Alzheimer’s and Neurodegenerative Diseases

Moving on from last week, I decided to pick up where I left off, which was on the discussion of neurodegenerative diseases, and particularly Alzheimer’s disease. This is a subject that I know very well having studied it for several years. At one time I was preparing to publish an audiobook on the subject, but then decided to wait a bit longer for a major discovery. I’m still waiting for that major discovery, but I must say, there are a number of encouraging developments.  For me, as with many people, Alzheimer’s and age-related dementia is personal. My sister Elaine died from dementia.  Ater a person experiences friends or loved ones with this condition, it leaves them with a feeling of helplessness and dread that they cannot forget. Seeing someone you know and love deteriorate into a living being that you no longer recognize… and that does not recognize you, stays in your mind.

Before going into depth regarding Alzheimer’s, I want to provide you with a brief history of the condition. Hopefully you will learn some of the things that I have become familiar with. First, I would like to point out the fact that the moniker “Alzheimer’s Disease” or AD is used loosely to describe this condition and most age-related dementias. It is a name that is easy to remember…  In point of fact, until recently, Alzheimer’s disease could not positively be identified until after death, when its specific microscopic features can be viewed. However, new tests that reveal key components are changing that. Regardless, the progression and treatment of the disease is essentially the same for all age-related dementias.

Note: Bold Blue Text indicates a hyperlink.

In November 1901, Dr. Alois Alzheimer, a German neurologist, made his first examination of a 51-year-old woman, Auguste Deter, who was experiencing problems with memory and language as well as various psychological problems such as disorientation and hallucinations. These symptoms matched the definition of what was then called dementia, but she was rather young to be displaying them, so he diagnosed her as having “presenile dementia”. Auguste Deter died on April 8, 1906. Since Dr. Alzheimer had never seen another case like hers, he obtained her family’s permission to perform an autopsy on her brain. When he examined it, he observed extensive atrophy, especially in the cortex—the thin outer layer of grey matter that is involved in memory, language, judgment, and thought in general. When Dr. Alzheimer sampled thin slices of this brain tissue and examined them under the microscope, he observed two types of abnormal deposits inside and in between the nerve cells. These two kinds of deposits—one outside the nerve cells, in modern terminology, “amyloid plaques", and the other inside, now known as “neurofibrillary tangles" made up of what we now call tau proteins.

Note: I am going to make use of a new tool I have not used before in my newsletters. It is my experience that some people want to learn everything they can about Alzheimer’s. To make this possible, I have embedded hyperlinks in the body of the text, indicated by a heavy underline. By clicking on the underline it will reveal an orange link where the cursor becomes a finger. By clicking on the underlined section, you will be taken to a different site. These are usually authoritative sites such as NIH. When finished reading, just click on the tab at the top of the page and you will be returned to my newsletter. ALSO, this will be a long newsletter. As a result, depending on your email provider, it may be shortened (truncated). If the newsletter is truncated you can click on "view entire message" and you will be able to view the entire post. You can always find any missing text or graphics at AlfredDGranite.substack.com.

One last thing…To provide maximum benefit to my readership, I want to suggest the following: If you are thoroughly familiar with the details of Alzheimer’s but know of someone that you believe may be at risk of developing or has already been diagnosed with Alzheimer’s, I suggest that you skip ahead to the section labeled “Nutrition”. I believe that nutrition and the use of “nutraceuticals” are the best way to combat the development and progression of the disease at this moment in time. Above all, I recommend that you watch the 40-minute podcast narrated by Dr. Mary Newport at the end of this newsletter. It provides a complete picture of Alzheimer’s and nutritional treatments that have been proven effective and at the same time, have no downsides regardless of health status.

Amyloid-β (Aβ) peptides can form protease-resistant aggregates within and outside of neurons. Accumulation of these aggregates is a hallmark of Alzheimer's disease (AD) neuropathology and contributes to devastating cognitive deficits associated with this disorder. The healthy human brain contains tens of billions of neurons—specialized cells that process and transmit information via electrical and chemical signals. They send messages between different parts of the brain, and from the brain to the muscles and organs of the body. Alzheimer’s disease disrupts this communication among neurons, resulting in loss of function and cell death.

The amyloid protein involved in Alzheimer’s comes in several different molecular forms that collect between neurons. It is formed from the breakdown of a larger protein, called amyloid precursor protein (APP). One form, beta-amyloid 42, is thought to be especially toxic. In the Alzheimer’s brain, abnormal levels of this naturally occurring protein clump together to form plaques that collect between neurons and disrupt cell function. Research is ongoing to better understand how, and at what stage of the disease, the various forms of amyloid influence Alzheimer’s.

Neurofibrillary tangles are abnormal accumulations of a protein called tau that collects inside neurons. Healthy neurons, in part, are supported internally by structures called microtubules, which help guide nutrients and molecules from the cell body to the axon and dendrites. In healthy neurons, tau normally binds to and stabilizes microtubules. In Alzheimer’s disease, however, abnormal chemical changes cause tau to detach from microtubules and stick to other tau molecules, forming threads that eventually join to form tangles inside neurons. These tangles block the neuron’s transport system, which harms the synaptic communication between neurons.

Emerging evidence suggests that Alzheimer’s-related brain changes may result from a complex interplay among abnormal tau and beta-amyloid proteins and several other factors. It appears that abnormal tau accumulates in specific brain regions involved in memory. Beta-amyloid clumps into plaques between neurons. As the level of amyloid reaches a tipping point, there is a rapid spread of tau throughout the brain. These beta-amyloid and tau proteins are the distinguishing factors between Alzheimer’s disease and other age-related dementias that can only be seen in a brain autopsy.

In 2010, we knew of just 10 genetic areas associated with Alzheimer’s. Today, thanks in large part to the work of NIH-funded researchers, we know of at least 80 genetic areas associated with this disease. Understanding which genes play a role — and what role they play — may help identify new methods to prevent, delay, or treat dementia.

One well-known gene that influences Alzheimer’s risk is the apolipoprotein E (APOE) gene. The APOE gene is involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream. Problems in this process are thought to contribute to the development of Alzheimer’s. APOE comes in several forms, called alleles (e.g., ε2, ε3).

• APOE ε2 may provide some protection against the disease. If Alzheimer’s occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE ε4 gene. Roughly 5% to 10% of people have this allele.

• APOE ε3, the most common allele, is believed to have a neutral effect on the disease — neither decreasing nor increasing risk of Alzheimer’s.

• APOE ε4 increases risk for Alzheimer’s and is associated with an earlier age of disease onset in certain populations. About 15% to 25% of people have this allele, and 2% to 5% carry two copies.

Each person inherits two APOE alleles, one from each biological parent, meaning people can have one of six possible combinations: 2/2, 2/3, 2/4, 3/3, 3/4, and 4/4. Having two copies of APOE ε4 is associated with a higher risk of Alzheimer’s than having one copy. While inheriting APOE ε4 increases a person’s risk of Alzheimer’s, some people with an APOE ε4 allele never develop the disease. This points to the fact that we still don’t have a complete picture of the disease or the factors that lead to cognitive decline. Research has shown that certain mutations that result in genetic variants prevent AD from manifesting itself may offer a clue to a possible cure.

A NIH-funded study identifies this gene variant as potential drug target while studying an individual at high risk for early-onset AD that remained dementia-free for many years beyond what was anticipated. This research focused on the case of a woman who carried a gene mutation known to cause early-onset Alzheimer’s. However, she did not develop signs of the disease until her seventies, nearly three decades after her expected age of onset. The researchers suspect that she may have been protected because in addition to the gene mutation causing early-onset Alzheimer’s in her family, she also had two copies of the APOE3 Christchurch (APOE3ch) gene variant. Findings of this case study as published in Nature Medicine suggest that two copies of the APOE3ch variant, named after Christchurch, New Zealand where it was first identified, may protect against Alzheimer’s.

Cases such as this one sometimes reveal helpful information that can lead to discoveries that have a profound effect on future treatments. My personal feeling regarding events like this make me wonder if the improved outcomes could be achieved by gene manipulation, since it is clear that naturally existing or mutated genes can have a significant effect on the disease that it is associated with. Oddly, this approach to treatment may in fact make it more difficult to obtain regulatory approval. Always keep in mind that such approvals require enormous sums of money for testing, trials, and data collection that must be paid for by conventional means. Most often, the promise of royalties from patents provide this funding. Unfortunately, this usually results from development of unique unnatural substances by Big Pharma instead of working with substances within the natural domain…e.g. peptides, where funding for large-scale scientific studies is generally unavailable.

Of the genetic variants so far associated with Alzheimer’s, three rare single-gene variants are known to cause the disease:

• Amyloid precursor protein (APP) on chromosome 21

• Presenilin 1 (PSEN1) on chromosome 14

• Presenilin 2 (PSEN2) on chromosome 1

There are accurate blood tests for Alzheimer's disease, and they may be a major step towards making Alzheimer's diagnosis more accessible:

• ptau-217 blood test - This blood test is comparable to FDA-approved cerebrospinal fluid tests in identifying amyloid build-up and is superior in determining tau tangle levels in the brain.

• APS2 blood test - This blood test is around 90% accurate at identifying Alzheimer's disease in memory clinics and primary care settings.

• Lund University blood test - This blood test is up to 90% accurate at identifying Alzheimer's disease in people experiencing memory loss. 

These blood tests could lead to more timely and accurate diagnosis, which could enable early intervention and better treatment. They could also make it possible to receive routine blood tests for cognitive impairment during primary care checkups, which would be ideal.  However, these blood tests have not yet been approved by the FDA, and more work is needed to establish guidelines for their use in clinical practice.

Brain Scans

• Computed tomography (CT): Uses X-rays to create cross-sectional images of the brain 

• Magnetic resonance imaging (MRI): Uses radio waves and magnets to create a detailed view of the brain 

• Positron emission tomography (PET): Uses a radioactive substance to detect substances in the body, including brain regions with decreased glucose metabolism 

Functional Evaluations

• Psychiatric evaluation

Determines if depression or another mental health condition is causing symptoms 

• Cognitive tests

These can include the Montreal Cognitive Assessment (MoCA), which assesses short-term memory, concentration, and understanding of time and place

• Cerebrospinal fluid (CSF) tests

Also called a spinal tap, this test involves collecting CSF to look for proteins from the brain

TTCM2-ms

July 2024 University of Texas Medical Branch discovered a new antibody termed TTCM2 which selectively targets toxic tau buildup. This antibody was packaged in a solution to enhance its delivery though a nasal spray directly to the brain.

Targeting Tau for Destruction. TTCM2-ms slips into cells, where the antibody latches onto various forms of pathological tau. TRIM21 binds the Fc fragment of the antibody, and ubiquitinates it, targeting the entire complex to the proteasome.

Donanemab

The FDA approved this anti-amyloid medication in 2024 to treat early-stage Alzheimer's. 

Lecanemab

The FDA approved this anti-amyloid medication in 2023 to treat early-stage Alzheimer's. It's the first traditionally approved treatment that addresses the underlying biology of Alzheimer's. 

Blarcamesine

This drug is being tested for Alzheimer's disease and Parkinson's disease dementia. It works to stop proteins from misfolding. 

Tau aggregation inhibitors and tau vaccines

These are currently being studied in clinical trials to prevent tau from forming tangles in the brain. 

Aducanumab (Aduhelm)

This anti-amyloid antibody was previously approved for early Alzheimer's disease, but its manufacturer is discontinuing it. 

Cholinesterase inhibitors

These medicines can help manage symptoms and slow decline. Some common cholinesterase inhibitors include Donepezil (Aricept), Galantamine, and Rivastigmine. 

Stem cell therapy

AstroStem is a stem-cell-based treatment that's administered intravenously.

Pulsed Soundwave Therapy

Using gamma soundwave propagation (40 Hz) is a non-invasive brain stimulation technique that uses sound waves to help treat Alzheimer's disease. 

Photobiomodulation

Red and Green Light and White Light modulated at 40 Hz has demonstrated positive effects on memory, cognition, and eye health. Inexpensive devices for each are now available.

Neurologists: These doctors specialize in the brain and nervous system and are often consulted for dementia diagnoses. 

Geriatricians: These doctors specialize in the care of older adults and dementia. 

Geriatric psychiatrists: These doctors are considered superspecialists for dementia diagnosis. 

Behavioral neurologists: These doctors are considered superspecialists for dementia diagnosis. 

Psychologists: These doctors have special training in testing to assess thinking abilities. 

Neuropsychologists: These doctors can perform more comprehensive mental cognitive status tests to evaluate executive function, judgment, attention, and language. 

As mentioned earlier, individuals with type 2 diabetes are twice as likely to develop Alzheimer’s, therefore, insulin resistance plays a significant role in the development and speed of cognitive decline associated with AD. This is especially true of non-AD age-related dementia. In this instance, glucose, the primary source of fuel for the brain, has great difficulty passing the blood brain barrier. In effect, this causes a “starvation” of the neurological tissues.

When I was in medical school, we were taught that the ONLY source of nutrition for the brain was glucose. We now know that that is not true. There is another, even more powerful, substance that can serve as food for the brain… Ketones, and they are unaffected by insulin resistance, and therefore for individuals with type 2 diabetes, ketones provide an excellent alternative for “Brain Fuel”. These can be produced by a ketogenic diet, or given directly as a Ketone ester or Ketone salt.

When discussing nutrition we need to start at the beginning, with the basic diet. Ultimately, we now realize that virtually all neurodegenerative diseases involve insulin resistance in one form or another that generally worsens with age. As stated before, this condition results in a shortage of intracellular energy in the brain because glucose cannot cross the blood brain barrier in sufficient quantities to provide the necessary energy. Therefore, the first order of business is to lower insulin resistance by modifying diet. Generally speaking, reducing sugar and refined carbohydrates is a good place to start. One of the best and easiest ways is to choose a diet low in carbohydrates and high in fats, but changing what you eat is never easy. Three diets that have shown promise in this area are the Mediterranean diet, the ketogenic diet, and the carnivore diet.

Given what you should already know about neurodegenerative diseases, there are two important objectives for any of the diets listed above. Number one, is to lower insulin resistance throughout the body, thereby reducing the effect of any of the metabolic diseases I have discussed over the past three weeks. By that action the amount of glucose that can enter a cell or cross the blood brain barrier will be commensurately increased. Obviously, in the case of Alzheimer’s or age-related dementia, this will have potentially a profound effect on the neurons of our brain, thereby significantly increasing cognition and memory. However, there is another step that can be taken regardless of dietary changes… And that is to directly introduce exogenous ketones into our bloodstream. Please allow me to explain…

Around 2010, when I was still living in the Washington DC metropolitan area, I was employed by a large nonprofit seeking to build a “green city” in nearby West Virginia. One of our objectives, aside from job oriented education for x-military, was to develop manufacturing facilities that would provide revenue sufficient to maintain the operation. Because of my position, I was very interested in anything of a medical/healthcare nature. As it turned out, I became acquainted with the chief scientist at Oxford University, Dr. Kieran Clarke, and her US counterpart, Dr. Richard Veech who was the chief of NIH metabolic lab. With approximately $10 million provided by a DARPA grant, doctors Clark and Veech developed an ingestible ketone ester earmarked for use by special forces of the US military.  This substance could serve both as a “food” and as a cognitive enhancer in addition to improving physical performance.

When I learned of this project, I immediately became excited, realizing its enormous potential. Anxious to find a way to synthesize this substance on our property. Dr. Veech and I tried to accomplish that goal, which because of the economy of the time, proved to be impossible. For several years following, I continued to work with Richard searching for a manufacturing facility without success. During this time, I learned that Dr. Veech was personally treating Steven Newport with his ketone ester. His spouse, Dr. Mary Newport previously treated him with coconut and MCT oil has written a number of popular books detailing the use of Coconut and MCT oil including“What if there was a cure for Alzheimer’s and nobody knew?”. Dr. Veech shared that he was able to keep Steven functional for about another two years after the coconut oil stopped working for him, before his eventual passing.

Fast forward to the summer of 2024 when I learned that Dr. Kieran Clarke had finally located a pharmaceutical company, Health Via Modern Nutrition, that agreed to synthesize the ketone ester that she and Richard Veech formulated. A short time later, I discovered that the product was being marketed in the United States under the name “Ketone-IQ”. Since then, I have become affiliated with the company and can now offer my readers a discount on the product. Understand that it requires no special diet for it to work, but it is best to combine it with the use of Coconut and/or MCT oil in a low-carb diet. Incidentally, there is a newly discovered, natural rare sugar “Allulose”, that can replace sucrose,  that is low in calories and may actually be good for you! Eliminating fructose from our diets would make a huge difference by improving insulin sensitivity and reducing fatty liver disease. Hopefully I will have a discount code for “RXSugar” for my readership soon.

To conclude this week's newsletter I am including a podcast by Dr. Mary Newport, the neonatologist that I mentioned above. I believe that it will provide all of you a very good overall understanding of AD and the use of Coconut, MCT, and ketone esters in the treatment of Alzheimer's. In many ways this nutritional approach provides more significant results than any drug created by big Pharma to date. Being familiar with the condition, I sometimes wonder what active role amyloid plaque and tau protein play in the cognitive decline seen in Alzheimer's. One would have to think there is a link, but as of yet, there is no clear understanding of pathology directly involved within the neurons. Perhaps there is a coincidental non-active association, whereby the amyloid plaque serves as an antimicrobial defense mechanism to entrap and sequester pathological microbes in the brain, such as herpes simplex one.

Following this, the body’s innate defenses take over to destroy these pathogens with substances such as hypochlorous acid (HOCl) produced by neutrophils (a type of white blood cell). Curiously, it seems that HOCl is often considered a biomarker for brain inflammation. If this is the case, it makes me think of a “chicken and egg” scenario. Is hypochlorous acid (HOCl) the cause of inflammation, or the reaction of the body to the presence of pathogens causing inflammation? If the latter is true, then this opens the possibility that the formation of beta-amyloid is a direct response to brain inflammation… Keep in mind that the genetic evolution of beta-amyloid is more than 4 million years old. This makes me think that its original purpose was as a protective mutation. I can’t begin to tell you the possibilities this generates in my mind for experimentation…

Whatever the case, it is clear that taking a nutritional treatment approach produces verifiable improvements within human studies in cognition and function. Of equal importance, these treatments are available now without a presciption, or the involvement of medical insurance. This does not mean that interested parties should forgo expert medical consultation. However, depending on geographical and financial circumstances, there may be no choice. Furthermore, use of coconut and MCT oil, or ketone esters and salts, have few negative side-effects.

In summary, I believe that the best treatment for neurodegenerative disorders, in addition to a low-carb diet, should include an array of supplements and nutraceuticals known to stimulate and support nerve growth. Refining this further, I recommend the use of freshwater algal omega 3 supplements as opposed to fish oil, because these do not contain mercury or lead that could affect brain health. To view the embedded podcast narrated by Dr. Mary Newport simply click on the underlined title. After finishing, click on the tab at the top of the page to return to my newsletter…leave a comment and tell others about my free newsletter.

Ketones Coconut Oil and MCT oil for Brain Health (click)

In order to obtain a 30% discount on a subscription of Ketone-IQ, the ketone ester discussed thought this newsletter simply click on the link below and you will automatically be taken to the site where your discount is waiting for you. As you will see, Ketone-IQ is also ideal for athletes. If you know someone who does not receive my newsletter, you can give them this link and they will qualify for the 30% discount. Link: Ketone.com/DRG

30% Discount on Ketone-IQ (Click)

Until next time, take care and stay positive… Dr. G