Alzheimer’s Disease and Advanced Research Therapy

My research is on Alzheimer' and its advanced research Therapy, Alzheimer' is a very devastating disease which has no cure, but there are new treatments to lower the Risk of symptoms of Alzheimer' I this research I also look into the mechanisms.
Muhammad Usman Mirza
Grade 8

Problem

Alzheimer's Disease and Advanced Research Therapy

Problem:

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide, regardless of gender or ethnicity. It remains one of the leading causes of dementia, significantly impacting cognitive function, memory, and behavior. Despite extensive research, there is currently no cure for Alzheimer's disease.

Treatment

Several treatment options are available to manage symptoms and slow disease progression. These include cholinesterase inhibitors, NMDA receptor antagonists, and emerging monoclonal antibody therapies targeting amyloid plaques. However, these treatments are not without limitations, such as adverse side effects, limited efficacy, and varying responses among patients. There remains a critical need to develop safer and more effective therapeutics that can halt or reverse the neurodegenerative process.

MEN1 Gene and Its Role in Alzheimer's Disease

My project focuses on investigating the role of the MEN1 gene in Alzheimer's disease. The MEN1 gene, primarily known for its tumor suppressor functions, has recently been linked to neurodegenerative disorders. Understanding its involvement in brain function and pathology could provide valuable insights into Alzheimer's disease mechanisms.

A key hypothesis of my research is that MEN1 gene dysregulation may contribute to cholinergic dysfunction, a hallmark of Alzheimer's disease. Cholinesterase inhibitors, which increase the availability of acetylcholine in the brain, are commonly used to manage symptoms. By exploring how MEN1 gene activity influences cholinergic pathways, I aim to uncover new therapeutic targets that could enhance the efficacy of existing treatments or lead to the development of novel drugs.

Through this research, I hope to bridge the gap in our understanding of Alzheimer's disease pathology and contribute to the advancement of targeted, effective treatments that address the underlying mechanisms of neurodegeneration.

Method

Method:

1. My Google Search

Search terms: 

  • "What is Alzheimer's Disease"
  • "Causes of Alzheimer's Disease"
  • "Alzheimer's Treatment Options"
  • "Advanced Treatments for Alzheimer's"
  • "Alzheimer's Disease Pathology and MEN1"

I started with a web search, using Google.ca to input queries. The search terms were:

I only used websites managed by government or medical bodies or had verified references in their articles.

I conducted a comprehensive search on Alzheimer's Disease using reliable sources such as government and medical websites. My search included topics like the causes, symptoms, diagnosis, types, and treatment options for Alzheimer's Disease. Additionally, I explored recent advancements and the disease's connection to MEN1, referencing peer-reviewed articles from PubMed.

Following is my literature review,

 

  1. "Establishment and Dysfunction of the Blood-Brain Barrier" by Daneman R, Prat A 

    • This article provided an in-depth understanding of how the blood-brain barrier (BBB) functions and its role in Alzheimer's Disease. I learned that BBB dysfunction allows harmful substances to enter the brain, contributing to neurodegeneration. The authors detailed how BBB breakdown exacerbates inflammation and oxidative stress, accelerating disease progression. Additionally, the paper highlighted potential therapeutic strategies targeting BBB restoration, offering a promising avenue for intervention.

  2. "Locus Coeruleus and Neurodegeneration" (Read more)

    • From this article, I gained knowledge on how the locus coeruleus (LC) is one of the first brain regions affected in Alzheimer's Disease. The article emphasized that LC degeneration results in reduced norepinephrine production, contributing to increased neuroinflammation and cognitive decline. It also noted the role of the LC in regulating the sleep-wake cycle, with disturbances often preceding Alzheimer's symptoms. Researchers are exploring therapies targeting norepinephrine pathways to mitigate the effects of LC degeneration.

  3. "The Role of Microglia in Alzheimer's Pathology" 

    • This research explored the involvement of microglia in disease progression. Microglia are immune cells of the brain, and their malfunction leads to excessive inflammation, accelerating neuronal damage. The authors highlighted how misregulated microglia contribute to amyloid-beta plaque accumulation and tau pathology. Moreover, therapeutic approaches modulating microglial function were discussed, underscoring the importance of balancing their protective and damaging effects.

  4. "Genetic Risk Factors and Alzheimer's Disease" (Read more)

    • I discovered how genetic mutations, including those in APP, PSEN1, and PSEN2 genes, significantly increase the risk of early-onset Alzheimer's. The article also explored the role of APOE4, a prominent genetic risk factor for late-onset Alzheimer's Disease. By analyzing genome-wide association studies (GWAS), the researchers identified novel genetic markers linked to disease susceptibility. These findings provide valuable insights into personalized medicine approaches targeting genetic vulnerabilities.

  5. "Innovative Therapeutic Approaches" (Read more)

    • This article introduced various novel treatment options targeting amyloid-beta plaques and tau protein tangles. Recent developments in monoclonal antibodies like Lecanemab and Donanemab were discussed as promising therapies. The authors also reviewed advancements in gene therapy, anti-inflammatory treatments, and stem cell-based interventions. Understanding these therapeutic strategies enhanced my perspective on the multifaceted approaches to combat Alzheimer's Disease.

  6. "MEN1 and Its Potential Link to Alzheimer's" (Read more)

    • Although MEN1 is primarily known as a genetic disorder leading to tumors, emerging evidence suggests it may influence neurodegeneration. The article highlighted the expression of MEN1-related proteins in the brain and their potential role in regulating neural pathways. I learned that MEN1 mutations could disrupt cellular processes, contributing to tau pathology and neuronal loss. The authors emphasized the importance of further research to establish a clear connection and explore therapeutic possibilities.

  7. "Amyloid Plaque Imaging Advances in Alzheimer's Research" (Read more)

    • This article discussed advancements in imaging techniques used to detect amyloid plaques in Alzheimer's patients. The researchers explained how positron emission tomography (PET) scans using specific tracers provide real-time visualization of amyloid accumulation. Improved imaging accuracy enables earlier diagnosis and better monitoring of disease progression. The study also outlined the role of imaging in evaluating the efficacy of anti-amyloid therapies.

  8. "Tau Protein Pathology and Therapeutic Approaches" (Read more)

    • I learned from this article about the significance of tau protein aggregation in Alzheimer's Disease. The study explained the mechanisms behind tau hyperphosphorylation and its role in forming neurofibrillary tangles. Researchers are investigating tau-targeting therapies, including small molecules and monoclonal antibodies, to prevent tangle formation and promote tau clearance. These approaches represent promising therapeutic strategies.

  9. "Inflammatory Pathways in Alzheimer's Disease Progression" (Read more)

    • This article explored the role of chronic inflammation in Alzheimer's progression. The authors emphasized how immune system dysregulation leads to sustained inflammation, damaging neurons. I gained insights into emerging treatments that aim to regulate inflammatory pathways using anti-inflammatory drugs and immune-modulating therapies. These interventions may help slow disease progression.

  10. "Neuroprotective Factors and Their Potential in Alzheimer's Treatment" (Read more)

  • This article highlighted various neuroprotective molecules that may counteract neuronal damage in Alzheimer's Disease. Factors like brain-derived neurotrophic factor (BDNF) and antioxidants were explored for their protective effects. Researchers suggested these molecules could be harnessed to develop therapies promoting neuronal survival and cognitive function.

 

Then I contacted researchers at the University of Calgary’s Cumming School of Medicine. These conversations contextualized my understanding of Alzheimer's Disease and exposed me to groundbreaking research on cholinesterase inhibitors and the MEN1 gene. These interactions provided valuable insights into current challenges and breakthroughs in the field, further enriching my knowledge of Alzheimer's research!

 

Research

Alzheimer’s Disease and Advanced Research Therapy

 

My Motivation!

What motivated me to choose this topic?

I became interested in this topic through my previous experience at the 2024 Science Fair, where I worked on a project about epilepsy. That project earned me the First Place Gold Medal and allowed me to collaborate with the Neuroscience Lab at the University of Calgary.

During my time in the lab, I observed a Ph.D. student researching Alzheimer’s disease. Hearing their discussions about its impact on the brain and the ongoing challenges in finding effective treatments sparked my curiosity. Even though it was a new topic for me, I was fascinated and immediately decided to explore it for my next project. With the lab’s approval, I started my research journey to learn about Alzheimer’s and share the latest findings through this project.”

Introduction:

Alzheimer’s disease is a Neurodegenerative progressive Brain disorder that affects memory, thinking, and behaviour. The language of the Brain is Electrical Signals between Neurons (Brain Cells) When there are Abnormal Changes in the Brain’s Electrical Activity and Nerve Cells Degenerate, this may be Alzheimer's.  Biologically, it is caused by a build-up of beta-amyloid plaques and tau tangles in the brain, leading to neuron damage, and inflammation.

Difference between Alzheimer’s and Dementia:

Alzheimer’s: Alzheimer's is a chronic Brain-based Disease, which is non-communicable (Non-Spreadable). It is not like Viral disease. 
Dementia:  
  • It is the Primary Symptom of Alzheimer’s.  
  • The Brain works by processing and transmitting Information through Neurons.

Damage or Death of Neurons can disrupt brain activity, leading to memory loss, confusion, and impaired thinking.

 

Key Facts:

  • Alzheimer’s disease can affect people of all genders, ethnicities, and backgrounds, though it primarily affects older adults. (ARE)
     
  • Approximately 55 million people worldwide live with Alzheimer’s disease and other forms of dementia.
     
  • Over 60% of people with dementia live in North and South America.
     
  • Neuroscientists estimate that with early diagnosis and proper care, the progression of Alzheimer’s can be slowed in many cases, improving quality of life.
     
  • Some people with Alzheimer’s and their families often face stigma and discrimination due to misunderstandings about the condition.

Symptoms of Alzheimer’s:

There are several symptoms of Alzheimer's which could range from Mild to Severe.                                                                                                                                  (From Cumming School of Medicine)

The Most Common Symptoms of Alzheimer's are the following:A comparison of a brain and a brainDescription automatically generated

  1. Memory Loss.
  2. Confusion with Time or Place.
  3. Age.
  4. Loss of Consciousness or Awareness. (PPS)
  5. Cognitive (Thoughts) or Emotional (Feelings) Changes.
  6. Difficulty with Problem-Solving. 

 

Causes of Alzheimer’s:

 There are many causes of Alzheimer’s.

  • Genetics: If Alzheimer’s is in the Family, there is a higher risk it can happen to the other family members.
  •  Plaques and Tangles: Abnormal protein clumps (amyloid plaques) and twisted tangles of protein (tau tangles) in the brain are hallmarks of the disease.
  • Age: The risk increases with age, especially after 65.
  • Family History: Having a close relative with Alzheimer’s increases the risk.
  • Other Risk Factors: High blood pressure, diabetes, smoking, and a lack of exercise can increase the risk.
  • Diet: Poor dietary habits, such as high consumption of processed foods and sugar, can negatively affect brain health.
  • Social Isolation: Lack of regular social interactions may contribute to cognitive decline

 

Types of Alzheimer’s:

Alzheimer's is divided into Three Types.

  1. Early-onset Alzheimer's Disease
  2. Late-onset Alzheimer's Disease
  3. Familial Alzheimer's Disease (FAD)

 

1:Early-Onset Alzheimer’s:

In Early-onset Alzheimer’s Disease occurs before the age of 65, and in some cases, it can happen in people as young as their 40s or 50s. Only around 5% of all Alzheimer’s cases are early-onset. 

  • Genetic Mutations: 

Mutations in the APP, PSEN1, or PSEN2 genes are common causes of early-onset Alzheimer's.

  • Family History: 

A strong family history of the disease increases the likelihood of developing it.

  • Early Symptoms: Difficulty in remembering recent events or conversations. Challenges in finding the right words to express thoughts. Trouble concentrating, solving problems, or planning daily activities. Mood swings, irritability, or mild personality changes.
  • Progression: Initially affects memory and language areas of the brain. Over time, it impacts decision-making, movement, and social interactions.

2:Late-Onset Alzheimer’s:

In this type, the brain is affected by age-related changes, such as the buildup of harmful proteins and nerve cell damage. This form of Alzheimer’s generally occurs after the age of 65 and is the most common type.

  • Causes and Risk Factors:

Age: The risk increases significantly with aging. Genetic Factors: Having the APOE-e4 gene raises the chances but does not guarantee the disease. Lifestyle Choices: Conditions like high blood pressure, smoking, poor diet, and inactivity increase the risk.

  • Symptoms:

Trouble remembering recent events or conversations. Confusion about time, place, or familiar tasks. Behavioral changes like mood swings, apathy, or irritability. Difficulty solving problems or following a plan.

  • Progression

Starts with mild memory lapses and confusion. Gradually leads to challenges in decision-making and motor skills. Severe stages result in the need for full-time care and assistance.

3: Familial Alzheimer’s Disease (FAD):

  • A rare form of Alzheimer’s, inherited in families across multiple generations.
  • Caused by genetic mutations that are passed from one generation to the next.
  • Symptoms typically begin earlier in life, between 30 and 60 years of age. 

 

Neurodevelopmental Basis of Alzheimer’s

Your brain is like a supercomputer made of billions of tiny cells called neurons. These neurons communicate with each other to help you think, remember, and learn. In Alzheimer’s disease, these cells get damaged and stop working properly.

Neurodevelopment is how the brain grows and forms connections during childhood. It’s like building the brain’s “wiring system.” The way your brain develops when you’re young can affect how strong or weak these connections are when you get older. Scientists now believe that these early brain-building processes might influence who develops Alzheimer’s later in life.

 

Treatments

 

There are several Clinical Treatment Options. 

However, my centre of attention will be on Current Advanced Treatment and understanding the Mechanisms of Neurodevelopment, Degeneration, and Alzheimer’s Disease .

1: Medications. 

These drugs target memory, thinking, and behaviour:

  • Cholinesterase Inhibitors
    • Examples: Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne).
    • How they help: Boost levels of acetylcholine, a chemical important for memory and learning.
  • Memantine (Namenda):
    • Helps regulate glutamate, a chemical involved in learning and memory.
    • Often used for moderate to severe stages of Alzheimer’s.

2: Vagus Nerve Stimulator 

There is one vagus nerve on each side of the body. The vagus nerve runs from the lower part of the brain which goes to the neck to the chest and stomach.  It regulates our Heart Rate, Blood Pressure and Breathing by sending Signals between your Brain, Heart and Lungs. It can also affect your Mood, Memory and Cognition by sending Electrical Signals between Brain and Limbic System.This is a experimental approach being studied for its potential to help with Alzheimer’s disease and Depression, This Device Stimulates the Vagus Nerve with Electrical Impulses.  FDA-approved, VNS: Uses a device (like a small pacemaker) to send mild electrical signals to the vagus nerve, either through an implant or a non-invasive device. 

Side-effects:  

  • Voice changes, 
  • Throat Pain, 
  • Cough, 
  • Headaches, 
  • Shortness of Breath, 
  • Difficulty Swallowing, 
  • and Skin itching.

3 : Antiepileptic Drugs. These drugs help to reduce some. There are around 30 approved drugs for the treatment of Alzheimer’s.

4: Ketogenic Diet. Another Treatment for Alzheimer’s which works on to Change in Diet.

 

Advanced Research Techniques

Advanced Brain Imaging:

This advanced technique is now being explored for its potential in Alzheimer's disease diagnosis and monitoring. By using high-resolution electrode implants to record brain activity, combined with cutting-edge machine-learning algorithms, researchers can analyze MRI images to detect subtle morphological signs of brain damage. This approach could enhance early detection, improve treatment strategies, and provide deeper insights into the progression of Alzheimer's disease.

Introduction of the MEN1 Gene:

The MEN1 gene, known for encoding the menin protein, has long been recognized for its role as a tumor suppressor. Traditionally associated with Multiple Endocrine Neoplasia Type 1, menin's primary functions include regulating cell growth and preventing tumor formation. However, recent groundbreaking research conducted by a team of scientists at the University of Calgary has unveiled new insights into its presence and significance in the human brain.

One of the most remarkable findings from this research is that the MEN1 gene is actively expressed in neural tissue. Menin has been shown to play a crucial role in cholinergic transmission ,  a key aspect of neuronal communication that is vital for memory, learning, and cognitive function. Additionally, menin has been found to induce synapse formation and contribute to synaptic plasticity, further underscoring its importance in maintaining brain health.

This discovery has opened up exciting avenues in Alzheimer's disease research. Studies have indicated a possible relationship between menin and the tau protein, a hallmark of Alzheimer's pathology. Understanding how menin interacts with tau and influences neurodegenerative processes could lead to breakthroughs in early diagnosis and therapeutic interventions. Machine-learning algorithms are now being applied to analyze brain imaging data, identifying subtle morphological signs of neurodegeneration that may be linked to MEN1 dysfunction. High-resolution electrode implants are also enhancing our ability to monitor brain activity and gain deeper insights into Alzheimer's disease progression.

I was fortunate to be involved in this cutting-edge research, working alongside a dedicated team of scientists. Contributing to this project has provided me with invaluable experience and has deepened my passion for exploring the complex mechanisms of neurological diseases.

The Objectives of My Project

The primary objective of my project is to further investigate the role of the MEN1 gene in the human brain, particularly its interaction with tau protein and its implications for Alzheimer's disease. By analyzing brain imaging data and conducting molecular studies, I aim to uncover potential biomarkers for early detection and monitor disease progression. Additionally, understanding how menin influences synaptic plasticity and neuronal health may reveal novel therapeutic targets.

This research has the potential to not only advance our understanding of Alzheimer's disease but also contribute to the development of more effective diagnostic tools and treatments. Ultimately, the goal is to improve the quality of life for those affected by neurodegenerative diseases through earlier intervention and personalized therapeutic strategies.

 

Two proteolytic fragments of menin coordinate the nuclear transcription and postsynaptic clustering of neurotransmitter receptors during synaptogenesis between Lymnaea neurons | Scientific Reports
Two proteolytic fragments of menin coordinate the nuclear transcription and  postsynaptic clustering of neurotransmitter receptors during synaptogenesis  between Lymnaea neurons. Taken from Neuroscience Lab at university of Calgary

Data

My project was a research study, which is why I presented only graphs to showcase the findings.

(Both males and females were included, with diagnoses confirmed for Alzheimer’s early-onset (ADEO) or late-onset (ADLO). This approach allowed us to study differences between early and late stages of the disease while considering individual variability.“)

 

A screenshot of a computer Description automatically generated

 

 

(This figure shows the expression of Menin in the human brain, comparing control (non-AD) and Alzheimer's disease (AD) samples. The images depict immunohistochemical staining, with the control brain tissue displaying more intense Menin expression compared to the AD tissue. The inset images provide a closer view of neuronal structures, further emphasizing the reduced Menin presence in the AD sample. The accompanying bar graph quantifies this difference, demonstrating significantly lower Menin levels in the AD group compared to the non-AD group.)

 

 

Conclusion

Alzheimer’s disease is a complex and challenging neurological condition with no cure. However, various treatments aim to slow its progression and manage symptoms. In my research, I explored the role of the MEN1 gene and its connection to Alzheimer’s pathology, including beta-amyloid plaques and tau tangles. Using advanced research techniques, I analyzed scientific data through PubMed and observed how molecular pathways contribute to neurodegeneration.

During my time at the Neurosciences Lab at the Cumming School of Medicine, University of Calgary, I had the opportunity to engage with leading neuroscientists, Ph.D. candidates, and graduate students. I observed cutting-edge research on human brain cells, glial cells, synapses, and neurotechnology, such as silicon-based chips designed for neurological studies. This experience deepened my understanding of Alzheimer’s disease and the innovative approaches being developed to study and combat it.

Inspired by this exposure, I am motivated to pursue a career in neuroscience and contribute to groundbreaking research and potential treatments for neurodegenerative diseases.

Acknowledgement

First and foremost, I will extend my special thanks to ALLAH, whose blessings made this possible. I also appreciate everyone who supported me in completing this project on Alzheimer’s Disease. 

 Special Thanks to my Respectable Teachers  Mrs. Jyoti, Bennacer, Khalil and Dr. Naweed Imam Syed, Neuroscientist, Professor of Medicine and their Ph.D. students, Mrs. Zainab Khan, and Mr. Fahad Iqbal from Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary

Lastly, I would like to thank my father as well.