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Genes Related To Alzheimer’s Disease

Biological Function Enrichment Analysis Of Alzgset

Landmark Alzheimer’s study finds dozens of genes connected to disease

Functional enrichment analysis revealed a more detailed biological function spectrum of these AD-related genes . Among the GO terms overrepresented in Alzgset, those related to lipid and/or lipoprotein-related processes, drug reactions, neural development, or synaptic transmission were included. GO terms associated with drug reactions and metabolic processes were overrepresented. These results were in line with previous findings that complicated correlations existed between the pathophysiological state of AD and drug abuse . Of significance, top-ranked terms included some lipid/lipoprotein-related processes, including phospholipid efflux, reverse cholesterol transport, cholesterol homeostasis, and lipoprotein metabolic processes. Biological process terms related to synaptic transmission , dopamine metabolism , and other neural functions were also enriched. Meanwhile, GO terms related to immunological function were overrepresented. The diversity in the function of AD-related genes demonstrated the complexity of the disease.

Quality Control And Imputation

A standard quality control was performed on variants and samples from all datasets individually. The samples were then imputed with the TOPMed reference panel,. The Haplotype Reference Consortium panel was also used for some datasets . For the UKBB, we used the provided imputed data generated from a combination of the 1000 Genomes, HRC and UK10K reference panels .

Biochemical Pathway Enriched In Alzgset

Detecting the biological pathways overrepresented among Alzgset may provide useful information about the pathogenic molecular mechanism underlying AD. For Alzgset, 68 enriched pathways were identified . Among them, several pathways related to immune processes were included , consistent with previous studies . Also, neurotransmitter signaling-related pathways were identified, such as cholinergic synapse, dopaminergic synapse, serotonergic synapse, and so forth. Additionally, in the Alzgset enriched pathway list, there were some pathways related to cell growth and/or survival, including neurotrophin signaling, PI3K-Akt signaling, mTOR signaling, Notch signaling, and so forth, which are vital for cell growth/survival state of neurons in the process of AD . Moreover, metabolism-related pathways, consisting of drug metabolism , glutathione metabolism, and metabolism of xenobiotics by cytochrome P450, were also significantly enriched, indicating that related metabolism processes were involved in the etiology and development processes of AD. What is more, the pathway of the intestinal immune network for IgA production was enriched, which might suggest a connection between AD and the intestinal microbiota . Furthermore, pathways involved in osteoclast differentiation and adipocytokine signaling were also detected, complying with prior studies .

Table 1 Pathways enriched in Alzgseta

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Dementia And Down Syndrome

People with Down syndrome are born with an extra piece of DNA. This means they also have an extra copy of the APP gene. This leads to the build-up of amyloid plaques in the brain, which play a role in the development of Alzheimers disease. While not everyone with Down syndrome will go on to develop symptoms of Alzheimers, most people with the condition over the age of 40 will have amyloid build-up. It is estimated that about 50% of people with Down syndrome develop symptoms like memory loss, usually in their 50s and 60s.

To find out more about Down syndrome and dementia you can contact Downs Syndrome Association helpline on 0333 1212 300 or visit their website www.downs-syndrome.org.uk.

Definition Of Associated Loci

Genetics of Alzheimer

A region of ±500kb was defined around each variant with a stage I P value below 1×105. These regions were then merged to define nonoverlapping regions. The region corresponding to the APOE locus was excluded. We then used the PLINK clumping procedure to define independent hits in each region. An iterative clumping procedure was applied to all variants with a stage I P value below 1×105, starting with the variant with the lowest P value . Variants with a stage I P value below 1×105, located within 500kb of this index variant and in LD with the index variant were assigned to the index variants clump. The clumping procedure was then applied until all the variants had been clumped. LD in the EADB-TOPMed dataset was computed using high-quality imputed genotypes.

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Chapter 9genes To Remember: The Growing Burden Of Alzheimers Disease

Hayworth became instantly recognizable as one of the most glamorous screen stars of her era. She made a series of musicals with Fred Astaire and Gene Kelly, as well as erotically charged films such as Blood and Sand, Gilda, and The Lady from Shanghai. A photograph of her kneeling on a bed in a negligee of satin and lace that appeared in Life magazine in 1941sent to millions of American soldierswas rivaled in popularity only by the one of Betty Grable in a white bathing suit. When Orson Welles saw the photograph while filming in South America, he told his friends that upon his return to the United States he would marry Hayworth, even though the director of Citizen Kane had not yet set eyes on the actress in person. And marry her he did.

Likely a result of her painful childhood, Hayworth suffered through difficult relationships with her five husbands and her many lovers, one of whom was the aviator and tycoon Howard Hughes. Outwardly the femme fatale, inwardly Hayworth remained a vulnerable little girl. Referring to her role as the eponymous sexual temptress Gilda in the sizzling film noir costarring Glenn Ford, she remarked, Men go to bed with Gilda, but wake up with me.

What is your name? he asked her.

Auguste.

Oh, you were so nice at our house.

Are you married?

Ah, I am so confused.

Another risk factor is also clear: ones parents. People with a parent or sibling with the disease are two to three times more likely to develop it themselves.

A42 Peptide Phagocytosis Assay And Flow Cytometry

Amyloid Beta 1-42 peptide conjugated to HiLyte 488 was initially resuspended and fibrilized as reported in,. Briefly, A42 was resuspend in 10 nM NaOH and then the concentration was adjusted to 1 mg/ml using PBS. Resuspended A42 was frozen at 20 °C until use. A42 was thawed and incubated at 37 °C overnight to fibrilize prior to the phagocytosis assay. A42 was added to culture with either young or aged enriched microglia. Duration of culture is noted in each figure. After microglial enrichment and/or phagocytosis assay, samples were stained for flow cytometry using a fixable LiveDead viability stain and surface stained with the following antibodies: anti-CD45 , -CD11b , and -TREM2 . A42 uptake was evidenced by the presence of HiLyte 488 in microglia and was quantified via flow cytometry. Data was acquired on a FACSCanto flow cytometer from BD Biosciences and analyzed using FlowJo software or an imaging flow cytometer .

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The Genetics Of Alzheimer’s Disease

In order to understand the genetics of Alzheimer’s disease , it is first necessary to understand the basics of genetics. Most cells of the body have 46 chromosomes, grouped into 23 pairs. One member of each chromosome pair is inherited from each parent. Each chromosome is composed of deoxyribonucleic acid , the genetic material that provides instructions for how the body grows and functions . Genes are segments of DNA found on each of our chromosomes. Each gene provides the instructions for a specific protein with a specific function. Certain variations within the genes may lead to differences in individual traits . Other variations in gene sequence may be disease-causing. When a gene variant causes disease, it is often referred to as a mutation.

Many studies have been carried out to identify gene variants associated with an increased risk for developing AD. Two different types of variants have been identified: disease-causing mutations in individuals with early-onset familial AD and susceptibility variants in individuals with late-onset AD. Those with early-onset familial AD are likely to develop AD before the age of 65 and are likely to have family members who also have early-onset AD. These individuals account for less than 5% of all AD cases. Those with late-onset AD account for the vast majority of AD cases. Those with late-onset AD may or may not have similarly affected family members.

Functional Enrichment Analysis Of Genes Related To Ad

What Role Do Genetics Play in Alzheimers? – On Our Mind

WebGestalt and ToppGene were utilized to detect the biological themes of the AD-related genes. As a web-based bioinformation-mining platform, WebGestalt integrates information from multiple resources to determine the biological themes, including identifying the overrepresented Gene Ontology terms, amid the candidate gene listing. In this study, only the GO biological process terms with false discovery rate value smaller than 0.05 were kept as the significantly enriched ones. ToppGene was used to identify and analyze the enriched biological pathways in the input genes. Pathways with FDR < 0.05 were considered to be significantly enriched.

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Compilation Of The Human Proteinprotein Interaction Network

To explore the correlation and interaction among the AD-related genes, we compiled a comprehensive proteinprotein interaction network, based on which the protein network topological properties of the gene set related to AD were calculated and analyzed. Briefly, the human proteinprotein interaction data were obtained from the Protein Interaction Network Analysis database by pooling and curating the unique physical interaction information from six main public protein interaction databases: BioGRID, IntAct, DIP, MINT, MIPS/MPact, and HPRD. In the meantime, another interactome for that contained 141,296 edges among 13,460 nodes , consisting of metabolic pathway-related interactions, regulatory and proteinprotein interactions, and interaction pairs for kinase and specific substrate, was selected as an additional source of interactome data. After merging the two interactome data by excluding the self-interacting and redundant pairs, the proteins in the list were mapped onto Entrez protein-coding genes for via the Uniprot ID mapping tool . Finally, we compiled a relatively comprehensive human physical interactome, which comprised 16,022 genes/proteins and 228,122 interactions .

The Genetics Of Alzheimers Disease

Robert C. BarberAcademic Editor: Received

Abstract

Alzheimers disease is a progressive, neurodegenerative disease that represents a growing global health crisis. Two major forms of the disease exist: early onset and late onset . Early onset Alzheimers is rare, accounting for less than 5% of disease burden. It is inherited in Mendelian dominant fashion and is caused by mutations in three genes . Late onset Alzheimers is common among individuals over 65 years of age. Heritability of this form of the disease is high , but the etiology is driven by a combination of genetic and environmental factors. A large number of genes have been implicated in the development of late onset Alzheimers. Examples that have been confirmed by multiple studies include ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A4A/MS4A4E/MS4A6E, PICALM, and SORL1. Despite tremendous progress over the past three decades, roughly half of the heritability for the late onset of the disease remains unidentified. Finding the remaining genetic factors that contribute to the development of late onset Alzheimers disease holds the potential to provide novel targets for treatment and prevention, leading to the development of effective strategies to combat this devastating disease.

1. Introduction

2. Familial Alzheimers Disease

To date, more than 160 highly penetrant but rare mutations have been described in three genes that cause familial Alzheimers disease . Each of these genes will be discussed later.

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Keep Blood Pressure And Cholesterol Levels In Check

Your heart beats roughly 115,000 times a day, and with every beat, it sends about 20% of the oxygen in your body to your brain.

High blood pressure can weaken your heart muscle, and is one of the leading causes of strokes. Ideally, your blood pressure should be no higher than 120/80.

Cholesterol is critical to your brain and nervous system health, too. The American Heart Association recommends getting your cholesterol levels measured every four to six years.

Health Environmental And Lifestyle Factors That May Contribute To Alzheimer’s Disease

How The Ageing Gene Functions Step by Step, Genes and Ageing Guidance ...

Research suggests that a host of factors beyond genetics may play a role in the development and course of Alzheimer’s disease. There is a great deal of interest, for example, in the relationship between cognitive decline and vascular conditions such as heart disease, stroke, and high blood pressure, as well as metabolic diseases, such as diabetes and obesity. Ongoing research will help us understand whether and how reducing risk factors for these conditions may also reduce the risk of Alzheimer’s.

A nutritious diet, physical activity, social engagement, sleep, and mentally stimulating pursuits have all been associated with helping people stay healthy as they age. These factors might also help reduce the risk of cognitive decline and Alzheimer’s disease. Clinical trials are testing some of these possibilities.

Early-life factors may also play a role. For example, studies have linked higher levels of education with a decreased risk of dementia. There are also differences in dementia risk among racial groups and sexesall of which are being studied to better understand the causes of Alzheimers disease and to develop effective treatments and preventions for all people.

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How Can Genes Cause Disease

Genes often play a role in the development of diseases. This can happen in two main ways.

Single-gene diseases Single-gene diseases.

Sometimes, a gene changes and this causes a disease. This is known as a single-gene disease because it is caused by a change in just one gene. Single-gene diseases are often serious, but they are rare.

It is possible to directly inherit a single-gene disease. This means that if a child inherits the same changed gene that a parent has, they are very likely in some cases almost certain to develop the same disease.

Complex or multiple-gene diseases Complex or multiple-gene diseases.

Complex diseases are less straightforward. They develop through the interaction between several different factors. These are known as risk factors for that disease. They include:

  • the persons environment or lifestyle for example, their diet and whether they smoke or not
  • multiple gene variants known as risk variants because they increase the persons risk of developing the disease.

It isnt possible to inherit a complex disease in the same way as a single-gene disease. This is because complex diseases are caused by multiple factors acting together.

However, a person with a family history of a complex disease will often have an increased chance of developing it. This is because they are likely to share risk factors with other birth relatives. Despite this increased chance, the person still might never develop the disease.

Expression In Various Cell Types

The expression of genes was assigned to specific cell classes of the adult brain, as described previously. Briefly, middle temporal gyrus single-nucleus transcriptomes from the Allen Brain Atlas dataset were used to annotate and select six main cell classes using Seurat 3.1.1 : glutamatergic neurons, GABAergic neurons, astrocytes, oligodendrocytes, microglia and endothelial cells. Enrichment analyses were performed by using the mean gene expression per nucleus for each cell type relative to the total expression summed across cell types as a quantitative covariate in a MAGMA gene property analysis.

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Identification Of Core Protein Glycosylation

Figure 1. Identification of core protein glycosylation-related genes in Alzheimers disease . Weighted gene co-expression network analysis analysis was performed on the training set, resulting in a cluster dendrogram of co-expressed genes. The soft threshold of a scale-free network. The module-character relationship was constructed, with each module containing the corresponding correlation and P-value. Transcription factors that regulate the expression of genes are represented by the MElightgreen module and their interactions. Differentially expressed PGRGs between the training set and control samples. The intersection of genes represented by the differentially expressed PGRGs and MElightgreen modules between the training set and control samples. The co-expression relationship of 7 core PGRGs.

Future Insights Into Ad Genetics: From Gwass To Next

How genes are related to dementia risk – Alzheimer’s Research UK

Since AD is a genetically heterogeneous disorder, GWASs have been performed for identification of novel disease risk-factor loci. Several genes and mutations have been tested to find association with disease-related phenotypes, such as changes in biomarker levels and/or neuropathology.189 Sanger sequencing is a widely used technology, but it has limitations in terms of cost, speed, and efficacy. High-throughput or NGS technologies are recent hot topics in genomic research of animals and humans. NGS technologies included sequencing by synthesis, ligation, or hybridization single-molecule sequencing nanopore sequencing and colony sequencing. NGS technologies provide fast and cost-effective sequencing strategies that can be used in various genetic applications for example, in high-throughput mutation detection, small RNA detection, or the monitoring of epigenetic changes. The most well-known NGS technologies have been developed by Illumina , Helicos BioSciences , ABI/SOLiD, and 454 Life Sciences and use a single-molecule template for mutation detection with cloning-free approaches.190,191

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Analysis Of Crosstalks Among Pathways

We further built crosstalks among pathways to investigate interlinks and interactions of the enriched pathways. To measure the overlap between two pathways, the overlap coefficient and the Jaccard coefficient were calculated using the corresponding formulas:

in which A and B are the lists of genes of the two examined pathways. Briefly, the following procedure was adopted to construct the pathway crosstalks:

  • Only pathways with FDR < 0.05 were kept for crosstalk analysis. Meanwhile, pathways with five or fewer candidate genes were discarded because pathways with too few candidate genes might present few or biased connections with other pathways.

  • Counting the common candidate genes of each pathway pairthose pathway pairs with less than two overlapped genes were removed.

  • Constructing the pathway crosstalk with Cytoscape software .

  • Continuously Learn New Skills

    Maintaining a strong memory is not all about brain games like Sudoku, Wordle and crossword puzzles.

    Learning skills and acquiring information are much more effective ways to make new connections in the brain. The more connections you make, the more likely you are to retain and even enhance your memory.

    When you think about learning something new, approach it the way you would with fitness training. You want to work out different muscles on different days. The same goes for the brain.

    Over the course of this week, try cross-training your brain by mixing mental activities and physical learning activities .

    , PhD, is a brain health expert and author of “The Age-Proof Brain: New Strategies to Improve Memory, Protect Immunity, and Fight Off Dementia.” He earned both his PhD in Biological Chemistry and his Bachelor of Science in Molecular, Cellular, and Developmental Biology from UCLA, and has conducted research on genetics, cancer biology and neuroscience. Follow him on and .

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