Alzheimer’s & Parkinson’s – Two Diseases On A Spectrum

Decades of disease research have led us to a unique perspective on Alzheimer’s, Parkinson’s and other neurodegenerative diseases: They are all closely related and lie on the same spectrum.

We Call It—The ParkinZheimer Spectrum.

Why is this ParkinZheimer viewpoint important to us?

Consider this: During the past three decades, Alzheimer’s and Parkinson’s drug development and clinical trials have failed to find a cure despite hefty spending of more than US$30 billion worldwide. The handful of drugs that has been approved by the US Food and Drug Administration (FDA) over this period offers only limited symptomatic relief, but nothing approaching a cure.

And yet, the need to find a cure for Alzheimer’s and Parkinson’s has never been greater. The number of people in the US diagnosed with Alzheimer’s and Parkinson’s are currently estimated at 5.8 million and 1 million, respectively.

These numbers will increase nearly threefold by 2050 without effective treatments, according to The Alzheimer’s Association and Parkinson’s Foundation (Parkinson.org).

These organizations also project that the combined cost of caring for Alzheimer’s and Parkinson’s patients in the US will rise to approximately $1.3 trillion by 2050, threatening our economy.

We believe the lack of successful drug development over the past three decades is due in large part to the way Alzheimer’s and Parkinson’s are perceived; namely that these are two distinct diseases, and therefore have been placed in separate silos.

In an effort to accelerate successful drug treatments, our group of scientists has gained significant ground in a new technique to diagnose Alzheimer’s and Parkinson’s based on tracking the biomarkers, aka Misfolded Protein or Prions, of both diseases.

This has led us to the ParkinZheimer Spectrum thesis.

Thanks to advancements in molecular biology, for the first time in history we are empowered to detect the biomarkers that drive the ParkinZheimer Spectrum. Early and with certainty. Why this change in paradigm?

Because this shift gives us a new lens in looking at an old problem where advancement had been impossible.

Our goal is simple: We want to share our new approach in analyzing and diagnosing these elusive diseases to innovate drug development and to find the cure before we lose another generation.  

In this article, we’ll examine the following fundamental areas of the ParkinZheimer Spectrum. 

  1. Traditional Views on Alzheimer’s and Parkinson’s
  2. What Are Misfolded Proteins?
  3. What Are the Key Characteristics Of Misfolded Proteins?
  4. What Are the Key Missing Answers For Misfolded Proteins?
  5. What Are The Parallels Between Alzheimer’s and Parkinson’s?
  6. When Do Alzheimer’s and Parkinson’s Occur?
    • Development or Asymptomatic Stage
    • Symptomatic Stage
  7. What Role Does Genetics Play in Alzheimer’s
  8. What Role Does Genetics Play in Parkinson’s?
  9. The Challenges Of Using Plague, Tangles and Synuclein As Biomarkers To Detect Alzheimer’s And Parkinson’s
  10. How To Detect Alzheimer’s and Parkinson’s’ With Accuracy
  11. How Does Amprion Science Work?
  12. Why Is Early Diagnosis of Alzheimer’s and Parkinson’s Important?
  13. Why ParkinZheimer?
  14. Conclusion

To understand the ParkinZheimer Spectrum thesis, let’s start by looking at our past approaches in dealing with Alzheimer’s and Parkinson’s, and the key elements that drive neurodegenerative diseases.  

We will also explore why we believe the ParkinZheimer paradigm is a much-needed shift in driving innovation and accelerating successful drug development.

TRADITIONAL VIEW OF ALZHEIMER’S & PARKINSON’S

Historically, Alzheimer’s and Parkinson’s have been viewed as two completely different diseases. This viewpoint has remained unchanged for more than 100 years.

Patients with Alzheimer’s and Parkinson’s go to different doctors often housed in different buildings on the same campus.

Funding opportunities for Alzheimer’s generally excludes Parkinson’s and vice versa. Neuroscientists and clinicians are encouraged to focus their careers on one of the diseases.

The National Institutes of Health (NIH) even go so far as funding research for these diseases from completely different institutes.

Alzheimer’s is funded through the National Institute on Aging (NIA) and Parkinson’s through the National Institute of Neurologic Disease and Stroke (NINDS).

According to a government website, www.clinicaltrials.gov, there are currently:

  • 2,280 clinical trials for Alzheimer’s
  • 2,259 clinical trials for Parkinson’s

Takeaway

These two disciplines are kept separate, with no cross fertilization or sharing of research, learning, or knowledge.

WHAT ARE MISFOLDED PROTEINS?

Neurodegenerative diseases as a whole share a set of unique biomarkers known as Misfolded Proteins or Prions.  We use these terms interchangeably throughout this article.  

Prions represent normal brain proteins that have misfolded into alternative, toxic shapes, much like a piece of paper being folded into completely different shapes through the art of origami. 

Prions display three characteristics that damage our brains:

  • They are soluble nanoparticles that spread disease by moving between connected nerve cells.
  • At lower concentrations, they appear to disrupt normal protein synthesis and degradation within nerve cells leading to cell death.
  • At high concentrations, they tend to form large insoluble aggregates that are easily detected under a microscope. This is commonly referred to as plaque and tangles in Alzheimer’s and Lewy Bodies in Parkinson’s.

PRION BIOMARKERS FOR ALZHEIMER’S AND PARKINSON’S

So far, scientists have discovered various types of misfolded proteins as biomarkers associated with Alzheimer’s and Parkinson’s.  It’s worth noting that some diseases may show more than one type of Prion biomarker. 

Alzheimer’s is almost always associated with the following two types of misfolded protein:

  • Abeta
  • Tau

Furthermore, the following misfolded proteins also have been identified in 20-40% of Alzheimer’s patients:

  • Synuclein
  • TDP43

Parkinson’s, in contrast, is almost always associated with a single misfolded protein biomarker:

  • Synuclein

WHAT ARE THE KEY CHARACTERISTICS OF MISFOLDED PROTEINS?

Misfolded proteins are known for the following key properties:

  • When a protein starts to misfold, it is triggered by various events that take place in the brain.  These events include:
    1. Physical Events such as traumatic head injuries.
    2. Hereditary Events linked to a family history of either Alzheimer’s or Parkinson’s
    3. Environmental Events involving infectious agents or toxic chemical reactions.

Prions Are Proteins Gone Rogue

  •  Once misfolding has been triggered, the prion is armed with the capability to “recruit” other normal proteins to misfold in the same way, causing a domino effect. This results in the formation of billions of new prions over time. These zombie proteins attack and convert normal proteins, essentially building a growing zombie protein army, that is undetectable.
  • During this incubation or development stage, the misfolded proteins accumulate silently within brain cells, remaining under the radar for decades.  We also refer to this development stage as the Asymptomatic Stage, and will use these terms interchangeably in this article.
  • Prions or Zombie Proteins are virtually impossible to detect using existing methods available in the marketplace to date, mainly because their basic structure is identical to that of normal proteins. 

Zombie Proteins Amass In Size Over Time, Doing Damage to the Brain In Stealth Mode For Decades Without Showing Signs of Clinical Symptoms

  • Once the concentration of prions reaches a certain threshold within a brain cell or neuron, it causes cell death.  Unlike most cells in the body, nerve cells in the brain cannot regenerate or be replaced with newer copies. This leads to an unrecoverable loss of normal mental functions.
  • Cracking the code on how misfolded proteins operate is the key to understanding the ParkinZheimer Spectrum.

WHAT ARE THE MISSING ANSWERS ON MISFOLDED PROTEINS?

As scientific pioneers researching misfolded proteins for nearly two decades, we are confident in our discoveries, and we are also confident in saying, “We know what we don’t know.”  We need to learn more about the fundamentals of the life cycle of misfolded proteins and how these “silent but deadly zombie proteins” work within the body, including:

  • How, where, and when do normal proteins start to “misfold”, turning into zombie proteins
  • How are misfolded proteins transported, both into the brain and within the brain
  • How do these prions disrupt critical intracellular processes to cause cell death inside the brain
  • What are the critical pathways that lead to the loss of cognition and motor control

WHAT ARE THE PARALLELS BETWEEN ALZHEIMER’S AND PARKINSON’S?

As science advances, molecular biology has opened the door to uncovering new biomarkers, enabling us to identify, localize, and track different types of disease with high accuracy and confidence.

The biomarker profile of various misfolded proteins has led us to perceive Alzheimer’s and Parkinson’s as closely linked diseases that share surprisingly similar traits:

  • Parkinson’s Disease frequently progresses to severe dementia at later stages that closely resemble that of Alzheimer’s Disease.
  • Misfolded Synuclein is found frequently in both Alzheimer’s (40%) and Parkinson’s (95%).
  • 10% of patients clinically diagnosed with Alzheimer’s may show only misfolded Synuclein.
  • We now have the power to diagnose and treat ParkinZheimer Spectrum diseases on the basis of misfolded protein biomarkers rather than clinical symptoms.

Takeaways

  • Our Ability to Identify Misfolded Protein Biomarkers Represents The Breakthrough That Has Eluded Us For More Than 100 Years.
  • The more we learn about Alzheimer’s and Parkinson’s, the more similar these diseases appear.  This brings us to a new understanding.
  • To Accelerate Drug Development, We Need To Focus On The Similarities Between Alzheimer’s And Parkinson’s, Not Their Differences.

WHEN DO ALZHEIMER’S AND PARKINSON’S REALLY OCCUR?

At present, we can diagnose Alzheimer’s and Parkinson’s only after clinical symptoms appear (Symptomatic Stage) when irreversible damage to the brain has already occurred.  As such, Alzheimer’s and Parkinson’s are both perceived as diseases of the elderly from a clinical perspective:

  • According to the Alzheimer’s Association, 81% of people with Alzheimer’s-type dementia in the US are older than 75 years of age (2019 Alzheimer’s Association: Fact and Figures). 
  • Parkinson’s occurrence is more than 100-fold greater in the seventh decade of life compared with the fourth (Kaiser Permanente Data, J. Epidemiology 2003). 

However, as discussed earlier, misfolded proteins—the culprits in driving Alzheimer’s and Parkinson’s—pass through decades of incubation. 

During this Asymptomatic Phase, there is no detection method available.  Herein lies the crux of our centuries-old diseases: 

Alzheimer’s and Parkinson’s Both Pass Through An Asymptomatic Phase.  Spanning Multiple Decades, This Development Stage Brings Invisible, Undetectable Damage To The Brain

Does This Mean Alzheimer’s And Parkinson’s Really Occur Earlier In Our Lives?

The answer is a resounding YES.  Recent findings suggest that both Alzheimer’s and Parkinson’s diseases first develop as early as our teens, and more frequently in our 20s and 30s.  Consider the following:

  • Young athletes experiencing repeated episodes of head trauma show an increased incidence of cognitive decline. In cases of multiple concussions, there is radiological evidence for early formation of misfolded Tau protein aggregates in the brain within a relatively short period of time. 
  • A significant number of these athletes eventually progress decades later to Alzheimer’s-like dementia, Parkinson’s, or other neurodegenerative diseases involving Tau Tangles, Lewy Bodies, or both.
  • Patients with Dominant Inherited Alzheimer’s carry a single gene that encodes a mutated Abeta protein with an increased ability to misfold spontaneously. These patients have misfolded Abeta from birth and onward, but do not exhibit clinical symptoms until approximately age 35.
  • Boxers experiencing multiple traumatic head injuries in their prime adult life (20s and 30s), have an increased incidence of both cognitive and motor neurodegeneration later in life. The best-known example for Parkinson’s is Muhammad Ali. 

Michael J Fox, the actor and founder of the Michael J Fox Foundation, was first diagnosed with Parkinson’s at age 29.  He attributes the unusually young age of his diagnosis to several possible environmental factors including Lyme Disease and alcohol abuse, according to an article published on May 14, 2002 in The New York Times.

  • Recent research indicates that Misfolded Protein Synuclein aggregates may originate in the gut for some individuals and travel to the brain via the vagus nerve, (also called X cranial nerve) which runs from the brain through the face and thorax to the abdomen. Patients who have had their vagus nerve surgically removed show a decreased relative risk or delayed onset of Parkinson’s in their older years. 
  • Misfolded Protein Synuclein aggregates have been found in the removed appendices of patients younger than 20, suggesting that Parkinson’s may be triggered relatively early in life (2018 Killinger et al, Science Translational Medicine 10:465).

Takeaways

  • For both Alzheimer’s and Parkinson’s patients, the misfolding of proteins may have already started in the brain during their youth and early adult years.  
  • During this Asymptomatic Phase, destruction of neurons (brain cells) progresses silently and undetected. 
  • Clinical symptoms appear decades later.

WHAT ROLE DOES GENETICS PLAY IN ALZHEIMER’S?

Both Alzheimer’s and Parkinson’s are largely sporadic diseases, meaning that genetics may increase the risk of disease, but is not the major determinant. 

Scientists have discovered a gene called ApoE, which may affect our individual risk in both diseases. 

Types of ApoE

Humans all carry two copies of ApoE, which comes in five (5) different forms:

  • ApoE-1 
  • ApoE-2 
  • ApoE-3 
  • ApoE-4 
  • ApoE-5.

Not All ApoE Are Created Equal

Good ApoE

Individuals who carry two copies of the ApoE-2 gene have a greatly reduced risk of Alzheimer’s. 

Bad ApoE 

  • Individuals who carry one copy of the ApoE-4 gene have a 3 to 4-fold
    increased risk of Alzheimer’s in their lifetime.
  • Individuals who carry two copies of the ApoE-4 gene have a 13-fold increased risk of Alzheimer’s.

WHAT ROLE DOES GENETICS PLAY IN PARKINSON’S?

For Parkinson’s patients, carrying certain mutations in the GBA-1 or LRRK2 genes significantly increases the lifetime risk of Parkinson’s.

The mechanism of action for any of these genes is not completely understood. However, both of these genes may be involved in the accumulation of misfolded proteins. 

  1. Mutations in GBA-1 causes accumulation of certain lipids (fats) in the brain that trigger Synuclein misfolding. 
  2. Mutations in LRRK2 may impair the removal and degradation of misfolded Synuclein proteins in nerve cells.  

Both mutations increase the level of Misfolded Synuclein, and therefore the risk of Parkinson’s.

THE CHALLENGES OF USING PLAQUE AND TANGLES AS BIOMARKERS TO DETECT ALZHEIMER’S AND PARKINSON’S 

Historically, plaque and tangles have been used as biomarkers for Alzheimer’s and Parkinson’s.

What Are Plaque And Tangles?  

Simply put, they are large insoluble aggregates of misfolded proteins.

  • Plaque is the result of Misfolded Protein Abeta. 
  • Tangles are the result of Misfolded Protein Tau.

Plaque vs. Tangle:

  • Plaque resides almost exclusively between cells.
  • Tangles are found within nerve cells. 

When Are Plaque and Tangles Formed?

After the first appearance of Misfolded Abeta and/or Misfolded Tau in the cerebral spinal fluid, the formation of plaque / tangles is expected years later, if not decades.

Is Plaque A Reliable Biomarker For Alzheimer’s?

Although the presence of plaque is frequently observed in Alzheimer’s patients, it is an unreliable marker of Alzheimer’s if used exclusively. 

Plaque is a useful guide when combined with many other biomarkers.

Consider the following statistics:

  • Approximately 20% of people older than 80 have plaque but no dementia. 
  • At least 20% of patients who have dementia have no plaque. 

So the presence or absence of plaque is not a single conclusive biomarker for Alzheimer’s.

Are Tangles Accurate Biomarkers For Alzheimer’s?

Using radioactive Tau tracers, tangles have been observed in patients with Alzheimer’s as well as with other neurodegenerative diseases.

For patients with Minimal Cognitive Impairment (MCI), the earliest Symptomatic Stage for Alzheimer’s and other Dementias, only 50-60% show increased Tau tangles in PET Scanning.  

This data further reinforces the reality that not all Alzheimer’s patients share the same molecular path to the disease. 

Takeaways

  • While plaque and tangles are clearly associated with the disease, they are not present in every patient. 
  • Furthermore, plaque and tangles may be present in older patients who show no clinical symptoms.

How To Detect Plaque and Tangles

Historically, PET Scanning is employed to detect plaque and tangles. First, radioactive tracers are injected into the patient’s body, immediately followed by imaging of the brain.

How About “Lewy Bodies” As A Biomarker For Alzheimer’s and Parkinson’s?

Lewy Bodies are the result of a large formation of insoluble aggregates of Misfolded Synuclein.  Presently, there are no radioactive tracers available for targeting Misfolded Synuclein to track Lewy Bodies for either Alzheimer’s and Parkinson’s diseases.

HOW TO DETECT ALZHEIMER’S AND PARKINSON’S DISEASES WITH ACCURACY

We believe the most effective method in detecting Alzheimer’s and Parkinson’s is by tracking and monitoring the elusive Prion biomarkers, such as Abeta, Tau, and Synuclein.

Tracking the prion forms of these misfolded proteins requires NO radioactive injections into the patient, and reduces costs associated with PET Scanning.

With the advances in molecular biology, we will soon offer early detection tests on all of the misfolded proteins associated with Alzheimer’s and Parkinson’s, using both cerebral spinal fluid (CSF) and blood.  

Takeaway

Misfolded Abeta, Synuclein, and Tau Prions appear to be highly accurate biomarkers for detecting ParkinZheimer Spectrum of diseases at every stage. 

It Is Worth Noting That A CSF Test Gives The Most Certainty. Why?

At the earliest stages during the Asymptomatic Phase, the Zombie Proteins are localized mostly in brain cells. 

This means the concentration of misfolded proteins is the highest in the brain and in CSF. 

At this development stage, the presence of misfolded proteins in the blood may be too low in concentration to allow for definitive early detection. 

Team Amprion recently has been awarded FDA’s Breakthrough Device Designation for detecting Misfolded Synuclein, associated with Parkinson’s Disease as well as several types of dementia.  

We are also working on commercial applications for testing Misfolded Abeta and Tau, which are both found in most Alzheimer’s patients.  This means that through our Prion Early Detection Testing, we can accurately and definitively track the presence of misfolded protein aggregates in the brain during the Asymptomatic Stages of ParkinZheimer Spectrum of diseases, with a single drop of CSF.

HOW AMPRION SCIENCE WORKS

Amprion detection science mimics the misfolded protein domino effect that occurs in the brains of Alzheimer’s and Parkinson’s patients. The conversion of normal proteins into Zombie Proteins, which often takes 20-50 years in the brain, can be accelerated to 100 hours in the laboratory.

WHY IS EARLY DIAGNOSIS OF ALZHEIMER’S AND PARKINSON’S IMPORTANT?

We believe early diagnosis is the HOLY GRAIL in finding cures for the entire ParkinZheimer Spectrum of neurodegenerative diseases. 

By identifying, analyzing, and tracking the critical biomarkers early, we will equip ourselves with essential information to innovate drug development and clinical trials.  

For individuals, recognizing the biomarker footprint early will empower them to work towards delaying the onset of symptoms through lifestyle, diet, and exercise. 

Delaying the onset of Alzheimer’s and Parkinson’s makes a significant impact in achieving longer quality of life. 

According to Alzheimer’s Association, delaying the onset of Alzheimer’s by just five years could decrease the number of people
with active disease by as much as 42%!

Understanding one’s biomarker footprint also can help both the physicians and their patients to select the most suitable clinical trials for participation. 

It is clear to us that misfolded proteins and formation of prions represent among the earliest biomarkers for ParkinZheimer diseases.  

Drugs that block the formation of new prions and stop the spreading of these prions from cell to cell are likely to offer a cure, but only if the drugs are given to patients at the earliest of stages when the numbers of prions are miniscule, and the area localized.

Prion biomarkers represent highly effective targets for new drugs.

Early detection of prion biomarkers greatly expands the development toolkit for drug companies seeking to invent effective cures. 

Early Detection Accelerates the Path to Finding Cures.  
Consider this:

  • A drug that slows down the rate of progression by only 30% when administered at the Asymptomatic Stage of the disease could delay the onset of clinical disease by a decade or more. This same drug administered at the Symptom Stage would show little, if any benefit.
  • Even a drug that is 100% effective would be unlikely to restore either lost memories or full awareness at the Symptomatic Stage. This same drug administered during the Asymptomatic Stage would be likely to prevent the onset of clinical symptoms during the patient’s lifetime!
  • It is likely that each individual with ParkinZheimer Spectrum disease will have a unique footprint of misfolded protein biomarkers. This footprint may enable personalized treatment for each individual using a cocktail of different drugs, each targeting a different misfolded protein biomarker.

With early testing, we strive to empower individuals to take a proactive approach in managing the disease, benefiting the patients, family members, and caretakers. 

Because in life, it takes a village.

WHY PARKINZHEIMER?

The ParkinZheimer paradigm expands the horizon in research and accelerates the development of diagnostics and treatments by connecting all the silos. 

It is time for us to work together to consolidate our knowledge base to gain a better understanding of this entire spectrum of diseases.

The similarities between these diseases stem from their common origins as misfolded protein or prion diseases. By focusing on the similarities between Alzheimer’s and Parkinson’s rather than the differences, we can unleash the combined creativity, innovation, and brainpower of thought leaders in both fields.

CONCLUSION

Based on our analysis and research both inside the lab and with real-life cases, we believe Alzheimer’s and Parkinson’s are related diseases on a spectrum of prion diseases. We refer to the entire spectrum as the ParkinZheimer Spectrum, which includes other neurodegenerative diseases.

Let us reiterate that ParkinZheimer is not caused by the aging process, contrary to centuries old thinking.  Rather, these diseases appear to be initiated either at birth or during the first half of life, triggered by events as described earlier.

Once the misfolding process is triggered, the Asymptomatic Stage starts and the disease progresses undetected for decades, causing invisible, irreversible damage in the brain along the way. By the time we seek help at the Symptomatic Stage, it is already TOO LATE.

The traditional viewpoint has governed the way we’ve been analyzing, designing, and evaluating drug development and clinical trials over the past three decades, offering limited benefit to patients, caregivers, and physicians.

Science has advanced, and the time has come to expand our horizons in looking at these diseases as the ParkinZheimer Spectrum.

With this shift in paradigm, we now direct our focus on looking at these diseases through the prism of similarities, instead of their differences.

Through Amprion’s Prion Detection Science, we aim to gather newfound knowledge on how and when ParkinZheimer starts in the human body and find the path to curing it.

We expect the commercial rollout of Amprion’s first test of Misfolded Protein Synuclein in the first quarter of 2021.

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