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Research Paper – Structure, Examples and Writing Guide

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Research Paper

Definition:

Research Paper is a written document that presents the author’s original research, analysis, and interpretation of a specific topic or issue.

It is typically based on Empirical Evidence, and may involve qualitative or quantitative research methods, or a combination of both. The purpose of a research paper is to contribute new knowledge or insights to a particular field of study, and to demonstrate the author’s understanding of the existing literature and theories related to the topic.

Structure of Research Paper

The structure of a research paper typically follows a standard format, consisting of several sections that convey specific information about the research study. The following is a detailed explanation of the structure of a research paper:

The title page contains the title of the paper, the name(s) of the author(s), and the affiliation(s) of the author(s). It also includes the date of submission and possibly, the name of the journal or conference where the paper is to be published.

The abstract is a brief summary of the research paper, typically ranging from 100 to 250 words. It should include the research question, the methods used, the key findings, and the implications of the results. The abstract should be written in a concise and clear manner to allow readers to quickly grasp the essence of the research.

Introduction

The introduction section of a research paper provides background information about the research problem, the research question, and the research objectives. It also outlines the significance of the research, the research gap that it aims to fill, and the approach taken to address the research question. Finally, the introduction section ends with a clear statement of the research hypothesis or research question.

Literature Review

The literature review section of a research paper provides an overview of the existing literature on the topic of study. It includes a critical analysis and synthesis of the literature, highlighting the key concepts, themes, and debates. The literature review should also demonstrate the research gap and how the current study seeks to address it.

The methods section of a research paper describes the research design, the sample selection, the data collection and analysis procedures, and the statistical methods used to analyze the data. This section should provide sufficient detail for other researchers to replicate the study.

The results section presents the findings of the research, using tables, graphs, and figures to illustrate the data. The findings should be presented in a clear and concise manner, with reference to the research question and hypothesis.

The discussion section of a research paper interprets the findings and discusses their implications for the research question, the literature review, and the field of study. It should also address the limitations of the study and suggest future research directions.

The conclusion section summarizes the main findings of the study, restates the research question and hypothesis, and provides a final reflection on the significance of the research.

The references section provides a list of all the sources cited in the paper, following a specific citation style such as APA, MLA or Chicago.

How to Write Research Paper

You can write Research Paper by the following guide:

• Choose a Topic: The first step is to select a topic that interests you and is relevant to your field of study. Brainstorm ideas and narrow down to a research question that is specific and researchable.
• Conduct a Literature Review: The literature review helps you identify the gap in the existing research and provides a basis for your research question. It also helps you to develop a theoretical framework and research hypothesis.
• Develop a Thesis Statement : The thesis statement is the main argument of your research paper. It should be clear, concise and specific to your research question.
• Plan your Research: Develop a research plan that outlines the methods, data sources, and data analysis procedures. This will help you to collect and analyze data effectively.
• Collect and Analyze Data: Collect data using various methods such as surveys, interviews, observations, or experiments. Analyze data using statistical tools or other qualitative methods.
• Organize your Paper : Organize your paper into sections such as Introduction, Literature Review, Methods, Results, Discussion, and Conclusion. Ensure that each section is coherent and follows a logical flow.
• Write your Paper : Start by writing the introduction, followed by the literature review, methods, results, discussion, and conclusion. Ensure that your writing is clear, concise, and follows the required formatting and citation styles.
• Edit and Proofread your Paper: Review your paper for grammar and spelling errors, and ensure that it is well-structured and easy to read. Ask someone else to review your paper to get feedback and suggestions for improvement.
• Cite your Sources: Ensure that you properly cite all sources used in your research paper. This is essential for giving credit to the original authors and avoiding plagiarism.

Research Paper Example

Note : The below example research paper is for illustrative purposes only and is not an actual research paper. Actual research papers may have different structures, contents, and formats depending on the field of study, research question, data collection and analysis methods, and other factors. Students should always consult with their professors or supervisors for specific guidelines and expectations for their research papers.

Research Paper Example sample for Students:

Title: The Impact of Social Media on Mental Health among Young Adults

Abstract: This study aims to investigate the impact of social media use on the mental health of young adults. A literature review was conducted to examine the existing research on the topic. A survey was then administered to 200 university students to collect data on their social media use, mental health status, and perceived impact of social media on their mental health. The results showed that social media use is positively associated with depression, anxiety, and stress. The study also found that social comparison, cyberbullying, and FOMO (Fear of Missing Out) are significant predictors of mental health problems among young adults.

Introduction: Social media has become an integral part of modern life, particularly among young adults. While social media has many benefits, including increased communication and social connectivity, it has also been associated with negative outcomes, such as addiction, cyberbullying, and mental health problems. This study aims to investigate the impact of social media use on the mental health of young adults.

Literature Review: The literature review highlights the existing research on the impact of social media use on mental health. The review shows that social media use is associated with depression, anxiety, stress, and other mental health problems. The review also identifies the factors that contribute to the negative impact of social media, including social comparison, cyberbullying, and FOMO.

Methods : A survey was administered to 200 university students to collect data on their social media use, mental health status, and perceived impact of social media on their mental health. The survey included questions on social media use, mental health status (measured using the DASS-21), and perceived impact of social media on their mental health. Data were analyzed using descriptive statistics and regression analysis.

Results : The results showed that social media use is positively associated with depression, anxiety, and stress. The study also found that social comparison, cyberbullying, and FOMO are significant predictors of mental health problems among young adults.

Discussion : The study’s findings suggest that social media use has a negative impact on the mental health of young adults. The study highlights the need for interventions that address the factors contributing to the negative impact of social media, such as social comparison, cyberbullying, and FOMO.

Conclusion : In conclusion, social media use has a significant impact on the mental health of young adults. The study’s findings underscore the need for interventions that promote healthy social media use and address the negative outcomes associated with social media use. Future research can explore the effectiveness of interventions aimed at reducing the negative impact of social media on mental health. Additionally, longitudinal studies can investigate the long-term effects of social media use on mental health.

Limitations : The study has some limitations, including the use of self-report measures and a cross-sectional design. The use of self-report measures may result in biased responses, and a cross-sectional design limits the ability to establish causality.

Implications: The study’s findings have implications for mental health professionals, educators, and policymakers. Mental health professionals can use the findings to develop interventions that address the negative impact of social media use on mental health. Educators can incorporate social media literacy into their curriculum to promote healthy social media use among young adults. Policymakers can use the findings to develop policies that protect young adults from the negative outcomes associated with social media use.

References :

• Twenge, J. M., & Campbell, W. K. (2019). Associations between screen time and lower psychological well-being among children and adolescents: Evidence from a population-based study. Preventive medicine reports, 15, 100918.
• Primack, B. A., Shensa, A., Escobar-Viera, C. G., Barrett, E. L., Sidani, J. E., Colditz, J. B., … & James, A. E. (2017). Use of multiple social media platforms and symptoms of depression and anxiety: A nationally-representative study among US young adults. Computers in Human Behavior, 69, 1-9.
• Van der Meer, T. G., & Verhoeven, J. W. (2017). Social media and its impact on academic performance of students. Journal of Information Technology Education: Research, 16, 383-398.

Appendix : The survey used in this study is provided below.

Social Media and Mental Health Survey

• How often do you use social media per day?
• Less than 30 minutes
• 30 minutes to 1 hour
• 1 to 2 hours
• 2 to 4 hours
• More than 4 hours
• Which social media platforms do you use?
• Others (Please specify)
• How often do you experience the following on social media?
• Social comparison (comparing yourself to others)
• Cyberbullying
• Fear of Missing Out (FOMO)
• Have you ever experienced any of the following mental health problems in the past month?
• Do you think social media use has a positive or negative impact on your mental health?
• Very positive
• Somewhat positive
• Somewhat negative
• Very negative
• In your opinion, which factors contribute to the negative impact of social media on mental health?
• Social comparison
• In your opinion, what interventions could be effective in reducing the negative impact of social media on mental health?
• Education on healthy social media use
• Counseling for mental health problems caused by social media
• Social media detox programs
• Regulation of social media use

Thank you for your participation!

Applications of Research Paper

Research papers have several applications in various fields, including:

• Advancing knowledge: Research papers contribute to the advancement of knowledge by generating new insights, theories, and findings that can inform future research and practice. They help to answer important questions, clarify existing knowledge, and identify areas that require further investigation.
• Informing policy: Research papers can inform policy decisions by providing evidence-based recommendations for policymakers. They can help to identify gaps in current policies, evaluate the effectiveness of interventions, and inform the development of new policies and regulations.
• Improving practice: Research papers can improve practice by providing evidence-based guidance for professionals in various fields, including medicine, education, business, and psychology. They can inform the development of best practices, guidelines, and standards of care that can improve outcomes for individuals and organizations.
• Educating students : Research papers are often used as teaching tools in universities and colleges to educate students about research methods, data analysis, and academic writing. They help students to develop critical thinking skills, research skills, and communication skills that are essential for success in many careers.
• Fostering collaboration: Research papers can foster collaboration among researchers, practitioners, and policymakers by providing a platform for sharing knowledge and ideas. They can facilitate interdisciplinary collaborations and partnerships that can lead to innovative solutions to complex problems.

When to Write Research Paper

Research papers are typically written when a person has completed a research project or when they have conducted a study and have obtained data or findings that they want to share with the academic or professional community. Research papers are usually written in academic settings, such as universities, but they can also be written in professional settings, such as research organizations, government agencies, or private companies.

Here are some common situations where a person might need to write a research paper:

• For academic purposes: Students in universities and colleges are often required to write research papers as part of their coursework, particularly in the social sciences, natural sciences, and humanities. Writing research papers helps students to develop research skills, critical thinking skills, and academic writing skills.
• For publication: Researchers often write research papers to publish their findings in academic journals or to present their work at academic conferences. Publishing research papers is an important way to disseminate research findings to the academic community and to establish oneself as an expert in a particular field.
• To inform policy or practice : Researchers may write research papers to inform policy decisions or to improve practice in various fields. Research findings can be used to inform the development of policies, guidelines, and best practices that can improve outcomes for individuals and organizations.
• To share new insights or ideas: Researchers may write research papers to share new insights or ideas with the academic or professional community. They may present new theories, propose new research methods, or challenge existing paradigms in their field.

Purpose of Research Paper

The purpose of a research paper is to present the results of a study or investigation in a clear, concise, and structured manner. Research papers are written to communicate new knowledge, ideas, or findings to a specific audience, such as researchers, scholars, practitioners, or policymakers. The primary purposes of a research paper are:

• To contribute to the body of knowledge : Research papers aim to add new knowledge or insights to a particular field or discipline. They do this by reporting the results of empirical studies, reviewing and synthesizing existing literature, proposing new theories, or providing new perspectives on a topic.
• To inform or persuade: Research papers are written to inform or persuade the reader about a particular issue, topic, or phenomenon. They present evidence and arguments to support their claims and seek to persuade the reader of the validity of their findings or recommendations.
• To advance the field: Research papers seek to advance the field or discipline by identifying gaps in knowledge, proposing new research questions or approaches, or challenging existing assumptions or paradigms. They aim to contribute to ongoing debates and discussions within a field and to stimulate further research and inquiry.
• To demonstrate research skills: Research papers demonstrate the author’s research skills, including their ability to design and conduct a study, collect and analyze data, and interpret and communicate findings. They also demonstrate the author’s ability to critically evaluate existing literature, synthesize information from multiple sources, and write in a clear and structured manner.

Characteristics of Research Paper

Research papers have several characteristics that distinguish them from other forms of academic or professional writing. Here are some common characteristics of research papers:

• Evidence-based: Research papers are based on empirical evidence, which is collected through rigorous research methods such as experiments, surveys, observations, or interviews. They rely on objective data and facts to support their claims and conclusions.
• Structured and organized: Research papers have a clear and logical structure, with sections such as introduction, literature review, methods, results, discussion, and conclusion. They are organized in a way that helps the reader to follow the argument and understand the findings.
• Formal and objective: Research papers are written in a formal and objective tone, with an emphasis on clarity, precision, and accuracy. They avoid subjective language or personal opinions and instead rely on objective data and analysis to support their arguments.
• Citations and references: Research papers include citations and references to acknowledge the sources of information and ideas used in the paper. They use a specific citation style, such as APA, MLA, or Chicago, to ensure consistency and accuracy.
• Peer-reviewed: Research papers are often peer-reviewed, which means they are evaluated by other experts in the field before they are published. Peer-review ensures that the research is of high quality, meets ethical standards, and contributes to the advancement of knowledge in the field.
• Objective and unbiased: Research papers strive to be objective and unbiased in their presentation of the findings. They avoid personal biases or preconceptions and instead rely on the data and analysis to draw conclusions.

Advantages of Research Paper

Research papers have many advantages, both for the individual researcher and for the broader academic and professional community. Here are some advantages of research papers:

• Contribution to knowledge: Research papers contribute to the body of knowledge in a particular field or discipline. They add new information, insights, and perspectives to existing literature and help advance the understanding of a particular phenomenon or issue.
• Opportunity for intellectual growth: Research papers provide an opportunity for intellectual growth for the researcher. They require critical thinking, problem-solving, and creativity, which can help develop the researcher’s skills and knowledge.
• Career advancement: Research papers can help advance the researcher’s career by demonstrating their expertise and contributions to the field. They can also lead to new research opportunities, collaborations, and funding.
• Academic recognition: Research papers can lead to academic recognition in the form of awards, grants, or invitations to speak at conferences or events. They can also contribute to the researcher’s reputation and standing in the field.
• Impact on policy and practice: Research papers can have a significant impact on policy and practice. They can inform policy decisions, guide practice, and lead to changes in laws, regulations, or procedures.
• Advancement of society: Research papers can contribute to the advancement of society by addressing important issues, identifying solutions to problems, and promoting social justice and equality.

Limitations of Research Paper

Research papers also have some limitations that should be considered when interpreting their findings or implications. Here are some common limitations of research papers:

• Limited generalizability: Research findings may not be generalizable to other populations, settings, or contexts. Studies often use specific samples or conditions that may not reflect the broader population or real-world situations.
• Potential for bias : Research papers may be biased due to factors such as sample selection, measurement errors, or researcher biases. It is important to evaluate the quality of the research design and methods used to ensure that the findings are valid and reliable.
• Ethical concerns: Research papers may raise ethical concerns, such as the use of vulnerable populations or invasive procedures. Researchers must adhere to ethical guidelines and obtain informed consent from participants to ensure that the research is conducted in a responsible and respectful manner.
• Limitations of methodology: Research papers may be limited by the methodology used to collect and analyze data. For example, certain research methods may not capture the complexity or nuance of a particular phenomenon, or may not be appropriate for certain research questions.
• Publication bias: Research papers may be subject to publication bias, where positive or significant findings are more likely to be published than negative or non-significant findings. This can skew the overall findings of a particular area of research.
• Time and resource constraints: Research papers may be limited by time and resource constraints, which can affect the quality and scope of the research. Researchers may not have access to certain data or resources, or may be unable to conduct long-term studies due to practical limitations.

About the author

Muhammad Hassan

Researcher, Academic Writer, Web developer

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Elements of a Research Essay

Stephanie Ojeda Ponce

This section is an overview of the elements or parts of a research essay. Scholarly essays are long. There are several different styles of research essays and each have their own structure. For the argument-driven research essay, these are the main elements:

• Purpose or research question
• Your claim or thesis.
• One or more reasons for your thesis.
• Evidence for each reason.
• Others’ objections, counterarguments, or alternative solutions.
• Your acknowledgment of others’ objections, counterarguments, or alternative solutions.
• Your response to others’ objections, counterarguments, or alternative solutions.

The Purpose or Goal

Sometimes your professor will give you the research question, but probably more often you will need to develop your own research topic. Even though you are likely writing an essay for an assignment or as part of a class, you are also developing your own purpose for the research and writing. This part of the essay may not be written down, but it can be helpful to keep in mind a purpose or overall question. That question might even be something you answer through your research, but don’t have

Examples: Purpose and Goal for Research Essays

• How do at least some animals’ bones help control their weight?
• Did the death of his beloved daughter have any effect on the writings of Mark Twain?

Your Claim or Thesis

You write the claim or thesis–it doesn’t come directly from a source. Instead, it is the conclusion you come to in answer to your question after you’ve read/listened to/viewed some sources. So it is a statement, not a question or a hypothesis that you plan to prove or disprove with your research.

After you’ve read/listened to/viewed more sources, you may need to change your thesis. That happens all the time–not because you did anything wrong but because you learned more.

Examples: Claims (or Theses) for Hypothetical Essays or Term Papers

• Bone cells monitor whether more or less weight is pressing down on the skeleton and send biochemical signals to appetite centers in their brains to turn appetite down or up, accordingly.
• Mark Twain wrote more urgently and with less humor during the four years immediately after the death of his daughter.

One or More Reasons

You write what you believe makes your claim or thesis (the answer to your research question) true. That’s your reason or reasons. Each reason is a summary statement of evidence you found in your research. The kinds of evidence considered convincing varies by discipline, so you will be looking at different sources, depending on your discipline. How many reasons you need depends on how complex your thesis and subject matter are, what you found in your sources, and how long your essay or research paper must be. It’s always a good idea to write your reasons in a way that is easy for your audience to understand and be persuaded by.

Examples: Reasons in Hypothetical Essays or Term Papers

• Animals (including humans) have a biological tendency to regain any weight that they lose and lose any weight that they gain, seemingly in an effort to maintain whatever weight they have sustained for some time. Skeletons are logical places where any gains or losses could be noted, and recent studies seem to show that osteocytes (a kind of bone cell) are involved in whether appetites go up or down after weight gain or loss.
• My content analysis and a comparison of publication rates four years before and after Mark Twain’s daughter died indicate that his writing was more urgent and less humorous for four years after. It is reasonable to conclude that her death caused that change.

Evidence for Each Reason

You write this also. This is the evidence you summarized earlier as each reason your thesis is true. You will be directly quoting, paraphrasing, and summarizing your sources to make the case that your answer to your research question is correct, or at least reasonable.

Examples: Evidence for Reasons in Hypothetical Essays or Term Papers

• Report the results of studies about osteocyctes’ possible effect on weight grain or loss.
• Report the results of your comparison of writing content and publication rate before and after Twain’s daughter’s death.

Others’ Objections, Counterarguments, or Alternative Solutions

Do any of your sources not agree with your thesis? You’ll have to bring those up in your research paper. In addition, put yourself in your readers’ shoes. What might they not find logical in your argument? In other words, which reason(s) and corresponding evidence might they find lacking? Did you find clues to what these could be in your sources? Or maybe you can imagine them thinking some aspect of what you think is evidence doesn’t make sense.

Examples: Objections, Counterarguments, or Alternative Solutions in Hypothetical Essays or Term Papers

• Imagine that some readers might think: The hormone leptin is released by fat cells when they are added to animals’ bodies so it is leptin that tells appetite centers to turn down when weight is gained.
• Imagine that some readers might think: Computerized content analysis tools are sort of blunt instruments and shouldn’t be used to do precise work like this.

Your Acknowledgement of Others’ Objections, Counterarguments, or Alternative Solutions

So what will you write to bring up each of those objections, counterarguments, and alternative solutions? Some examples:

• I can imagine skeptics wanting to point out…
• Perhaps some readers would say…
• I think those who come from XYZ would differ with me…

It all depends on what objections, counterarguments, and alternative solutions your audience or your imagination come up with.

Examples: Acknowledgement of Others’ Objections, Counterarguments, or Alternative Solutions in Hypothetical Essays or Term Papers:

• Some readers may point out that the hormone leptin, which is released by fat cells, signals appetite centers to lower the appetite when weight is gained.
• Readers may think that a computerized content analysis tool cannot do justice to the subtleties of text.

Response to Others’ Objections, Counterarguments, or Alternative Solutions

You must write your response to each objection, counterargument, or alternative solution brought up or that you’ve thought of. (You’re likely to have found clues for what to say in your sources.) The reason you have to include this is that you can’t very easily convince your audience until you show them how your claim stacks up against the opinions and reasoning of other people who don’t at the moment agree with you.

Examples: Response to Others’ Objections, Counterarguments, or Alternative Solutions in Hypothetical Essays or Term Papers:

• But leptin must not be the entire system, since many animals do keep on the new weight.
• Unlike other content tools, the XYZ Content Analysis Measure is able to take into account an author’s tone.

Adaptations

This page has been adapted from Where you Get the Components from Choosing & Using Sources: A Guide to Academic Research Copyright © 2015 by Teaching & Learning, Ohio State University Libraries. CC BY 4.0 DEED .

Reading and Writing Research for Undergraduates Copyright © 2023 by Stephanie Ojeda Ponce is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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12.3 Glance at Genre: Introducing Research as Evidence

Learning outcomes.

By the end of this section, you will be able to:

• Identify key terms and characteristics of evidence-based research writing.
• Participate effectively in a continuing scholarly conversation by synthesizing research and discussing it with others.
• Identify and analyze genre conventions as shaped by purpose, culture, and expectation.

Good writing satisfies audience expectations in genre, style, and content. Similarly, careful research, conducted according to the scope and method of each discipline, is a precondition of good research writing. In the humanities, research usually focuses on texts, individual ideas, speculations, insights, and imaginative connections. On the other hand, research in the social and physical sciences tends to focus on data and ideas that can be verified through observation, measurement, and testing. However, regardless of differences in disciplines and preferences of varying audiences, certain principles of research, writing, and supporting a position hold true across the curriculum.

The Genre of Research: Joining Scholarly Conversations

Conducting research on topics about which you have limited knowledge can be intimidating. To feel more comfortable with research, you can think of it as participating in a scholarly conversation, with the understanding that all knowledge on a particular subject is connected. Even if you discover only a small amount of information on your topic, the conversations around it may have begun long before you were born and may continue beyond your lifetime. Your involvement with the topic is your way of entering a conversation with other students and scholars at this time, as you discuss and synthesize information. After you leave the conversation, or finish your research, others are likely to pick it up again.

What you find through research helps you provide solid evidence that empowers you to add productively to the conversation. Thinking of research in this way means understanding the connections among your topic, your course materials, and larger historical, social, political, and economic contexts and themes. Understanding such connectedness begins with choosing your topic and continues through all phases of your research.

Key Terms in Research Writing

These are key terms and characteristics of evidence-based research writing:

• Citation . When reporting research, writers use citations to acknowledge and give credit for all borrowed materials. Citation also strengthens the credibility, or ethos, of the researcher. Citations always have two parts. Internal citations are short references that lead readers to more detailed information about how to find the sources. External citations are the entries listed, with publishing information, on the Works Cited or References page of the paper. Formatting of both internal and external citations is disciplinary specific. See the Handbook for specific information about MLA Documentation and Format and APA Documentation and Format .
• claim . Claims are the points you make in your report. They are based on and supported by research and evidence.
• Counterclaims . When it comes to research, the counterclaim is the writer’s thoughtful consideration and addressing of the other side’s objections to claims made or even to the topic itself. Counterclaims may need to be supported by further research and evidence.
• Evidence . Within the genre of research, evidence is either findings from original research or, more often, borrowed information that helps you develop your thesis and support your organizational structure and line of reasoning.
• Field research . Field research is basically primary research you conduct through observation or experimentation. Depending on your research question, you may need to seek answers by visiting museums or businesses, attending concerts, conducting interviews, observing classrooms or professionals at work, performing experiments, or following leads. Field research is covered extensively in Research Process: How to Create Sources .
• Research question . Your research question dictates your general line or lines of inquiry that ultimately guide your research. In developing your research question(s), you are narrowing the scope of your topic. Your research question(s) will come from the purpose of your research, the audience of your research product, and the genre for reporting your research.
• Thesis . The thesis is the claim, position, or hypothesis by which you attempt to answer your formulated research question(s).
• Reasoning . Similar to an argumentative essay, the line of reasoning in a research essay, report, or presentation is the organizational arrangement of the supports and evidence that back up your thesis.
• Topic . The topic is the general subject or content area of your research. Strong topics are usually those that involve some controversy or debate. Topics that are not debatable or have no nuanced perspectives do not make for strong research questions or lines of inquiry.

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Research: Definition, Characteristics, Goals, Approaches

Research is an original and systematic investigation undertaken to increase existing knowledge and understanding of the unknown to establish facts and principles.

Let’s understand research:

What is Research?

Research is a voyage of discovery of new knowledge. It comprises creating ideas and generating new knowledge that leads to new and improved insights and the development of new materials, devices, products, and processes.

It should have the potential to produce sufficiently relevant results to increase and synthesize existing knowledge or correct and integrate previous knowledge.

Good reflective research produces theories and hypotheses and benefits any intellectual attempt to analyze facts and phenomena.

Where did the word Research Come from?

The word ‘research’ perhaps originates from the old French word “recerchier” which meant to ‘ search again.’ It implicitly assumes that the earlier search was not exhaustive and complete; hence, a repeated search is called for.

In practice, ‘research’ refers to a scientific process of generating an unexplored horizon of knowledge, aiming at discovering or establishing facts, solving a problem, and reaching a decision. Keeping the above points in view, we arrive at the following definition of research:

Research Definition

Research is a scientific approach to answering a research question, solving a research problem, or generating new knowledge through a systematic and orderly collection, organization, and analysis of data to make research findings useful in decision-making.

When do we call research scientific? Any research endeavor is said to be scientific if

• It is based on empirical and measurable evidence subject to specific principles of reasoning;
• It consists of systematic observations, measurement, and experimentation;
• It relies on the application of scientific methods and harnessing of curiosity;
• It provides scientific information and theories for the explanation of nature;
• It makes practical applications possible, and
• It ensures adequate analysis of data employing rigorous statistical techniques.

The chief characteristic that distinguishes the scientific method from other methods of acquiring knowledge is that scientists seek to let reality speak for itself, supporting a theory when a theory’s predictions are confirmed and challenging a theory when its predictions prove false.

Scientific research has multidimensional functions, characteristics, and objectives.

Keeping these issues in view, we assert that research in any field or discipline:

• Attempts to solve a research problem;
• Involves gathering new data from primary or first-hand sources or using existing data for a new purpose;
• is based upon observable experiences or empirical evidence;
• Demands accurate observation and description;
• Employs carefully designed procedures and rigorous analysis;
• attempts to find an objective, unbiased solution to the problem and takes great pains to validate the methods employed;
• is a deliberate and unhurried activity that is directional but often refines the problem or questions as the research progresses.

Characteristics of Research

Keeping this in mind that research in any field of inquiry is undertaken to provide information to support decision-making in its respective area, we summarize some desirable characteristics of research:

• The research should focus on priority problems.
• The research should be systematic. It emphasizes that a researcher should employ a structured procedure.
• The research should be logical. Without manipulating ideas logically, the scientific researcher cannot make much progress in any investigation.
• The research should be reductive. This means that one researcher’s findings should be made available to other researchers to prevent them from repeating the same research.
• The research should be replicable. This asserts that there should be scope to confirm previous research findings in a new environment and different settings with a new group of subjects or at a different point in time.
• The research should be generative. This is one of the valuable characteristics of research because answering one question leads to generating many other new questions.
• The research should be action-oriented. In other words, it should be aimed at solving to implement its findings.
• The research should follow an integrated multidisciplinary approach, i.e., research approaches from more than one discipline are needed.
• The research should be participatory, involving all parties concerned (from policymakers down to community members) at all stages of the study.
• The research must be relatively simple, timely, and time-bound, employing a comparatively simple design.
• The research must be as much cost-effective as possible.
• The research results should be presented in formats most useful for administrators, decision-makers, business managers, or community members.

3 Basic Operations of Research

Scientific research in any field of inquiry involves three basic operations:

• Data collection;
• Data analysis;
• Report writing .

• Data collection refers to observing, measuring, and recording data or information.
• Data analysis, on the other hand, refers to arranging and organizing the collected data so that we may be able to find out what their significance is and generalize about them.
• Report writing is the ultimate step of the study . Its purpose is to convey the information contained in it to the readers or audience.

If you note down, for example, the reading habit of newspapers of a group of residents in a community, that would be your data collection.

If you then divide these residents into three categories, ‘regular,’ ‘occasional,’ and ‘never,’ you have performed a simple data analysis. Your findings may now be presented in a report form.

A reader of your report knows what percentage of the community people never read any newspaper and so on.

Here are some examples that demonstrate what research is:

• A farmer is planting two varieties of jute side by side to compare yields;
• A sociologist examines the causes and consequences of divorce;
• An economist is looking at the interdependence of inflation and foreign direct investment;
• A physician is experimenting with the effects of multiple uses of disposable insulin syringes in a hospital;
• A business enterprise is examining the effects of advertisement of their products on the volume of sales;
• An economist is doing a cost-benefit analysis of reducing the sales tax on essential commodities;
• The Bangladesh Bank is closely observing and monitoring the performance of nationalized and private banks;
• Based on some prior information, Bank Management plans to open new counters for female customers.
• Supermarket Management is assessing the satisfaction level of the customers with their products.

The above examples are all researching whether the instrument is an electronic microscope, hospital records, a microcomputer, a questionnaire, or a checklist.

Research Motivation – What makes one motivated to do research?

A person may be motivated to undertake research activities because

• He might have genuine interest and curiosity in the existing body of knowledge and understanding of the problem;
• He is looking for answers to questions that have remained unanswered so far and trying to unfold the truth;
• The existing tools and techniques are accessible to him, and others may need modification and change to suit the current needs.

One might research ensuring.

• Better livelihood;
• Better career development;
• Higher position, prestige, and dignity in society;
• Academic achievement leading to higher degrees;
• Self-gratification.

At the individual level, the results of the research are used by many:

• A villager is drinking water from an arsenic-free tube well;
• A rural woman is giving more green vegetables to her child than before;
• A cigarette smoker is actively considering quitting smoking;
• An old man is jogging for cardiovascular fitness;
• A sociologist is using newly suggested tools and techniques in poverty measurement.

The above activities are all outcomes of the research.

All involved in the above processes will benefit from the research results. There is hardly any action in everyday life that does not depend upon previous research.

Research in any field of inquiry provides us with the knowledge and skills to solve problems and meet the challenges of a fast-paced decision-making environment.

9 Qualities of Research

Good research generates dependable data. It is conducted by professionals and can be used reliably for decision-making. It is thus of crucial importance that research should be made acceptable to the audience for which research should possess some desirable qualities in terms of.

9 qualities of research are;

Purpose clearly defined

Research process detailed, research design planner, ethical issues considered, limitations revealed, adequate analysis ensured, findings unambiguously presented, conclusions and recommendations justified..

We enumerate below a few qualities that good research should possess.

Good research must have its purposes clearly and unambiguously defined.

The problem involved or the decision to be made should be sharply delineated as clearly as possible to demonstrate the credibility of the research.

The research procedures should be described in sufficient detail to permit other researchers to repeat the research later.

Failure to do so makes it difficult or impossible to estimate the validity and reliability of the results. This weakens the confidence of the readers.

Any recommendations from such research justifiably get little attention from the policymakers and implementation.

The procedural design of the research should be carefully planned to yield results that are as objective as possible.

In doing so, care must be taken so that the sample’s representativeness is ensured, relevant literature has been thoroughly searched, experimental controls, whenever necessary, have been followed, and the personal bias in selecting and recording data has been minimized.

A research design should always safeguard against causing mental and physical harm not only to the participants but also those who belong to their organizations.

Careful consideration must also be given to research situations when there is a possibility for exploitation, invasion of privacy, and loss of dignity of all those involved in the study.

The researcher should report with complete honesty and frankness any flaws in procedural design; he followed and provided estimates of their effects on the findings.

This enhances the readers’ confidence and makes the report acceptable to the audience. One can legitimately question the value of research where no limitations are reported.

Adequate analysis reveals the significance of the data and helps the researcher to check the reliability and validity of his estimates.

Data should, therefore, be analyzed with proper statistical rigor to assist the researcher in reaching firm conclusions.

When statistical methods have been employed, the probability of error should be estimated, and criteria of statistical significance applied.

The presentation of the results should be comprehensive, easily understood by the readers, and organized so that the readers can readily locate the critical and central findings.

Proper research always specifies the conditions under which the research conclusions seem valid.

Therefore, it is important that any conclusions drawn and recommendations made should be solely based on the findings of the study.

No inferences or generalizations should be made beyond the data. If this were not followed, the objectivity of the research would tend to decrease, resulting in confidence in the findings.

The researcher’s experiences were reflected.

The research report should contain information about the qualifications of the researchers .

If the researcher is experienced, has a good reputation in research, and is a person of integrity, his report is likely to be highly valued. The policymakers feel confident in implementing the recommendations made in such reports.

4 Goals of Research

The primary goal or purpose of research in any field of inquiry; is to add to what is known about the phenomenon under investigation by applying scientific methods. Though each research has its own specific goals, we may enumerate the following 4 broad goals of scientific research:

Exploration and Explorative Research

Description and descriptive research, causal explanation and causal research, prediction and predictive research.

The link between the 4 goals of research and the questions raised in reaching these goals.

Let’s try to understand the 4 goals of the research.

Exploration is finding out about some previously unexamined phenomenon. In other words, an explorative study structures and identifies new problems.

The explorative study aims to gain familiarity with a phenomenon or gain new insights into it.

Exploration is particularly useful when researchers lack a clear idea of the problems they meet during their study.

Through exploration, researchers attempt to

• Develop concepts more clearly;
• Establish priorities among several alternatives;
• Develop operational definitions of variables;
• Formulate research hypotheses and sharpen research objectives;
• Improve the methodology and modify (if needed) the research design .

Exploration is achieved through what we call exploratory research.

The end of an explorative study comes when the researchers are convinced that they have established the major dimensions of the research task.

Many research activities consist of gathering information on some topic of interest. The description refers to these data-based information-gathering activities. Descriptive studies portray precisely the characteristics of a particular individual, situation, or group.

Here, we attempt to describe situations and events through studies, which we refer to as descriptive research.

Such research is undertaken when much is known about the problem under investigation.

Descriptive studies try to discover answers to the questions of who, what, when, where, and sometimes how.

Such research studies may involve the collection of data and the creation of distribution of the number of times the researcher observes a single event or characteristic, known as a research variable.

A descriptive study may also involve the interaction of two or more variables and attempts to observe if there is any relationship between the variables under investigation .

Research that examines such a relationship is sometimes called a correlational study. It is correlational because it attempts to relate (i.e., co-relate) two or more variables.

A descriptive study may be feasible to answer the questions of the following types:

• What are the characteristics of the people who are involved in city crime? Are they young? Middle-aged? Poor? Muslim? Educated?
• Who are the potential buyers of the new product? Men or women? Urban people or rural people?
• Are rural women more likely to marry earlier than their urban counterparts?
• Does previous experience help an employee to get a higher initial salary?

Although the data description in descriptive research is factual, accurate, and systematic, the research cannot describe what caused a situation.

Thus, descriptive research cannot be used to create a causal relationship where one variable affects another.

In other words, descriptive research can be said to have a low requirement for internal validity. In sum, descriptive research deals with everything that can be counted and studied.

But there are always restrictions on that. All research must impact the lives of the people around us.

For example, finding the most frequent disease that affects the people of a community falls under descriptive research.

But the research readers will have the hunch to know why this has happened and what to do to prevent that disease so that more people will live healthy lives.

It dictates that we need a causal explanation of the situation under reference and a causal study vis-a-vis causal research .

Explanation reveals why and how something happens.

An explanatory study goes beyond description and attempts to establish a cause-and-effect relationship between variables. It explains the reason for the phenomenon that the descriptive study observed.

Thus, if a researcher finds that communities with larger family sizes have higher child deaths or that smoking correlates with lung cancer, he is performing a descriptive study.

If he explains why it is so and tries to establish a cause-and-effect relationship, he is performing explanatory or causal research . The researcher uses theories or at-least hypotheses to account for the factors that caused a certain phenomenon.

Look at the following examples that fit causal studies:

• Why are people involved in crime? Can we explain this as a consequence of the present job market crisis or lack of parental care?
• Will the buyers be motivated to purchase the new product in a new container ? Can an attractive advertisement motivate them to buy a new product?
• Why has the share market shown the steepest-ever fall in stock prices? Is it because of the IMF’s warnings and prescriptions on the commercial banks’ exposure to the stock market or because of an abundant increase in the supply of new shares?

Prediction seeks to answer when and in what situations will occur if we can provide a plausible explanation for the event in question.

However, the precise nature of the relationship between explanation and prediction has been a subject of debate.

One view is that explanation and prediction are the same phenomena, except that prediction precedes the event while the explanation takes place after the event has occurred.

Another view is that explanation and prediction are fundamentally different processes.

We need not be concerned with this debate here but can simply state that in addition to being able to explain an event after it has occurred, we would also be able to predict when it will occur.

Research Approaches

There are two main approaches to doing research.

The first is the basic approach, which mostly pertains to academic research. Many people view this as pure research or fundamental research.

The research implemented through the second approach is variously known as applied research, action research, operations research, or contract research.

Also, the third category of research, evaluative research, is important in many applications. All these approaches have different purposes influencing the nature of the respective research.

Lastly, precautions in research are required for thorough research.

So, 4 research approaches are;

• Basic Research .
• Applied Research .
• Evaluative Research .
• Precautions in Research.

Areas of Research

The most important fields or areas of research, among others, are;

• Social Research .
• Health Research .
• Population Research .
• Business Research .
• Marketing Research .
• Agricultural Research .
• Biomedical Research.
• Clinical Research .
• Outcomes Research.
• Internet Research.
• Archival Research.
• Empirical Research.
• Legal Research .
• Education Research .
• Engineering Research .
• Historical Research.

Check out our article describing all 16 areas of research .

Precautions in Research

Whether a researcher is doing applied or basic research or research of any other form, he or she must take necessary precautions to ensure that the research he or she is doing is relevant, timely, efficient, accurate, and ethical .

The research is considered relevant if it anticipates the kinds of information that decision-makers, scientists, or policymakers will require.

Timely research is completed in time to influence decisions.

• Research is efficient when it is of the best quality for the minimum expenditure and the study is appropriate to the research context.
• Research is considered accurate or valid when the interpretation can account for both consistencies and inconsistencies in the data.
• Research is ethical when it can promote trust, exercise care, ensure standards, and protect the rights of the participants in the research process.

What is the definition of research?

What are the characteristics of good research, what are the three basic operations involved in scientific research, what are the four broad goals of scientific research, what distinguishes the scientific method from other methods of acquiring knowledge, what is the origin of the word ‘research’, how is “research methodology” defined, how does research methodology ensure the appropriateness of a research method.

After discussing the research definition and knowing the characteristics, goals, and approaches, it’s time to delve into the research fundamentals. For a comprehensive understanding, refer to our detailed research and methodology concepts guide .

Research should be relevant, timely, efficient, accurate, and ethical. It should anticipate the information required by decision-makers, be completed in time to influence decisions, be of the best quality for the minimum expenditure, and protect the rights of participants in the research process.

The two main approaches to research are the basic approach, often viewed as pure or fundamental research, and the applied approach, which includes action research, operations research, and contract research.

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What Should Be the Characteristics of a Good Research Paper?

by team@blp

In miscellaneous.

When people want to get answers to various issues, they search for information on the problems. From their findings, they expand them, aiming to agree or refute them. Research papers are common assignments in colleges. 

They follow specific research and writing guidelines to answer particular questions or assigned topics. They look into the critical topic of credible research sources and argue their findings in an orderly manner. To be termed as good, the research paper must bear the following characteristics.

In this Article

Gives credit to previous research work on the topic

• It’s hooked on a relevant research question.

It must be based on appropriate, systematic research methods

• The information must be accurate and controlled.
• It must be verifiable and rigorous.

Be careful with the topic you choose

Decide the sources you want to use, create your thesis statement , plan your points, write your paper, characteristics of a good research paper.

Writing a research paper aims to discover new knowledge, but the knowledge must have a base. Its base is the research done previously by other scholars. The student must acknowledge the previous research and avoid duplicating it in their writing process.

A college student must engage in deep research work to create a credible research paper. This makes the process lengthy and complex when choosing your topic, selecting sources, and developing its design. In addition, it requires a great deal of knowledge to piece everything together. Fortunately, Studyclerk will give you professional help anytime you need it. If you do not have enough knowledge and time to write a paper on your own, you can ask for  research paper help  by StudyClerk, where experienced paper writers will write your paper in no time. You can trust their expert writers to handle your assignment well and get a well-written paper in a short time.

It’s hooked on a relevant research question .

All the time a student spends researching multiple sources is to answer a specific research question. The question must be relevant to the current needs. This question guides them into the information they use or the line of argument they take.

The methodology of research a student chooses will determine the value of the information they get or give. The methods must be valid and credible to provide reliable outcomes. Whether the student chooses a qualitative, quantitative, or mixed approach, they must all be valuable and relevant. 

The information must be accurate and controlled .

A good research paper cannot be generalized information but specific, scientific information. That is why they must include references and record tests or information accurately. Moreover, they must keep the information controlled by staying within the topic from the first step of research to the last. 

It must be verifiable and rigorous .

The student must use information or write arguments that can be verified. If it’s a test, it must be replicable by another researcher. The sources must be verifiable and accurate. Without rigorous deep  research strategies , the paper cannot be good. They must put a lot of labor into both the writing and research processes to ensure the information is credible, clear, concise, original, and precise. 

How to write a good research paper

To write a good research paper, you must first understand what kind of question you have been assigned. Then, you will choose the best topic that you will love to write about. The following points will help you write a good research paper.

You must select a topic you love. Go for a topic that will be easier to research, which will give you a broader area of study. 

Your instructor doesn’t restrict you on the sources you must use. Broaden your mind so that you don’t limit yourself to specific sources of information. Sometimes you will get helpful information from sources you slightest thought as good.

Write your central statement to base your position on the research. Make it coherent contentious, and let it be a summary of your arguments.

Create an outline that will guide you when arguing your points

• Start  with the most vital points and smooth the flow.
• Pay attention to  paragraph structure  and let your arguments be clear.
• Finish with a compelling conclusion, and don’t forget to cite your sources.

A research paper requires extensive research methods to get solid points for supporting your stand. First, the sources you use must be verifiable by any other researcher. You must ensure your research work is original for your paper to be credible. Third, each point should be coherent with each paragraph. Finally, your research findings must be tagged on the research question and provide answers that apply to the current society. 

Author’s Bio

Helen Birk is an online freelance writer who holds an outstanding record of helping numerous students do their academic assignments. She is an expert in essays and thesis writing, and students simply love her for her high-quality work. In addition, she enjoys cycling, doing pencil sketching, and listening to spiritual podcasts in her free time.

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Types of Research Papers: Overview

• Types of Research Questions

A research paper is simply a piece of writing that uses outside sources. There are different types of research papers with varying purposes and expectations for sourcing.

While this guide explains those differences broadly, disciplines and assignments vary. Ask your professor for clarification on the purpose,  types of appropriate research questions , and expectations of sources for your assignment.

Need More Help?

Related guides.

• Literature Reviews
• Annotated Bibliographies
• Starting Your Research

Research and Writing Lab

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Tuesdays 3:00pm - 4:30pm via Zoom @   https://smu.zoom.us/j/92637892352  and in-person, Fondren Red 1st floor (near elevators)

• Next: Types of Research Questions >>
• Last Updated: Apr 22, 2024 1:10 PM
• URL: https://guides.smu.edu/researchpapertypes

6 Important Tips on Writing a Research Paper Title

When you are searching for a research study on a particular topic, you probably notice that articles with interesting, descriptive research titles draw you in. By contrast, research paper titles that are not descriptive are usually passed over, even though you may write a good research paper with interesting contents. This shows the importance of coming up with a good title for your research paper when drafting your own manuscript.

Importance of a Research Title

The research title plays a crucial role in the research process, and its importance can be summarized as follows:

Why do Research Titles Matter?

Before we look at how to title a research paper, let’s look at a research title example that illustrates why a good research paper should have a strong title.

Imagine that you are researching meditation and nursing, and you want to find out if any studies have shown that meditation makes nurses better communicators.  You conduct a keyword search using the keywords “nursing”, “communication”, and “meditation.” You come up with results that have the following titles:

• Benefits of Meditation for the Nursing Profession: A Quantitative Investigation
• Why Mindful Nurses Make the Best Communicators
• Meditation Gurus
• Nurses on the Move: A Quantitative Report on How Meditation Can Improve Nurse Performance

All four of these research paper titles may describe very similar studies—they could even be titles for the same study! As you can see, they give very different impressions.

• Title 1 describes the topic and the method of the study but is not particularly catchy.
• Title 2 partly describes the topic, but does not give any information about the method of the study—it could simply be a theoretical or opinion piece.
• Title 3 is somewhat catchier but gives almost no information at all about the article.
• Title 4 begins with a catchy main title and is followed by a subtitle that gives information about the content and method of the study.

As we will see, Title 4 has all the characteristics of a good research title.

Characteristics of a Good Research Title

According to rhetoric scholars Hairston and Keene, making a good title for a paper involves ensuring that the title of the research accomplishes four goals as mentioned below:

• It should predict the content of the research paper .
• It should be interesting to the reader .
• It should reflect the tone of the writing .
• It should contain important keywords that will make it easier to be located during a keyword search.

Let’s return to the examples in the previous section to see how to make a research title.

As you can see in the table above, only one of the four example titles fulfills all of the criteria of a suitable research paper title.

Related: You’ve chosen your study topic, but having trouble deciding where to publish it? Here’s a comprehensive course to help you identify the right journal .

Tips for Writing an Effective Research Paper Title

When writing a research title, you can use the four criteria listed above as a guide. Here are a few other tips you can use to make sure your title will be part of the recipe for an effective research paper :

• Make sure your research title describes (a) the topic, (b) the method, (c) the sample, and (d) the results of your study. You can use the following formula:

[ Result ]: A [ method ] study of [ topic ] among [ sample ] Example : Meditation makes nurses perform better: a qualitative study of mindfulness meditation among German nursing students

• Avoid unnecessary words and jargons. Keep the title statement as concise as possible. You want a title that will be comprehensible even to people who are not experts in your field. Check our article for a detailed list of things to avoid when writing an effective research title .
• Make sure your title is between 5 and 15 words in length.
• If you are writing a title for a university assignment or for a particular academic journal, verify that your title conforms to the standards and requirements for that outlet. For example, many journals require that titles fall under a character limit, including spaces. Many universities require that titles take a very specific form, limiting your creativity.
• Use a descriptive phrase to convey the purpose of your research efficiently.
• Most importantly, use critical keywords in the title to increase the discoverability of your article.

Resources for Further Reading

In addition to the tips above, there are many resources online that you can use to help write your research title. Here is a list of links that you may find useful as you work on creating an excellent research title:

• The University of Southern California has a guide specific to social science research papers: http://libguides.usc.edu/writingguide/title
• The Journal of European Psychology Students has a blog article focusing on APA-compliant research paper titles: http://blog.efpsa.org/2012/09/01/how-to-write-a-good-title-for-journal-articles/
• This article by Kristen Hamlin contains a step-by-step approach to writing titles: http://classroom.synonym.com/choose-title-research-paper-4332.html

Are there any tips or tricks you find useful in crafting research titles? Which tip did you find most useful in this article? Leave a comment to let us know!

• Hairston, M., & Keene, M. 2003. Successful writing . 5th ed. New York: Norton.
• University of Southern California. 2017. Organizing your social sciences research paper: choosing a title . [Online] Available at: http://libguides.usc.edu/writingguide/title

Thank you so much:) Have a nice day!

Thank you so much, it helped me.. God bless..

Thank you for the excellent article and tips for creating a research work, because I always forget about such an essential element as the keywords when forming topics. In particular, I have found a rapid help with the formation of informative and sound titles that also conforms to the standards and requirements.

I am doing a research work on sales girls or shop girls using qualititative method. Basicly I am from Pakistan and writing on the scenario of mycountry. I am really confused about my research title can you kindly give some suggestions and give me an approperaite tilte

Hi Zubair, Thank you for your question. However, the information you have provided is insufficient for drafting an appropriate title. Information on what exactly you intend to study would be needed in order to draft a meaningful title. Meanwhile, you can try drafting your own title after going through the following articles our website: https://www.enago.com/academy/top-10-tips-on-choosing-an-attractive-research-title/ , https://www.enago.com/academy/writing-a-good-research-title-things-to-avoid/ , https://www.enago.com/academy/write-irresistible-research-paper-title/ We would be happy to give you feedback and suggest changes if required. Did you get a chance to install our free Mobile App? https://www.enago.com/academy/mobile-app/ . Make sure you subscribe to our weekly newsletter https://www.enago.com/academy/subscribe-now/ .

thanks for helping me like this!!

Thank you for this. It helped me improve my research title. I just want to verify to you the title I have just made. “Ensuring the safety: A Quantitative Study of Radio Frequency Identification system among the selected students of ( school’s name ).

(I need your reply asap coz we will be doing the chap. 1 tomorrow. Thank u in advance. 🙂 )

I am actually doing a research paper title. I want to know more further in doing research title. Can you give me some tips on doing a research paper?

Hi Joan, Thank you for your question. We are glad to know that you found our resources useful. Your feedback is very valuable to us. You can try drafting your own title after going through the following articles on our website: https://www.enago.com/academy/top-10-tips-on-choosing-an-attractive-research-title/ , https://www.enago.com/academy/writing-a-good-research-title-things-to-avoid/ , https://www.enago.com/academy/write-irresistible-research-paper-title/

We would be happy to give you feedback and suggest changes if required. Did you get a chance to install our free Mobile App? https://www.enago.com/academy/mobile-app/ . Make sure you subscribe to our weekly newsletter https://www.enago.com/academy/subscribe-now/ .

That really helpful. Thanks alot

Thank you so much. It’s really help me.

Thanks for sharing this tips. Title matters a lot for any article because it contents Keywords of article. It should be eye-catchy. Your article is helpful to select title of any article.

nice blog that you have shared

This blog is very informative for me. Thanks for sharing.

nice information that you have shared

i’m found in selecting my ma thesis title ,so i’m going to do my final research after the proposal approved. Your post help me find good title.

I need help. I need a research title for my study about early mobilization of the mechanically ventilated patients in the ICU. Any suggestions would be highly appreciated.

Thank you for posting your query on the website. When writing manuscripts, too many scholars neglect the research title. This phrase, along with the abstract, is what people will mostly see and read online. Title research of publications shows that the research paper title does matter a lot. Both bibliometrics and altmetrics tracking of citations are now, for better or worse, used to gauge a paper’s “success” for its author(s) and the journal publishing it. Interesting research topics coupled with good or clever yet accurate research titles can draw more attention to your work from peers and the public alike. You can check through the following search results for titles on similar topics: https://www.google.com/search?q=early+mobilization+of+the+mechanically+ventilated+patients+in+the+icu&rlz=1C1GCEU_enIN907IN907&oq=&aqs=chrome.0.69i59.4920093j0j7&sourceid=chrome&ie=UTF-8 .

We hope this would be helpful in drafting an attractive title for your research paper.

Please let us know in case of any other queries.

I’ve been surfing online more than 3 hours these days, but I never found any interesting article like yours. It is lovely worth enough for me. In my opinion, if all website owners and bloggers made just right content material as you did, the internet will be much more helpful than ever before.

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Wow that was odd. I just wrote an very long comment but after I clicked submit my comment didn’t show up. Grrrr… well I’m not writing all that over again. Anyhow, just wanted to say fantastic blog!

In case the topic is new research before you’re writing. And then to stand out, you end up being different.and be inclined to highlight yourself.

There are many free directories, and more paid lists.

To be honest your article is informative. I search many site to know about writing but I didn’t get the information I needed. I saw your site and I read it. I got some new information from here. I think some of your tips can be applied to those too! Thank you so very much for such informative and useful content.

Nice and well written content you have shared with us. thanks a lot!

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Research Paper

29 December 2023

last updated

A research paper is a product of seeking information, analysis, human thinking, and time. Basically, when scholars want to get answers to questions, they start to search for information to expand, use, approve, or deny findings. In simple words, research papers are results of processes by considering writing works and following specific requirements. Besides, scientists research and expand many theories, developing social or technological aspects of human science. However, in order to write relevant papers, they need to know a definition of the research, structure, characteristics, and types.

Definition of What Is a Research Paper and Its Meaning

A research paper is a common assignment. It comes to a situation when students, scholars, and scientists need to answer specific questions by using sources. Basically, a research paper is one of the types of papers where scholars analyze questions or topics , look for secondary sources , and write papers on defined themes. For example, if an assignment is to write a research paper on some causes of global warming or any other topic, a person must write a research proposal on it, analyzing important points and credible sources . Although essays focus on personal knowledge, writing a research paper means analyzing sources by following academic standards. Moreover, scientists must meet the structure of research papers. Therefore, writers need to analyze their research paper topics , start to research, cover key aspects, process credible articles, and organize final studies properly.

The Structure of a Research Work

The structure of research papers depends on assignment requirements. In fact, when students get their assignments and instructions, they need to analyze specific research questions or topics, find reliable sources , and write final works. Basically, the structure of research papers consists of the abstract , outline , introduction , literature review , methodology, results , discussion, recommendations, limitations, conclusion , acknowledgments , and references. However, students may not include some of these sections because of assigned instructions that they have and specific types of research papers. For instance, if instructions of papers do not suppose to conduct real experiments, the methodology section can be skipped because of the data’s absence. In turn, the structure of the final work consists of:

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🔸 The First Part of a Research Study

Abstract or an executive summary means the first section of a research paper that provides the study’s purpose, research questions or suggestions, main findings with conclusions. Moreover, this paragraph of about 150 words should be written when the whole work is finished already. Hence, abstract sections should describe key aspects of studies, including discussions about the relevance of findings.

Outline serves as a clear map of the structure of a research study.

Introduction provides the main information on problem statements, the indication of methodology, important findings, and principal conclusion. Basically, this section of a research paper covers rationales behind the work or background research, explanation of the importance, defending its relevance, a brief description of experimental designs, defined research questions, hypotheses, or key aspects.

🔸 Literature Review and Research or Experiment

Literature Review is needed for the analysis of past studies or scholarly articles to be familiar with research questions or topics. Hence, this section summarizes and synthesizes arguments and ideas from scholarly sources without adding new contributions. In turn, this part is organized around arguments or ideas, not sources.

Methodology or Materials and Methods covers explanations of research designs. Basically, techniques for gathering information and other aspects related to experiments must be described in a research paper. For instance, students and scholars document all specialized materials and general procedures. In this case, individuals may use some or all of the methods in further studies or judge the scientific merit of the work. Moreover, scientists should explain how they are going to conduct their experiments.

Results mean the gained information or data after the research or experiment. Basically, scholars should present and illustrate their findings. Moreover, this section may include tables or figures.

🔸 Analysis of Findings

Discussion is a section of a research paper where scientists review the information in the introduction part, evaluate gained results, or compare it with past studies. In particular, students and scholars interpret gained data or findings in appropriate depth. For example, if results differ from expectations at the beginning, scientists should explain why that may have happened. However, if results agree with rationales, scientists should describe theories that the evidence is supported.

Recommendations take its roots from a discussion section where scholars propose potential solutions or new ideas based on obtained results in a research paper. In this case, if scientists have any recommendations on how to improve this research so that other scholars can use evidence in further studies, they must write what they think in this section.

Limitations mean a consideration of research weaknesses and results to get new directions. For instance, if researchers found any limitations of studies that could affect experiments, scholars must not use such knowledge because of the same mistakes. Moreover, scientists should avoid contradicting results, and, even more, they must write it in this section.

🔸 The Final Part of a Conducted Research

Conclusion includes final claims of a research paper based on findings. Basically, this section covers final thoughts and the summary of the whole work. Moreover, this section may be used instead of limitations and recommendations that would be too small by themselves. In this case, scientists do not need to use headings for recommendations and limitations. Also, check out conclusion examples .

Acknowledgments or Appendix may take different forms, from paragraphs to charts. In this section, scholars include additional information on a research paper.

References mean a section where students, scholars, or scientists provide all used sources by following the format and academic rules.

Research Characteristics

Any type of work must meet some standards. By considering a research paper, this work must be written accordingly. In this case, the main characteristics of research papers are the length, style, format, and sources. Firstly, the length of research work defines the number of needed sources to analyze. Then, the style must be formal and covers impersonal and inclusive language. In turn, the format means academic standards of how to organize final works, including its structure and norms. Finally, sources and their number define works as research papers because of the volume of analyzed information. Hence, these characteristics must be considered while writing research papers.

Types of Research Papers

In general, the length of assignments can be different because of instructions. For example, there are two main types of research papers, such as typical and serious works. Firstly, a typical research paper may include definitive, argumentative, interpretive, and other works. In this case, typical papers are from 2 to 10 pages, where students analyze research questions or specific topics. Then, a serious research study is the expanded version of typical works. In turn, the length of such a paper is more than 10 pages. Basically, such works cover a serious analysis with many sources. Therefore, typical and serious works are two types of research papers.

Typical Research Papers

Basically, typical research works depend on assignments, the number of sources, and the paper’s length. So, a typical research paper is usually a long essay with the analyzed evidence. For example, students in high school and colleges get such assignments to learn how to research and analyze topics. In this case, they do not need to conduct serious experiments with the analysis and calculation of data. Moreover, students must use the Internet or libraries in searching for credible secondary sources to find potential answers to specific questions. As a result, students gather information on topics and learn how to take defined sides, present unique positions, or explain new directions. Hence, typical research papers require an analysis of primary and secondary sources without serious experiments or data.

Serious Research Studies

Although long papers require a lot of time for finding and analyzing credible sources, real experiments are an integral part of research work. Firstly, scholars at universities need to analyze the information from past studies to expand or disapprove of researched topics. Then, if scholars want to prove specific positions or ideas, they must get real evidence. In this case, experiments can be surveys, calculations, or other types of data that scholars do personally. Moreover, a dissertation is a typical serious research paper that young scientists write based on the research analysis of topics, data from conducted experiments, and conclusions at the end of work. Thus, serious research papers are studies that take a lot of time, analysis of sources with gained data, and interpretation of results.

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Comprehensive Review on Alzheimer’s Disease: Causes and Treatment

Alzheimer’s disease (AD) is a disorder that causes degeneration of the cells in the brain and it is the main cause of dementia, which is characterized by a decline in thinking and independence in personal daily activities. AD is considered a multifactorial disease: two main hypotheses were proposed as a cause for AD, cholinergic and amyloid hypotheses. Additionally, several risk factors such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors play a role in the disease. Currently, there are only two classes of approved drugs to treat AD, including inhibitors to cholinesterase enzyme and antagonists to N -methyl d -aspartate (NMDA), which are effective only in treating the symptoms of AD, but do not cure or prevent the disease. Nowadays, the research is focusing on understanding AD pathology by targeting several mechanisms, such as abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage, aiming to develop successful treatments that are capable of stopping or modifying the course of AD. This review discusses currently available drugs and future theories for the development of new therapies for AD, such as disease-modifying therapeutics (DMT), chaperones, and natural compounds.

1. Introduction

Alzheimer’s disease (AD) (named after the German psychiatric Alois Alzheimer) is the most common type of dementia and can be defined as a slowly progressive neurodegenerative disease characterized by neuritic plaques and neurofibrillary tangles ( Figure 1 ) as a result of amyloid-beta peptide’s (Aβ) accumulation in the most affected area of the brain, the medial temporal lobe and neocortical structures [ 1 ]. Alois Alzheimer noticed a presence of amyloid plaques and a massive loss of neurons while examining the brain of his first patient that suffered from memory loss and change of personality before dying and described the condition as a serious disease of the cerebral cortex. Emil Kraepelin named this medical condition Alzheimer’s disease for the first time in his 8th edition psychiatry handbook [ 2 , 3 ]. Progressive loss of cognitive functions can be caused by cerebral disorder like Alzheimer’s disease (AD) or other factors such as intoxications, infections, abnormality in the pulmonary and circulatory systems, which causes a reduction in the oxygen supply to the brain, nutritional deficiency, vitamin B12 deficiency, tumors, and others [ 4 , 5 ].

The physiological structure of the brain and neurons in ( a ) healthy brain and ( b ) Alzheimer’s disease (AD) brain.

At present, there are around 50 million AD patients worldwide and this number is projected to double every 5 years and will increase to reach 152 million by 2050. AD burden affects individuals, their families, and the economy, with estimated global costs of US$1 trillion annually. At present, there is no cure for Alzheimer’s disease, although there are available treatments that just improve the symptoms [ 6 , 7 ]. The purpose of this review is to give a brief description about AD diagnosis, pathology, causes, and current treatments, and to highlight the recent development of compounds that could prevent or treat AD by targeting several pathogenic mechanisms, such as Aβ and tau aggregation, and misfolding, inflammation, oxidative damage, and others.

2. Alzheimer’s Disease Diagnostic Criteria

A patient suspected to have AD should undergo several tests, including neurological examination, magnetic resonance imaging (MRI) for neurons, laboratory examinations such as vitamin B12, and other tests besides the medical and family history of the patients [ 8 ]. Vitamin (vit.) B12 deficiency has been long known for its association with neurologic problems and increasing risks of AD, according to some studies. A special marker of vit. B12 deficiency is elevated homocysteine levels, which can cause brain damage by oxidative stress, increasing calcium influx and apoptosis. Diagnoses of vit. B12 deficiency can be done by measuring serum vit. B12 level alongside complete blood count and serum homocysteine levels tests [ 9 , 10 ].

In 1984, The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association (ADRDA) formed a work group (NINCDS-ADRDA) to establish a clinical diagnostic’s criteria for Alzheimer’s disease. This criteria includes: (1) probable Alzheimer’s disease, which can be diagnosed by dementia that is confirmed by neuropsychological tests, progressive memory loss, impaired daily-life activity, and other symptoms like aphasia (impairment of a language), apraxia (a motor skills disorder), and agnosia (a loss of perception). All of these symptoms can start from age 40–90, with the absence of any systemic or brain diseases, (2) possible Alzheimer’s disease can be applied in the absence of neurologic, psychiatric disorders, and the presence of another illness like systemic or brain disorder, but they are not the primary cause of dementia, and (3) definite Alzheimer’s disease, that is confirmed by histopathologic confirmation obtained from a biopsy or autopsy [ 11 , 12 ].

In 2011, The National Institute on Aging—Alzheimer’s Association made several changes and updated the 1984 NINCDS-ADRDA criteria for higher specificity and sensitivity in the diagnosis of Alzheimer’s disease. The newly proposed criteria include probable and possible AD dementia for the use in clinical settings and probable or possible AD dementia with pathophysiological evidence for research purposes, in addition to clinical biomarkers. There are two categories of Alzheimer’s disease biomarkers: (a) markers of brain amyloid such as positron emission tomography (PET) and cerebrospinal fluid (CSF), and (b) markers of neuronal injury like cerebrospinal fluid tau, fluorodeoxyglucose (FDG) for metabolic activity, and magnetic resonance imaging (MRI) for atrophy measurement [ 13 , 14 , 15 ].

3. Alzheimer’s Disease’s Neuropathology

There are two types of neuropathological changes in AD which provide evidence about disease progress and symptoms and include: (1) positive lesions (due to accumulation), which are characterized by the accumulation of neurofibrillary tangles, amyloid plaques, dystrophic neurites, neuropil threads, and other deposits found in the brains of AD patients. In addition to (2) negative lesions (due to losses), that are characterized by large atrophy due to a neural, neuropil, and synaptic loss. Besides, other factors can cause neurodegeneration such as neuroinflammation, oxidative stress, and injury of cholinergic neurons [ 16 , 17 , 18 ].

3.1. Senile Plaques (SP)

The senile plaques are extracellular deposits of beta-amyloid protein (Aβ) with different morphological forms, including neuritic, diffuse, dense-cored, or classic and compact type plaques. Proteolytic cleavage enzymes such as β-secretase and γ-secretase are responsible for the biosynthesis of Aβ deposits from the transmembrane amyloid precursor protein (APP) [ 19 , 20 , 21 ]. These enzymes cleave APP into several amino acid fragments: 43, 45, 46, 48, 49, and 51 amino acids, which reach the final forms Aβ40 and Aβ42. There are several types of Aβ monomers, including large and insoluble amyloid fibrils which can accumulate to form amyloid plaques and soluble oligomers that can spread throughout the brain. Aβ plays a major role in neurotoxicity and neural function, therefore, accumulation of denser plaques in the hippocampus, amygdala, and cerebral cortex can cause stimulation of astrocytes and microglia, damage to axons, dendrites, and loss of synapses, in addition to cognitive impairments [ 21 , 22 , 23 ].

3.2. Neurofibrillary Tangles (NFTs)

NFT are abnormal filaments of the hyperphosphorylated tau protein that in some stages can be twisted around each other to form paired helical filament (PHF) and accumulate in neuralperikaryal cytoplasm, axons, and dendrites, which cause a loss of cytoskeletal microtubules and tubulin-associated proteins. The hyperphosphorylated tau protein is the major constituent of NFTs in the brains of AD patients, and its evolution can reflect NFTs morphological stages, which include: (1) pre-tangle phase, one type of NFT, where phosphorylated tau proteins are accumulated in the somatodendritic compartment without the formation of PHF, (2) mature NFTs, which are characterized by filament aggregation of tau protein with the displacement of the nucleus to the periphery part of the soma, and (3) the extracellular tangles, or the ghost NFTs stage, that results from a neuronal loss due to large amounts of filamentous tau protein with partial resistance to proteolysis [ 24 , 25 ].

3.3. Synaptic Loss

A synaptic damage in the neocortex and limbic system causes memory impairment and generally is observed at the early stages of AD. Synaptic loss mechanisms involve defects in axonal transport, mitochondrial damage, oxidative stress, and other processes that can contribute to small fractions, like the accumulation of Aβ and tau at the synaptic sites. These processes eventually lead to a loss of dendritic spines, pre-synaptic terminals, and axonal dystrophy [ 26 ]. Synaptic proteins serve as biomarkers for the detection of synapses loss, and severity, such as neurogranin, a postsynaptic neuronal protein, visinin-like protein-1 (VILIP-1), and synaptotagmin-1 [ 27 , 28 ].

4. The Stages of Alzheimer’s Disease

The clinical phases of Alzheimer’s disease can be classified into (1) pre-clinical or the pre-symptomatic stage, which can last for several years or more. This stage is characterized by mild memory loss and early pathological changes in cortex and hippocampus, with no functional impairment in the daily activities and absence of clinical signs and symptoms of AD [ 1 , 29 , 30 ]. (2) The mild or early stage of AD, where several symptoms start to appear in patients, such as a trouble in the daily life of the patient with a loss of concentration and memory, disorientation of place and time, a change in the mood, and a development of depression [ 30 , 31 ]. (3) Moderate AD stage, in which the disease spreads to cerebral cortex areas that results in an increased memory loss with trouble recognizing family and friends, a loss of impulse control, and difficulty in reading, writing, and speaking [ 30 ]. (4) Severe AD or late-stage, which involves the spread of the disease to the entire cortex area with a severe accumulation of neuritic plaques and neurofibrillary tangles, resulting in a progressive functional and cognitive impairment where the patients cannot recognize their family at all and may become bedridden with difficulties in swallowing and urination, and eventually leading to the patient’s death due to these complications [ 1 , 32 ].

5. Causes and Risk Factors of Alzheimer’s Disease

AD has been considered a multifactorial disease associated with several risk factors ( Figure 2 ) such as increasing age, genetic factors, head injuries, vascular diseases, infections, and environmental factors (heavy metals, trace metals, and others). The underlying cause of pathological changes in Alzheimer’s disease (Aβ, NFTs, and synaptic loss) is still unknown. Several hypotheses were proposed as a cause for AD but two of them are believed to be the main cause: some believe that an impairment in the cholinergic function is a critical risk factor for AD, while others suggest that alteration in amyloid β-protein production and processing is the main initiating factor. However, at present, there is no accepted theory for explaining the AD pathogenesis [ 33 , 34 ].

The risk factors for Alzheimer’s disease.

5.1. Alzheimer’s Disease Hypotheses

5.1.1. cholinergic hypothesis.

In the 1970s, neocortical and presynaptic cholinergic deficits were reported to be related to the enzyme choline acetyltransferase (ChAT), which is responsible for the synthesis of acetylcholine (ACh). Due to the essential role of ACh in cognitive function, a cholinergic hypothesis of AD was proposed. ACh is synthesized in the cytoplasm of cholinergic neurons from choline and acetyl-coenzyme A by the ChAT enzyme and transported to the synaptic vesicles by vesicular acetylcholine transporter (VAChT) ( Figure 3 ). In the brain, ACh is involved in several physiological processes such as memory, attention, sensory information, learning, and other critical functions. Degeneration of the cholinergic neurons was found to take place in AD and to cause alternation in cognitive function and memory loss. Β -amyloid is believed to affect cholinergic neurotransmission and to cause a reduction in the choline uptake and a release of ACh. Studies demonstrated that cholinergic synaptic loss and amyloid fibril formation are related to Aβ oligomers’ neurotoxicity and to interactions between AChE and Aβ peptide. Additional factors also contribute to the progression of AD, such as a reduction in nicotinic and muscarinic (M2) Ach receptors, located on presynaptic cholinergic terminals, and the deficit in excitatory amino acid (EAA) neurotransmission, where glutamate concentration and D-aspartate uptake are significantly reduced in many cortical areas in AD brains. This is in addition to the use of cholinergic receptor antagonists such as scopolamine, which was found to induce amnesia. This effect can be reversed by using compounds that activate acetylcholine formation [ 35 , 36 , 37 ].

The pathway for the synthesis and transportation of acetylcholine between presynaptic and postsynaptic nerve terminals.

As a result, the cholinergic hypothesis is based on three concepts: reduced presynaptic cholinergic markers in the cerebral cortex, severe neurodegeneration of nucleus basalis of Meynert (NBM) in the basal forebrain, which is the source of cortical cholinergic innervation, and the role of cholinergic antagonists in memory decline compared to the agonists, which have the opposite effect [ 38 ].

5.1.2. Amyloid Hypothesis

For decades, it was recognized that abnormal deposition of β-sheets in the central nervous system has a strong correlation with dementia, which led to the concept of the amyloid hypothesis. However, it was found that the amyloid plaques (AP) also deposit in normal healthy brains with aging, which raised the question of whether AP deposition is responsible for AD onset or not? Therefore, in the recent years, alternative hypotheses were proposed for the non-inherited form of AD (NIAD), but at present, the amyloid hypothesis remains the most accepted pathological mechanism for inherited AD (IAD). The amyloid hypothesis suggests that the degradation of Aβ, derived from APP by β- and γ-secretase, is decreased by age or pathological conditions, which leads to the accumulation of Aβ peptides (Aβ40 and Aβ42). Increasing the ratio of Aβ42/Aβ40 induces Aβ amyloid fibril formation, resulting in neurotoxicity and tau pathology induction, and consequently, leading to neuronal cell death and neurodegeneration. AD risk factors and mutations of several genes like APP, PSEN1, and PSEN2 were found to affect Aβ catabolism and anabolism, which rapidly cause an accumulation of Aβ and fast progression of neurodegeneration [ 39 , 40 , 41 ].

5.2. Alzheimer’s Disease Risk Factors

5.2.1. aging.

The most important risk factor in AD is aging. Younger individuals rarely have this disease, and most AD cases have a late onset that starts after 65 years of age [ 42 ]. Aging is a complex and irreversible process that occurs through multiple organs and cell systems with a reduction in the brain volume and weight, a loss of synapses, and ventricles’ enlargement in specific areas accompanied by SP deposition and NFT. Moreover, several conditions might emerge during aging such as glucose hypometabolism, cholesterol dyshomeostasis, mitochondria dysfunction, depression, and cognitive decline. These changes also appear in normal aging, which makes it difficult to distinguish the cases in early AD [ 43 , 44 ]. AD can be divided based on age of onset into early-onset AD (EOAD), the rare form with around 1–6% of cases, in which most of them are familial AD characterized by having more than one member in more than one generation with AD, and ranges from 30–60 or 65 years. The second type is the late-onset AD (LOAD), which is more common with age of onset above 65 years. Both types may occur in people who have a family with a positive history of AD and families with a late-onset disease [ 45 ].

5.2.2. Genetics

Genetic factors were discovered over the years and were found to play a major role in the development of AD. 70% of the AD cases were related to genetic factors: most cases of EOAD are inherited in an autosomal dominant pattern and mutations in the dominant genes such as Amyloid precursor protein (APP) , Presenilin-1 (PSEN-1), Presenilin-2 (PSEN-2) , and apolipoprotein E (ApoE) are associated with AD [ 46 , 47 ].

Herein, we discuss the strong genetic risk factors in AD.

• Amyloid Precursor Protein (APP)

APP is a type I transmembrane protein cleaved by α-, β-, and γ-secretase to release Aβ and other proteins and is encoded by the APP gene on chromosome 21. Thirty mutations have been found in the APP gene in which twenty-five of them are related to AD and cause an accumulation of Aβ with elevated amounts. Meanwhile, there is one protective mutation, A673T, which protects against AD by decreasing Aβ, Aβ40, and Aβ42 secretion [ 48 , 49 ]. All mutations surround the secretase cleavage site, for example, the KM670/671NL mutation in mouse models has shown an increasing level of amyloid plaques in the hippocampus and cortex with no NFTs. A673V, D678H, D678N, E682K, and K687N mutations have shown cortical atrophy, whereas E682K has shown hippocampal atrophy. Neuropathological reports for the A673V mutation demonstrated a presence of NFTs and Aβ, activation of microglia and astrocytes, and neuronal loss, compared to the rest of the mentioned mutations, which show no change in the intracellular Aβ according to neuropathological reports [ 48 , 50 ]. Other mutations such as T714I, V715A, V715M, V717I, V717L, L723P, K724N, and I716V affect the γ-secretase cleavage site and cause an increase in the Aβ42/Aβ40 ratio, while E693G, E693K, D694N, and A692G mutations affect the α-secretase cleavage site and cause polymorphic aggregates with the ability to disrupt bilayer integrity. Also, the E693delta is a deletion mutation that enhances the formation of synaptotoxic Aβ [ 51 , 52 ].

• Presenilin-1 (PSEN-1) and Presenilin-2 (PSEN-2)

PSEN1 and PSEN2 genes are also the autosomal dominant form of EOAD located on chromosomes 14 and 1, respectively. PSEN-2 and PSEN-1 are homologous, with 67% similarity, with a difference in the N -terminus and the hydrophilic region. Mutation in PSEN1 gene is more common, with more than 200 mutations, while a rare form with less than 40 mutations was identified in the PSEN2 gene [ 53 , 54 ].

PSEN1 is a core protein that activates the γ-secretase complex and plays an important role in the production of Aβ from APP. Knockout studies of PSEN1 showed synaptic dysfunction and memory impairment in mice, which indicate its essential role in maintaining memory and neurons [ 51 ]. PSEN1 mutations are simple ones which include single amino acid substitution, and severe mutation can result from the substitutions of two amino acids [ 55 ]. Mutations in the PSEN1 gene increase the ratio of Aβ42/Aβ40 by decreasing Aβ40 levels. The results obtained by Sun et al. study demonstrated that C410Y or L435F mutations in PSEN1 knock-in mice increased the Aβ42/Aβ40 ratio due to a greater reduction in Aβ40 [ 56 ].

In contrast, PSEN-2 mutations are rare and play a minor role in Aβ production. Any mutation in PSEN-2 might have a severe effect on the Aβ 42/40 ratio, causing familial AD in the presence of normal PSEN-1 alleles. Some of the PSEN-2 mutations cause a significant increase in γ-secretase activity with an elevation in the Aβ-42 and Aβ 42/40 ratio level, such as N141I, T122P, M239V, and M239I, while others are rare polymorphisms and have no effect on Aβ-42, -40, and Aβ 42/40 ratio levels and are not considered as pathogenic mutations [ 53 , 57 ].

• Apolipoprotein E (ApoE)

ApoE protein is a glycoprotein expressed highly in the liver and brain astrocytes and some microglia and serves as a receptor-mediated endocytosis ligand for lipoprotein particles like cholesterol, which is essential for myelin production and normal brain function. The ApoE gene located on chromosome 19 has three isoforms, ApoE2, ApoE3, and ApoE4, due to single-nucleotide polymorphisms (SNPs) which cause changes in the coding sequence. The ApoEε4 allele is a strong risk factor for both EOAD and LOAD compared to ApoEε2 and ApoEε3 alleles that are associated with a lower risk and protective effect, respectively [ 58 ]. ApoEε4 plays an important role in Aβ deposition as a senile plaque and causes cerebral amyloid angiopathy (CAA), which is known as a marker for AD [ 59 ]. ApoEε4 was also shown to be associated with vascular damage in the brain, which leads to AD pathogenesis [ 60 ].

• ATP Binding Cassette Transporter A1 (ABCA1)

Adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) is part of a large ABC transporters family that regulate cholesterol efflux in the circulation, like apolipoproteins-AI (ApoAI), and into the brain, like ApoE. In addition, ABCA1 maintains the stability of ApoE lipidation and serves as a mediator for high-density lipoprotein (HDL) generation, which reflects its role in atherosclerosis and cardiovascular diseases. Studies on the AD mice model showed that ABCA1 deficiency increases amyloid plaques and eliminates the lipidation of ApoE [ 61 ]. In humans, a mutation in ABCA1 results in Tangier disease, which is characterized by low levels of high-density lipoprotein (HDL) and ApoAI in plasma, accumulation of cholesterol in tissues, and AD pathogenesis [ 62 ].

• Clusterin Gene (CLU) and Bridging Integrator 1 ( BIN1 )

In contrast to PSEN1 , PSEN2 , and APP mutations, which result in familial or EOAD, clusterin ( CLU) and Bridging Integrator 1 ( BIN1 ) genes are novel risk factors for LOAD. In 2009, Genome-Wide Association Studies (GWAS) identified the CLU gene located on chromosome 8, which is upregulated in the cortex and hippocampus of AD brains, in addition to AD cerebrospinal fluid (CSF) and plasma, which make the CLU a promising biomarker for AD. The CLU may play a protective role by interacting with Aβ and promoting its clearance, or a neurotoxic role by reducing Aβ clearance. The Aβ ratio values determine whether the CLU role is neuroprotective or neurotoxic [ 63 ].

BIN1 is a Bin-Amphiphysin-Rvs (BAR) adaptor protein that is involved in the production of membrane curvature and other endocytosis cellular functions. BIN1 has several isoforms: some are found in the brain, where they interact with different proteins such as clathrin, synaptojanin, and amphiphysin 1, and others in which they regulate synaptic vesicle endocytosis. Recently, BIN1 was recognized as the second most important risk factor for LOAD after ApoE, where it plays a role in Aβ production and as a tau and NFT pathology modulator [ 64 , 65 ].

• Evolutionarily Conserved Signaling Intermediate in Toll pathway (ECSIT)

A significant accumulation of Aβ in AD brains increases protein oxidation, which reflects the critical role of mitochondria in Aβ cytotoxicity and AD pathogenesis. Evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene is located on chromosome 19 and is associated with increasing the risk of AD. ECSIT encodes the adapting protein that functions as a cytoplasmic and signaling protein and is responsible for stabilizing the mitochondrial respiratory complex. Moreover, the adaptor protein is involved in the activation of nuclear factor (NF)-κB, interferon regulatory factors (IRFs), and activating protein-1. Also, it is involved in coupling immune toll-like receptor (TLR), homeostatic bone morphogenetic pathway (BMP), and transforming growth factor-beta (TGF-b) pathways [ 66 , 67 ].

ECSIT interacts with mitochondrial proteins such as Lon protease homolog (LONP1) and glutaryl-CoA dehydrogenase (GCDH), which are involved in intra-mitochondrial proteolysis and redox signaling respectively, followed by interactions with AD seed nitric oxide synthase (NOS3). Moreover, studies have shown certain interactions of ECSIT with the AD genes ApoE , PSEN-1 , and PSEN-2 . These interactions support the role of ECSIT as a molecular link in oxidative stress, inflammation, and mitochondrial dysfunction in AD [ 66 , 68 ].

• Estrogen Receptor Gene (ESR)

AD affects both women and men, but nearly two-thirds of AD cases are women. Several studies have shown that women with AD experience worse mental deterioration than men. Additionally, on the genetic level, some genes’ variation, like the ApoE4 allele, significantly increases AD risk in women compared to men. Other studies documented that AD risk in women is associated with the loss of ovarian hormones during menopause due to the fact that estrogen regulates several activities in the brain, such as neurotransmission, neural development, survival, protection against oxidative stress, reduction of Aβ peptide levels, and attenuation of tau hyperphosphorylation. The estrogen activity is mediated through estrogen receptors (ERs) (intracellular, transmembrane, and membrane-bound ERs). The two major subtypes of these receptors are ERα and Erβ, which are encoded by two distinct genes and are located on chromosome 6 and 14, respectively. ERα receptor is found in the hypothalamus and amygdala, whereas ERβ receptors are in the hippocampus and cortex. Single nucleotide polymorphisms (SNPs) in ERβ and ERα genes may affect exogenous estrogen in older women and influence cognitive aging. PvuII (rs9340799) and Xbal (rs223493) are examples of SNPs found in ERα and are associated with AD and cognitive impairment. Also, several SNPs in ERβ have been proven to increase the risk of AD in women [ 69 , 70 , 71 , 72 ].

• Other Genes

Other genes’ polymorphism associated with increasing the risk of AD include vitamin D receptor (VDR) gene polymorphism, which affects the affinity of vitamin D to its receptor and may cause neurodegenerative diseases and neuronal damage [ 73 ]. Moreover, epigenetic factors like DNA methylation, histone, and chromatin modifications were demonstrated to be involved in AD [ 33 , 74 ].

5.2.3. Environmental Factors

Aging and genetic risk factors cannot explain all cases of AD. Environmental risk factors including air pollution, diet, metals, infections, and many others may induce oxidative stress and inflammation and increase the risk for developing AD. Herein, we report the most important environmental factors and their relationships with AD [ 75 , 76 ].

• Air Pollution

The air pollution is characterized by modifying the nature of the atmosphere through the introduction of chemical, physical, or biological pollutants. It is associated with respiratory and cardiovascular diseases and recently, its association with AD was documented. Six air pollutants have been defined by National Ambient Air Quality Standards (NAAQSs) in the USA as a threat to human health, including ozone (O 3 ), nitrogen oxides (NO x ), carbon monoxide (CO), particulate matter (PM), sulfur dioxide (SO 2 ), and lead. Studies on animals and cellular models have shown that an exposure to high levels of air pollution can result in a damage to the olfactory mucosa and bulb, in addition to the frontal cortex region, similar to that observed in AD. In individuals exposed to air pollutants, there is a link between oxidative stress, neuroinflammation, and neurodegeneration, with the presence of hyper-phosphorylated tau and Aβ plaques in the frontal cortex. The air pollution can cause an increase in Aβ 42 formation, accumulation, and impaired cognitive function [ 77 , 78 ].

In recent years, the number of studies on the role of nutrition in AD have been increased. Several dietary supplements such as antioxidants, vitamins, polyphenols, and fish were reported to decrease the risk of AD, whereas saturated fatty acids and high-calorie intake were associated with increasing the risk of AD [ 79 ]. The food processing causes degradation of heat-sensitive micronutrients (e.g., vitamin C and folates), loss of large amounts of water, and formation of toxic secondary products (advanced glycation end products, AGEs) from non-enzymatic glycation of free amino groups in proteins, lipids, and nucleic acids. The toxic effect of AGEs is referred to as their ability to induce oxidative stress and inflammation by modifying the structure and function of the cell surface receptors and body proteins. Different studies demonstrated that elevated AGEs serum level is associated with cognitive decline and progression of AD. The AGE receptor (RAGE) is located in different places within the body, including microglia and astrocytes, and was established to be overexpressed in the brain of AD patients and serve as a transporter and a cell surface receptor for Aβ [ 80 ]. Malnutrition is another risk factor for AD. Deficiency in nutrients such as folate, vitamin B12, and vitamin D may cause a decrease in cognitive function, in addition to the fact that patients with AD suffer from problems associated with eating and swallowing, which may increase the risk of malnutrition [ 81 ].

Metals are found in nature and biological systems and can be divided into bio-metals that have a physiological function in living organisms (e.g., copper, zinc, and iron), and toxicological metals which do not possess any biological function (e.g., aluminum and lead) [ 82 ]. Aluminum is used significantly in the industries such as processed foods, cosmetics, medical preparations, medicines, and others. In the body, aluminum is bound to plasma transferrin and to citrate molecules that can mediate the transfer of aluminum to the brain. Studies demonstrated that Al accumulates in the cortex, hippocampus, and cerebellum areas, where it interacts with proteins and causes misfolding, aggregation, and phosphorylation of highly phosphorylated proteins like tau protein, characteristic of AD [ 83 ]. Lead competes with the binding site of bio-metals like calcium and can cross the blood–brain barrier (BBB) rapidly, where it can modify neural differentiation and synaptogenesis and cause severe damage. Studies revealed that an acute exposure to lead was associated with AD and caused an increase of β-secretase expression and Aβ accumulation. Cadmium is a carcinogenic water-soluble metal that can cross the BBB and cause neurological diseases like AD. Results have demonstrated that Cadmium ions are involved in the aggregation of Aβ plaques and the self-aggregation of tau in the AD brain. The data accumulated on metals support the notion that they are among the risk factors involved in the development of AD [ 84 ].

Chronic infections to the central nervous system (CNS) can cause an accumulation of Aβ plaques and NFT, therefore, they are included among the risk factors in AD. Studies by Dr. Itzhaki showed that the DNA of herpes simplex virus (HSV-1) was found in patients with ApoE-ε4 allele carriers, which explains the high risk for developing AD. HSV-1 can replicate in the brain, which can result in the activation of the inflammatory response and an increase in Aβ deposition, resulting in damage to neurons and gradual development of AD. On the other hand, the study results by Miklossy and Balin’s have revealed the role of chronic bacterial infections in AD. For example, syphilitic dementia caused by spirochete bacteria ( Treponema pallidum ), which are accumulated in the cerebral cortex, produced lesions similar to neurofibrillary tangles, which led to devastating neurodegenerative disorders. Besides, Chlamydia pneumonia bacterium can trigger late-onset AD by activation of astrocyte and cytotoxic microglia, disrupt calcium regulation and apoptosis, resulting in deterioration of cognitive function, and increase the risk of AD [ 85 , 86 , 87 ].

5.2.4. Medical Factors

Several risk factors are related to the development of Alzheimer’s disease. Adding to this list, older people with AD usually have medical conditions such as cardiovascular disease (CVD), obesity, diabetes, and others. All of these conditions are associated with increased risk of AD [ 88 , 89 ].

• Cardiovascular Disease (CVDs)

CVDs are recognized as an important risk factor for AD, such as the stroke that is associated with increased risk of dementia due to a neural tissue loss, which enhances degenerative effect and influences amyloid and tau pathology. Atrial fibrillation also causes embolisms which leads to stroke and a decrease in memory and cognitive functions. Moreover, heart failure affects the pumping function of the heart and results in insufficient blood supply to the body and hypo-perfusion of the brain that leads to hypoxia and neural damage. The coronary heart disease’s hypothesis indicates that atherosclerosis, peripheral artery disease, hypo-perfusion, and emboli are all related to increased risk of AD. Hypertension is associated with thickening of vessel walls and narrowing of the lumen which reduce the cerebral blood flow, and in chronic cases, it may cause cerebral edema, which all participate as risk factors for AD and CVD. The CVD is a modifiable risk factor and by focusing on its relationship with AD, a pathway to prevent and delay the disease can be obtained [ 89 , 90 ].

• Obesity and Diabetes

Obesity is a term used for too much body fat in individuals due to consuming more calories than they burn and can be calculated by using the body mass index (BMI). Increasing the body fat is associated with a decreased brain blood supply which promotes brain ischemia, memory loss, and vascular dementia. The obesity, unhealthy diet, and other factors can cause impaired glucose tolerance (IGT) or diabetes, which is characterized by hyperglycemia that affects peripheral tissues and blood vessels. Chronic hyperglycemia can induce cognitive impairment as a result of increasing amyloid-beta accumulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation. Obesity is characterized by increasing pro-inflammatory cytokines secretions from adipose tissue, which stimulate macrophages and lymphocytes and eventually lead to local and systemic inflammation. This inflammation promotes insulin resistance, hyperinsulinemia, and as a consequence, hyperglycemia. Obesity is a well-known risk factor for type 2 diabetes, CVDs, and cancer, which are identified as risk factors for dementia and AD. The brain inflammation causes an increase in microglia and results in reduced synaptic plasticity and impaired neurogenesis. Microglia can affect insulin receptor substrate 1 (IRS-1) and block intracellular insulin signaling, which has an important role in neural health. Therefore, alteration in insulin action can result in Aβ accumulation and reduce the tau protein degradation associated with AD [ 91 , 92 , 93 , 94 ].

6. Treatment

Currently, Alzheimer’s disease cases worldwide are reported to be around 24 million, and in 2050, the total number of people with dementia is estimated to increase 4 times. Even though AD is a public health issue, as of now, there is only two classes of drugs approved to treat AD, including inhibitors to cholinesterase enzyme (naturally derived, synthetic and hybrid analogues) and antagonists to N -methyl d -aspartate (NMDA). Several physiological processes in AD destroy Ach-producing cells which reduce cholinergic transmission through the brain. Acetylcholinesterase inhibitors (AChEIs), which are classified as reversible, irreversible, and pseudo-reversible, act by blocking cholinesterase enzymes (AChE and butyrylcholinesterase (BChE)) from breaking down ACh, which results in increasing ACh levels in the synaptic cleft [ 95 , 96 , 97 ]. On the other hand, overactivation of NMDAR leads to increasing levels of influxed Ca 2+ , which promotes cell death and synaptic dysfunction. NMDAR antagonist prevents overactivation of NMDAR glutamate receptor and hence, Ca 2+ influx, and restores its normal activity. Despite the therapeutic effect of these two classes, they are effective only in treating the symptoms of AD, but do not cure or prevent the disease [ 98 , 99 ]. Unfortunately, only a few clinical trials on AD have been launched in the last decade and their outcome was a big failure. Several mechanisms have been proposed to understand AD pathology in order to modify its pathway and develop successful treatments, which include abnormal tau protein metabolism, β-amyloid, inflammatory response, and cholinergic and free radical damage [ 30 , 100 ]. On the other hand, most AD modifiable risk factors such as cardiovascular or lifestyle habits can be prevented without medical intervention. Studies showed that physical activity can improve the brain health and reduce AD by activating the brain vascularization, plasticity, neurogenesis, and reducing inflammation by decreasing Aβ production, which all result in improving cognitive function in older people. Moreover, the Mediterranean diet (MD), intellectual activity, and higher education all may reduce the progression of AD and memory loss and increase the brain capacity and cognitive functions. Several studies revealed that multi-domain intervention which includes lifestyle (diet, exercise, and cognitive training), depression of AD symptoms, and controlling cardiovascular risk factors, can increase or maintain cognitive function and prevent new cases of AD in older people [ 101 ]. Herein, we summarize the currently available drugs and theories for the development of new therapies for AD.

6.1. Symptomatic Treatment of AD

6.1.1. cholinesterase inhibitors.

According to the cholinergic hypothesis, AD is due to the reduction in acetylcholine (ACh) biosynthesis. Increasing cholinergic levels by inhibiting acetylcholinesterase (AChE) is considered one of the therapeutic strategies that increases cognitive and neural cell function. AChEIs are used to inhibit acetylcholine degradation in the synapses, which results in continuous accumulation of ACh and activation of cholinergic receptors. Tacrine (tetrahydroaminoacridine) ( 1, Figure 4 ) was the first FDA (Food and Drug Administration)-approved cholinesterase inhibitor drug for the treatment of AD, which acts by increasing ACh in muscarinic neurons, but it exited the market immediately after its introduction due to a high incidence of side effects like hepatotoxicity and a lack of benefits, which was observed in several trials. Later on, several AChEIs were introduced, such as donepezil ( 2 , Figure 4 ), rivastigmine ( 3 , Figure 4 ), and galantamine ( 4 , Figure 4 ), and are currently in use for the symptomatic treatment of AD [ 34 , 97 , 102 , 103 ]. Another strategy that may help in the treatment of AD is increasing choline reuptake and as a result, increasing acetylcholine synthesis at the presynaptic terminals. This can be achieved by targeting choline transporter (CHT1) which is responsible for supplying choline for the synthesis of ACh. Developing drugs that are capable of increasing CHT1 at the plasma membrane may become the future therapy of AD [ 36 ].

The chemical structures of approved drugs for symptomatic treatment of AD (tacrine 1 , donepezil 2 , rivastigmine 3 , galantamine 4 , and memantine 5 ) and disease-modifying compounds that entered clinical trials (semagacestat 6 , avagacestat 7 , tarenflurbil 8 , lanabecestat 9 , verubecestat 10 , atabecestat 11 , umibecestat 12 , methylene blue 13 , tideglusib 14 , and saracatinibin 15 ).

Donepezil ( 2 , Figure 4 ) is an indanonebenzylpiperidine derivative and a second generation of AChEIs and is considered the leading drug for AD treatment. Donepezil binds to acetylcholinesterase reversibly and inhibits acetylcholine hydrolysis, which leads to a higher concentration of ACh at the synapses. The drug is well-tolerated with mild and transient cholinergic side effects which are related to the gastrointestinal and nervous systems. It should be noted that donepezil is used to treat symptoms of AD such as improving cognition and behavior without altering the AD progression [ 104 , 105 , 106 ].

• Rivastigmine

Rivastigmine ( 3 , Figure 4 ) is a pseudo irreversible inhibitor of AChE and butyrylcholinesterase (BuChE) that acts by binding to the two active sites of AChE (anionic and estearic sites), which results in preventing ACh metabolism. BuChE is found mostly in glial cells with only 10% of AChE activity in the normal brain, whereas in the AD brain, its activity is increased to 40–90%, while ACh activity is reduced simultaneously, which suggests that BuChE action may indicate a moderate to severe dementia. Rivastigmine dissociates more slowly than AChE, which is why it is called a pseudo-irreversible, and it undergoes metabolism at the synapse by AChE and BuChE. The drug is used in mild to moderate AD cases. It improves cognitive functions and daily life activities. Oral administration of the drug is associated with adverse effects such as nausea, vomiting, dyspepsia, asthenia, anorexia, and weight loss. In many cases, these side effects are the main reason behind stopping taking the medicine, however, they can be settled down in time and consequently, the drug becomes more tolerated. Rivastigmine can be delivered by transdermal patches for controlled and continuous delivery of the drug through the skin, with enhanced tolerability and caregiver satisfaction. Also, the patches can deliver a lower dosage compared to pills, which results in reduced side effects. Most AD patients suffer from memory loss and swallowing problems which affect their compliance in administering oral drugs at regular intervals. Therefore, the use of transdermal patches is the most appropriate method for delivering the drug in AD patients [ 107 , 108 , 109 , 110 ].

• Galantamine (GAL)

Galantamine ( 4 , Figure 4 ) is considered a standard first-line drug for mild to moderate AD cases. GAL is a selective tertiary isoquinoline alkaloid with a dual mechanism of action in which it acts as a competitive inhibitor of AChE and can bind allosterically to the α-subunit of nicotinic acetylcholine receptors and activate them. GAL can improve behavioral symptoms, daily life activities, and cognitive performance with good efficacy and tolerability, similar to other AChE inhibitors. Several delivery systems were developed to improve the drug delivery to the brain: Wahba et al. attached GAL to ceria-containing hydroxyapatite particles for selective delivery of the drug to the affected regions in the brain. Misra et al. and Fornaguera et al. used solid-lipid nanoparticles and nano-emulsification approaches respectively, to carry GAL hydrobromide. The results of these studies demonstrated a promising strategy for safe delivery of the drug. Hanafy et al. developed nasal GAL hydrobromide/chitosan complex nanoparticles which showed good pharmacological efficacy, while Woo et al. utilized the patch system as a carrier for a controlled release dosage form of the drug [ 111 , 112 , 113 , 114 ].

6.1.2. N -methyl d -aspartate (NMDA) Antagonists

NMDAR is believed to have a dominant role in the pathophysiology of AD. NMDAR stimulation results in Ca 2+ influx which activates signal transduction and as a consequence, it triggers gene transcription essential for the formation of a long-term potentiation (LTP), which is important for synaptic neurotransmission, plasticity, and memory formation. Over-activation of NMDARs causes an abnormal level of Ca 2+ signaling and overstimulation of glutamate, which is the primary excitatory amino acid in the CNS, which results in excitotoxicity, synaptic dysfunction, neuronal cell death, and a decline in cognitive functions. Several NMDAR uncompetitive antagonists have been developed and entered clinical trials, however, most of them failed due to low efficacy and side effects. Memantine ( 5 , Figure 4 ) is the only approved drug in this category to treat moderate to severe AD; in addition, other NMDAR uncompetitive antagonist compounds are being developed, such as RL-208 (3,4,8,9-tetramethyltetracyclo [4.4.0.0 3,9 .0 4,8 ]dec-1-yl)methylamine hydrochloride), a polycyclic amine compound that may possess a promising therapeutic effect in age-related cognitive problems and AD [ 115 , 116 , 117 ].

Memantine ( 5 , Figure 4 ) is a low-affinity uncompetitive antagonist of the NMDAR, a subtype of glutamate receptor that prevents over-activation of the glutaminergic system involved in the neurotoxicity in AD cases. Memantine is used for the treatment of moderate to severe AD alone or in combination with AChEI. The drug is safe and well-tolerated, it blocks the excitatory receptor without interfering with the normal synaptic transmission due to memantine’s low affinity, where it is displaced rapidly from NMDAR by high concentrations of glutamate, thus avoiding a prolonged blockage. The latter is associated with high side effects, especially on learning and memory [ 99 , 118 ].

6.2. Promising Future Therapies

6.2.1. disease-modifying therapeutics (dmt).

Disease-modifying treatment or therapy (DMT) alter the progression of AD by working on several pathophysiological mechanisms. This is in contrast to symptomatic therapy which works on improving the cognitive functions and decreasing symptoms such as depression or delusions without affecting or modifying the disease. DMTs, either immunotherapies or small molecules, are administrated orally and are being developed to prevent AD or decrease its progression. Several DMTs have been developed and entered the clinical trials, such as AN-1792, a synthetic Aβ peptide (human Aβ 1–42 peptide of 42-amino acids with the immune adjuvant QS-21) and the first active immunotherapy for AD which entered phase II clinical trials and discontinued due to a meningoencephalitis side effect in 6% of the patients. Other drugs were also developed and failed in the clinical trials, including the anti-Aβ antibody (solanezumab and bapineuzumab), γ-Secretase inhibitors (semagacestat 6 , avagacestat 7 , and tarenflurbil 8 ) ( Figure 4 ) and β-secretase inhibitors (BACE) (Lanabecestat 9, verubecestat 10 , and atabecestat 11 ) ( Figure 4 ). DMTs failures are due to several factors, such as starting therapy too late, giving treatment for the wrong main target, use of inappropriate drug doses, and misunderstanding of the pathophysiology of AD. Several immunotherapies described in Table 1 have been developed over decades, including: CAD106, an active Aβ immunotherapy that induces Aβ antibodies in animal models and consists of multiple copies of Aβ1–6 peptide coupled to Qβ coat protein, a virus-like particle, and is still in clinical trials, and CNP520 (umibecestat, 12 ) ( Figure 4 ), a small molecule that inhibits beta-scretase-1 (BACE-1) and therefore inhibits Aβ production. CNP520 was found to reduce Aβ plaque deposition and Aβ levels in the brain and CSF in rats, dogs, and healthy adults ≥ 60 years old, and is still under clinical trials. Furthermore, aducanumab, gantenerumab, and crenezumab are all human Aβ monoclonal antibody that bind with high affinity to aggregated Aβ, and they are still under study in the clinical phases with other DMTs described in Table 1 [ 6 , 119 , 120 , 121 , 122 , 123 , 124 ].

Disease modifying agents for the treatment of Alzheimer’s disease in clinical trials.

Another class targeting the α-secretase enzyme was developed and has been considered as therapeutic agents. α-secretase modulators or activators stimulate the cleavage of APP. There is little knowledge about the activation pathway, but research assumes that it is promoted by the phosphatidylinositol 3-kinase (PI3K)/Akt pathway or by γ-aminobutyric acid (GABA) receptor signaling. Targeting these pathways may give potential therapeutic agents for AD [ 6 ].

In addition to the anti-amyloid agents, the tau aggregation inhibitors are another promising DMT. The tau is a biomarker for neurofibrillary tangles (NFT) in AD and naturally modulates microtubule stability, signaling pathways, and axonal transport. A modification in tau conformation results in toxic aggregation. Therefore, the prevention of tau aggregation becomes an interesting approach for drug discovery to reduce AD progression. Studies in mice have shown that tau oligomers cause mitochondrial damage, disruption of neuronal signaling, synaptic loss, and memory impairment. Disease-modifying therapeutics (DMT) like small molecules can be used to inhibit the initial step in the tau aggregation and thereby reduce its accumulation. Methylene blue ( 13 , Figure 4 ) is a blue dye that inhibits the tau aggregation and entered phase II clinical trials to treat mild to moderate AD. Upon administration of the drug, the color of the urine becomes blue, which indicates a lack of binding, and because of that, the study was highly criticized. Other approaches suggest that an inhibition of specific kinases such as glycogen synthase kinase 3 (GSK3β) can inhibit tau hyperphosphorylation and block tau deposition. Examples of these entities include tideglusib ( 14 , or NP-031112 (NP-12), Figure 4 ), a thiazolidinedione-derived compound, lithium, pyrazolopyridines, pyrazolopyrazines, sodium valproate, and others. Another protein kinase inhibitor is saracatinib (AZD0530) ( 15 , Figure 4 ), which acts by inhibiting tyrosine kinase and has shown good results in improving memory in transgenic mice and is currently in phase II trials [ 125 , 126 , 127 ]. Davidowitz et al. utilized the hatu mouse model of tauopathy to study the efficacy of a lead small molecule in preventing tau accumulation. The study results demonstrated a significant reduction in tau levels and its phosphorylated form levels, which indicates the ability to inhibit the entire pathway of the tau aggregation by using an optimized lead compound [ 128 ].

6.2.2. Chaperones

Protein misfolding caused by mutations or environmental factors results in aggregations that are toxic, and their accumulation causes neurodegenerative disorders like AD. Naturally, cells develop protein quality control (PQC) systems that inhibit protein misfolding before exerting their toxic effects. With age, this balance is altered and the misfolded shapes overwhelm the PQC system, which in turn activates the unfolded protein response (UPR) that stops the protein synthesis and increases chaperone production. Generally, the cells in humans have proteins that are responsible for other proteins to function and arrive to their destination in the cell. These proteins are called “chaperones”. Chaperones are involved in protein folding and improvement of the PQC system efficiency. Therefore, it is considered a promising candidate for treating neurodegenerative diseases. It can be classified into three groups: (1) molecular chaperones, which are proteins that assist other nonnative proteins in their folding or unfolding, like overexpression of heat shock proteins (Hsps) that serve as neuroprotective agents, (2) pharmacological chaperones, which are low molecular weight compounds (enzymes or receptor-ligand or selective binding molecules) that induce refolding of proteins, stabilize their structure, and restore their function, and (3) chemical chaperones, also low molecular weight compounds, which are divided into two groups, osmolytes and hydrophobic compounds. The members in these two groups have no specific mechanism of action and need high concentrations to exert their therapeutic effects [ 129 ].

• Heat Shock Proteins (Hsps)

The causes for most neurodegenerative diseases are protein misfolding and aggregation, which lead to cell death. The molecular chaperone can be intracellular, such as in the case of heat shock proteins (e.g., Hsp40, Hsp60, Hsp70, Hsp90, Hsp100, and Hsp110), and extracellular, such as clustering and alpha-macroglobulin. HSPs play an essential role in the protein folding process and protect cells from harmful stress-related events. There are two families of Hsps: (a) classic Hsps that possess an ATP-binding site with a molecular weight of 60 kD or more. This family includes Hsp100, Hsp90, Hsp70, and Hsp60, and (b) the small Hsps such as αB-crystalline, Hsp27, Hsp20, HspB8, and HspB2/B3 that lack ATP-binding site, with a molecular weight of 40 kD or less. These proteins can assist other Hsps in their refolding function. Failure of these mechanisms can lead to oxidative stress, mitochondrial dysfunction, and many other conditions that cause damage, a loss of neurons, and a progression of neurodegenerative diseases. Different HSPs can block the aggregation process of misfolded proteins, like amyloidogenic proteins (Aβ and tau), and promote their degradation [ 130 , 131 ].

Hsp60 plays an important role in mitochondrial protein folding. Its role in AD is not clear, some believe that the protein has a protective role and others think it has a harmful effect where it can be over-expressed by activated microglia, which increases pro-inflammatory factors such as toll-like receptor 4 (TLR-4) that stimulate neuronal cell death. Therefore, inhibiting activated microglia and Hsp60 expression is a promising strategy for preventing neurodegenerative diseases. Examples of compounds that inhibit Hsp60 are mizoribine (Immunosuppressant) ( 16 , Figure 5 ) and pyrazolopyrimidine EC3016 ( 17 , Figure 5 ). Both compounds act by blocking ATPase activity of Hsp60 and inhibiting protein folding. On the other hand, avrainvillamide, a fungal metabolite ( 18 , Figure 5 ), and epolactaene, a bacterial metabolite ( 19 , Figure 5 ), act by binding to the Hsp60′s cysteine residues and inhibit its folding activity. However, Hsp60’s role in AD remains controversial and there is a need for more investigations to understand its role [ 130 ].

The chemical structures of different chaperone molecules: Mizoribine 16 , EC3016 17 , Avrainvillamide 18 , Epolaztaene 19 , MKT-077 20 , YM-01 21 , JG-98 22 , Radicicol 23 , Geldanamycin 24 , 17-AAG 25 , Pochoxime C (OS47720) 26 , R55 27 , and OT1001 28 .

Studies have shown that Hsp70 binds to Aβ42 and prevents self-aggregation. Martín-Peña et al. studied two isoforms of Hsp70, cytosolic and extracellular, in Drosophila flies AD models and evaluated their protective role against memory decline that results from Aβ42 aggregation. The animal studies showed that Hsp70 has a dual function: intracellularly and extracellularly, where it protects against Aβ42 neurotoxicity and synaptic loss. In addition to its ability to bind to tau and its hyper-phosphorylated form and prevent its formation, it decreases aggregation and promotes tau binding to microtubules. Hsp70 acts by activating microglia, insulin-degrading enzyme, and tumor growth facto r- β1, which degrades β-amyloids and prevents memory impairments [ 132 , 133 ]. Some studies in AD brain tissue demonstrated an overexpression of Hsp70 levels and a correlation with the presence of activated glia and stressed neurons. Also, it was found that Hsp70 is associated with extracellular deposits in AD. Drug therapies targeting Hsp70, mainly referring to previous anticancer drugs which target and inhibit Hsp70 ATP-binding site, are considered as candidates in AD treatment due to their ability to reduce tau levels in vitro and ex vivo. MKT-077(1-ethyl-2-(( Z )-(( E )-3-ethyl-5-(3-methylbenzo [ d ]thiazol-2(3 H )-ylidene)-4-oxothiazolidin-2-ylidene)methyl)pyridin-1-ium chloride) ( 20 , Figure 5 ), is an anticancer rhodacyanine compound that binds to mortalin, a mitochondrial Hsp70 site, and acts as an anti-proliferative agent, but the use of this compound was stopped due to toxicity side effects and low BBB penetration. On the other hand, YM-01 ( 21 , Figure 5 ), a more potent MKT-077 derivative, was developed with a single replacement of the ethyl group on the pyridinium nitrogen of MKT-077 with a methyl group. JG-98 ( 22 , Figure 5 ) is also an MKT-077 derivative with a 60-fold higher binding affinity to Hsp70 than YM-01 [ 130 , 134 , 135 , 136 ].

Hsp90 is another type of HSP that regulates the tau phosphorylation and dephosphorylation. An inhibition of Hsp90 results in a decrease in phosphorylation of tau due to a reduction in tau kinases, which is thought to be responsible for tau pathogenesis when it is hyperactivated. Hsp90 inhibitors are used for cancer therapy, but recently, they are considered as promising therapy for AD. Radicicol (RDC) ( 23 , Figure 5 ) and geldanamycin (GA) ( 24 , Figure 5 ) are Hsp90 inhibitors. GA is a natural antifungal compound and the first discovered Hsp90 inhibitor. Studies on this inhibitor were stopped due to its toxicity. On the other hand, 17-AAG (17-(Allylamino)-17-demethoxygeldanamycin) ( 25 , Figure 5 ) is a GA derivative with a lower toxicity and better pharmacokinetic profile that showed a good improvement of the cognitive function by inducing other HSPs, like Hsp70, in addition to reducing NFTs in the transgenic mouse model by blocking the tau phosphorylation pathway, indirectly [ 137 , 138 ]. Pochoxime C (OS47720) ( 26 , Figure 5 ) is also a CNS-permeable Hsp90 inhibitor that showed good safety and efficacy profiles when tested in the AD mouse model. Studies revealed that OS47720 acts by strengthening synaptic function via heat shock factor (HSF-1) activation and dependent transcriptional events [ 139 ].

The combined studies demonstrate that targeting HSPs is a promising strategy to develop drugs with a new mechanism of action for reducing pathogenic tau levels and restoring normal tau homeostasis.

• Vacuolar sorting protein 35 (VPS35)

An accumulation of proteins in neurons and glial cells leads to disturbance of cellular protein homeostasis. The endosomal-lysosomal system is responsible for transporting proteins for recycling and degradation. Any malfunction in the system can lead to several diseases, such as Alzheimer’s disease. Retromer is a complex of regulator proteins composed of sorting nexin (SNX1, 2, 5, 6) and vacuolar sorting proteins (VPS 26, 29, 35), which are responsible for transporting cargo molecules from the endosome to the trans -Golgi network. A loss of retromer’s function results in the downregulation of VPS35, which can increase Aβ formation, induce cognitive impairments, and cause synaptic dysfunction, which is reported in AD patients [ 140 , 141 ]. A study on 3xTg mice brains was conducted to evaluate the effect of VPS35 overexpression on memory function. The study showed that a significant reduction of the Aβ peptide and tau neuropathology (soluble, insoluble, and phosphorylated tau) was associated with overexpression of VPS35, in addition to a reduction in neuroinflammation and ameliorating synaptic dysfunction [ 142 ]. Therefore, VPS35 is an important promising therapeutic target for AD treatment. A small pharmacological chaperones molecule called R55 (thiophene-2,5-diylbis(methylene) dicarbamimidothioatedihydrochloride) ( 27 , Figure 5 ), a thiophenethiourea derivative, can enhance retromer stability and function by increasing retromer proteins, shifting AOO from the endosome, and reducing pathogenic processing of APP, which may serve as a promising therapeutic molecule for neurodegenerative diseases [ 143 ].

Studies demonstrated that the accumulation of gangliosides has been associated with misfolding and aggregation of proteins in neurodegenerative diseases. Abnormal levels of mono-sialoganglioside (GM1, GM2, and GM3) have been reported in AD brains. Mutant forms of Aβ, like Dutch mutant APPE693Q, showed susceptibility to pro-aggregation properties of GM2 and GM3, resulting in the formation of Aβ peptides complexes with gangliosides (ganglioside-bound Aβ (GAβ) peptide) and subsequently leading to an acceleration of aggregation and accumulation of Aβ peptides.

β-hexosaminidase (β-hex) is a lysosomal enzyme that acts by catabolizing GM2 ganglioside, and increasing its activity can lead to a reduction of GM2 levels and Aβ aggregation and accumulation. Small molecules like pharmacological chaperones (PC) can selectively bind and stabilize wild-type proteins and restore their normal folding. OT1001 ( 28 , Figure 5 ) is an iminosugar PC that targets β-hex and increases its level in the brain and reduces GAβ pathology. Studies on Dutch APPE693Q transgenic mice showed that OT1001 has good pharmacokinetics, brain penetration ability, and tolerability, with lower side effects. These make the compound a good drug candidate for increasing the β-hex activity [ 144 ].

6.2.3. Natural Extract

For a long time, natural compounds have been used as therapeutic agents for several pathological diseases, and recent studies showed that they possess a neuroprotective effect. In vitro and in vivo studies have proven that natural compounds possess a therapeutic potential for AD, which allowed some of them to enter the clinical trials stages. Nicotine was the first natural compound entered in the clinical trials for AD, then other compounds like vitamins C, E, and D gained more attention and interest due to their protective role against neuroinflammation and oxidative damage. Recently, bryostatin, a macrolide lactone extract from bryozoan Bugula neritina, has been evaluated and showed the ability to induce α-secretase activity, reduce Aβ production, and enhance the learning and memory in an AD mice model [ 145 ]. Other natural compounds used in folk medicine (traditional Chinese medicine (TCM)) demonstrated a great potential in treating AD by acting on several mechanisms, as shown in Table 2 below [ 146 ].

Natural compounds used in folk medicine and their mechanism of actions.

7. Conclusions

Alzheimer’s disease is now considered a world health concern; as a consequence, the National Institute on Aging—Alzheimer’s Association reclassified and updated the 1984 NINCDS-ADRDA criteria for higher specificity, sensitivity, and early identification of patients at risk of developing AD. Several criteria have been proposed for a more accurate diagnosis of AD, including clinical biomarkers, bodily fluids, and imaging studies. Despite that, the treatment of AD remains symptomatic, without alteration in the disease’s prognosis. Inhibitors to cholinesterase enzyme such as galantamine, donepezil, and rivastigmine, and NMDA antagonists such as memantine, improve memory and alertness but do not prevent progression. Several studies have shown that modification in lifestyle habits like diet and exercise can improve brain health and reduce AD without medical intervention and is considered as a first-line intervention for all AD patients. Recently, the research is focusing on targeting the pathological features of AD such as Aβ and p-tau. Future therapies such as disease-modifying treatment can alter the progression of AD by targeting the Aβ pathway, and many drugs have entered the clinical trials, like AN-1792, solanezumab, bapineuzumab, semagacestat, avagacestat, and tarenflurbil, but failed in demonstrating efficacy in the final clinical stages. Other DMTs are still under investigation, such as those targeting Aβ and tau pathologies, such as aducanumab, gantenerumab, crenezumab, tideglusib, lithium, and others. Other promising compounds called chaperones like heat shock proteins and vacuolar sorting protein 35 (VPS35) function by assisting other proteins to function normally and to arrive at their destination in the cell safely, and therefore can be used as a treatment for neurodegenerative diseases. Moreover, the natural extracts used in folk Chinese medicine showed great potential in treating AD by acting on several mechanisms’ pathways. In conclusion, the success of AD treatment depends on its early administration and patient monitoring for disease progression using biomarkers diagnosis. Future therapies that target tau pathology and the use of combination therapy may have a potential to slow the progression of AD pathology. Designing a potent, selective, and effective drug is urgently needed to treat patients with AD and those at risk for developing the disease.

Author Contributions

Literature survey and first draft writing were done by Z.B., and final draft, including the revisions, were accomplished by R.K. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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