss and possibly leading to loss of the ability to carry on a conversation and respond to the environment.
- Alzheimers disease involves parts of the brain that control thought, memory, and language.
- It can seriously affect a persons ability to carry out daily activities.
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From The Amyloid Hypothesis To The Autoimmune Hypothesis Of Alzheimers Disease
Diagnosis You currently have no access to view or download this content. Please log in with your institutional or personal account if you should have access to this content through either of these. Showing a limited preview of this publication:Corresponding author: Eleftherios P. Diamandis,
Research funding: None declared.
All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Not applicable.
Ethical approval: Not applicable.
Autoimmune Disorders Linked To An Increased Risk Of Dementia
Alzheimers disease: is chronic inflammation to blame?
Zephyr/Science Photo Library
People who have autoimmune disorders may be 20 per cent more likely to develop dementia. Thats according to an analysis of 1.8 million hospital cases in England.
Based on data collected between 1999 and 2012, the studys findings add to mounting evidence that chronic inflammation a common feature of many autoimmune disorders may be a trigger of dementia and Alzheimers disease.
Previous studies have found that if infections or chronic inflammatory diseases including diabetes have pushed a persons immune system into overdrive, this can lead to immune cells attacking healthy brain tissue.
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Relevance Of Inflammation And Risk Factors For Ad
A number of risk factors have been identified that confer greater risk for developing AD. These include age , cardiovascular changes, traumatic brain injury , , , , and metabolic disorders such as diabetes. Interestingly, each of the aforementioned risk factors also is associated with an immune response, including in the brain. This has led to hypotheses that elevated inflammation and/or inflammatory signaling may be increasing the risk . As mechanisms are numerous, we have explained one example below in more detail.
4.4.1. Diabetes mellitus , AD, and inflammation
In addition to the aforementioned pathological hallmarks, AD is also characterized by abnormal metabolic changes. Decreased cerebral glucose metabolism is now considered a distinct characteristic of the AD brain , , . The association between T2DM and AD is well established, along with other neurodegenerative diseases, including vascular dementia and PD , , . One of the first key studies, the 1999 Rotterdam Study, found that type-2 diabetes mellitus could double the risk for the development of AD . Since that seminal Rotterdam Study, numerous studies have since substantiated this finding that T2DM nearly doubles the risk for AD , , including that T2DM serves as a useful predictor for the development of AD in a 12-year longitudinal study , .
4.4.2. APOE and inflammation
How Many Americans Have Alzheimers Disease
Estimates vary, but experts suggest that more than 6 million Americans age 65 and older may have Alzheimers. Many more under age 65 also have the disease. Unless Alzheimer’s can be effectively treated or prevented, the number of people with it will increase significantly if current population trends continue. This is because increasing age is the most important known risk factor for Alzheimers disease.
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Association With Autoimmune Diseases
Complex disease such as AD, often shares common pathways or causal genes with other diseases . For instance, TOMM40 is a shared disease-associated gene between AD and Type II diabetes . Recent studies showing autoimmune diseases have closed relation with AD . Among all the genes we identified through TWAS method, eight of them are related to autoimmune diseases.
As shown in Figure 3, PICALM, PVRL2, PVR, and CLU have shown to be related to systemic, an autoimmune disease characterized by vascular injury and debilitating tissue fibrosis . CR1 and CLU gene are related to thymus function which could potentially cause an autoimmune disorder . MLH3 and BIN1 gene have shown to be associated with Lupus, another severe autoimmune disease . Although with existing result, we dont have enough evidence to prove these genes are both disease causal genes for AD and autoimmune disease, further research from areas such as metabolomics and proteomics is needed to study the disease association between AD and autoimmune diseases .
Figure 3. Shared disease associated gene between Alzheimers disease and Autoimmune diseases.
Is Alzheimer’s An Autoimmune Disease
Synopsis: Brain levels of the lipid ceramide are high in Alzheimer’s disease, and now scientists have found increased levels of an antibody to the lipid in their disease model.. Autoimmune diseases arise from an abnormal immune response of the body against substances and tissues normally present in the body . One in nine individuals over age 65 has Alzheimer’s, and nearly two-thirds of Americans with it are women, possibly because women tend to live longer, according to the Alzheimer’s Association.
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