ALZHEIMER’S DISEASE: an overview, for the layman

ABSTRACT: a brief description, to save you time – the full text is rather long!

Above, Fig1: nature’s phenomenal, symmetrical design: artistic prowess, at its best.

Below, Fig 2: nature’s finest freeform piece: a delicate, electrochemical marvel !

The human brain

And here below, Fig 3: the visual definition of the verb, “to ravage”

By the time the symptoms a
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What is Alzheimer’s disease?

Alzheimer’s disease, a slow process of cognitive decline, causes progressive loss of brain cells (over a very long time: 30 – 40 years). We can’t see what’s going on inside the brain cells in Alzheimer’s disease, but we can see twisted, ruined beta-amyloid piled up around and between them and twisted, tangled tau peptides inside them. We know that they have become nonfunctional: we know that they are dead.

Beta-amyloid
“Beta-Amyloid peptide” * inside sick brain cells twists, breaks and is ejected, piling up outside of the newly nonfunctional cells. The clumps of beta-amyloid indicate that the cell is dead, or dying: they are not the cause of brain cell death.

TAU

The TAU (tubulin-associated unit) protein **, a mesh that supports the transport and signalling channels inside each affected neuron, also breaks. It twists and tangles up inside the cells, so even if the cell is still alive, the ruined channels can no longer carry nerve signals ***. Again, tangled tau does not kill the cell: it is evidence of the cell’s demise.

What kills the brain cells?

Scientists assume that the beta-amyloid and TAU waste kills the brain cells.
However it is more likely that the cells are killed by some metabolic aberration, as a result of which beta-amyloid and tau proteins become deformed, broken and nonfunctional.
The beta-amyloid fragments are ejected from the cell and the TAU fragments tangle within. By the time we can see the accumulation of amyloid and TAU, the neuron has stopped working and is dead, or dying.

Whatever the process, affected cells are lost from the working population: neurons die and are removed by the brain’s clean-up process.

* Peptides are short chains of amino acids, with which proteins are built.
** The walls of the “microtubules” that carry nerve signals are made from Tubulin, a special protein built from “Tubulin Associated Unit” (TAU) peptides.
*** When a nerve cell is deteriorating in Alzheimer’s disease, the Microtubules are destroyed and the Tubulin Associated Unit (TAU) peptides are released.

Cognitive decline

Cognitive decline is masked by ad hoc “rewiring” until severe damage has been done: the brain can do “workarounds” and reconfigure itself, continuing to think and respond to the surroundings, even when more than 50% of its brain cells have disappeared. So by the time we recognise the symptoms and realise that someone has Alzheimer’s disease, 70+% of the brain cells have died and been reabsorbed.

Amyloid-removing medications

Recently, the pharmaceutical industry has designed medications that can speed up the removal of beta-amyloid. However logically, the hope that removing amyloid will “cure” Alzheimer’s disease is wasted thought. The disease is due to the cells dying, not to blocking of signals from living cells. Further, the collection of beta-amyloid waste which we see around the cells isn’t just sitting there – it is being actively removed, but the “brain’s housekeeper” can’t remove it fast enough.

Anyway by the time dementia starts, we can see that the brain is shrinking (Figure 3).
70% of our 86 billion brain cells (neurons) have died and been reabsorbed, so cleanup drugs only slow the progress of disease, because they do nothing to address the cause of brain cell death. Curing Alzheimer’s disease would involve regenerating the missing brain cells, and that is a faint hope, indeed.

Below, I outline our knowledge of the brain, its cleanup process and Alzheimer’s.
I suggest books, by smarter people than myself, to awaken your “self-help-ability”.
I make some guesses about how beta-amyloid forms and tau is damaged – and
I make some suggestions as to what we can do to prevent the process or, slow it.

However as you will realise, I can offer only my opinion, gleaned from others’ research and from my (hopefully) logical thought. My statements should not be taken as “gospel truths”: rather, the reader should view them as ideas, to promote understanding of the problem and perhaps, to trigger investigation and innovation by better brains than mine.

Please see the final section of this monograph, titled “SLOWING DOWN? FUZZYHEADED? CONFUSED? – SHOULD YOU SEE YOUR DOCTOR?” … Skim through everything in between, if you wish, but you must read the final chapter!

Otherwise, get Dr. Dale Bredesen’s book, “the end of Alzheimer’s” and read it, instead (this article will take you less time).

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Adrenal Fatigue

A misnomer, derived from a misconception

The adrenal glands sit like caps, one above the upper pole of each kidney. They produce an extensive range of hormones, including the Neurosteroids, DHEA and Cortisol, which is said to be deficient in “Adrenal Fatigue” (a popular urban myth).

Diurnal Cortisol levels: the black dots represent results of testing saliva samples.
Results lying within the area in blue are normal.

“Adrenal Fatigue” (AF), a term invented in 1998 by Naturopath and Chiropractor, James Wilson, is a misnomer, derived from a misconception.

The misnomer

As the Wikipedia article says, “adrenal fatigue” is a pseudo-scientific term, applied to suggest that the adrenal glands are exhausted and unable to produce adequate quantities of hormones, primarily cortisol, due to chronic stress or infections. “Adrenal Fatigue” bears no relation to true adrenal insufficiency (Addison’s disease), in which, due to accident, pituitary failure or local disease, the adrenal glands fail to produce cortisol and aldosterone.

The misconception

The misconceived term,“Adrenal fatigue”, is based on the idea that cortisol, the “stress hormone”, is curative – that it has a positive effect in terms of healing and a direct, positive effect on alertness, mood, strength, motivation and fatigue.

The truth

The truth is precisely the reverse: Cortisol’s main action is to shut all metabolic systems down, not to stimulate, or actively heal them. Cortisol deters healing, reduces cognition, causes depression and generally interferes with normal brain function.
Further, via reduction of intracellular triiodothyronine availability, it has negative effects on all bodily functions. Therefore to attribute negative symptoms, such as fatigue, cognitive loss, reduced motivation and psychological depression, to insufficient cortisol supply is an obvious “oxymoron”.

The “clincher” is that if the alleged “adrenal fatigue symptoms” were due to reduced cortisol availability, administration of exogenous cortisol would be a therapeutic success: a quick perusal of articles on “AF” reveals no suggestion of corticoid therapy for adrenal fatigue.

A question:

is “adrenal fatigue” important enough to warrant a post in the “aging and your hormones” substack?

The answer:

Absolutely. The term is applied to ubiquitous symptoms: the sheer volume of citizens complaining of low-thyroid symptoms should command the full attention of the research community.

Less-than-scientific, profit-oriented “health info” websites

However the less-than-scientific, profit-oriented “health info” systems/websites, dedicated to AF, sidetrack the public’s energies, reducing the impact of stress-related fatigue symptoms on the medical system and thereby, inhibiting research on the subject.

In brief, the symptoms of adrenal fatigue, as described by those who believe in it, are mainly those of Intracellular Hypothyroidism (IH). As such, they are due to intracellular T3 starvation, which results from stress-related cortisol overproduction, not to the adrenals failing to produce enough cortisol.

So let’s recognize the misconception and get rid of the misnomer:
There is no such disease as “adrenal fatigue”.

Pathogenesis of chronic-stress-related fatigue

Protracted exhaustion may follow viral illnesses like influenza, Covid 19, Chickungunya, Dengue fever, West Nile fever, Lyme disease etc. and it even presents a problem in diabetes, heart failure, chronic infections such as tuberculosis, conditions such as lupus, Cancers, malignancies involving bone marrow infiltration, major surgery, severe physical injury or other conditions in which the body’s healing processes are severely taxed.

However a chronic fatigue, of varying degree, accompanies all stressful diseases and situations. In these situations, the fatigue is the result of stress-related hypercortisolemia, leading to cortisol-mediated suppression of intracellular T3 production and manifesting as the “low T3 syndrome”, or as I prefer to call it, “intracellular hypothyroidism”.

The Low T3 Syndrome

This is the situation in which the symptoms of LT3S, a symptomatically severe form of hypothyroidism, are interpreted by laypersons and poorly informed professionals as “adrenal fatigue”. Any condition in which fatigue is a significant factor should be investigated for the presence of intracellular hypothyroidism (IH), which is the true cause of the symptoms.

Intracellular Hypothyroidism

IH, a condition which accompanies all severe illnesses, chronic diseases and life-threatening conditions, results from chronic stress, even in the absence of identifiable disease. It is endemic in our modern, high-stress civilization and it produces symptoms which are identical with those attributed to “adrenal fatigue”.

IH is reliably diagnosable, via the (serum) T3/rT3 ratio and easily, safely treatable. For an explanation of the metabolic background, diagnostic tests and therapy,
(1) consult “Undiagnosed Hypothyroidism”, at SUBSTACK, or “Intracellular Hypothyroidism” at ResearchGate (the two articles are almost identical) and
(2) See “stress causes hypothyroidism”, which will tell you why chronic stress causes intracellular hypothyroidism.

Caveat

IH is also called “Low T3 Syndrome”, “Nonthyroidal Illness”, “Euthyroid Sick Syndrome”, and “Subclinical Hypothyroidism”: however I prefer my term, ”intracellular hypothyroidism” because it explains the pathophysiology of the condition accurately and succinctly.

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Why is Mainstream Medicine missing the boat?

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Vitamin D3

It’s actually a Hormone…….your skin is the gland that makes it!

VITAMIN D, THE HORMONE FROM OUR SUN!, IS ACTIVE IN ALL OUR SYSTEMS.

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Q: Why don’t you “catch a cold”, outside, on sunny days?
A: Because your body makes Vitamin D, in the sunshine!

Vitamin D is essential.

Vitamin D is not a vitamin: you don’t eat it!
It’s a hormone – a classical hormone!
It’s made by an organ (the skin) and transported in the blood to other organs, where it produces beneficial changes.

It is necessary for many systems, including heart-muscle contraction, bone and brain maintenance and repair, absorption of calcium and magnesium from the bowel, maintenance of mood, cancer prevention and infection control.

It is also (surprise!) helpful in cases of calcific arteriosclerosis: in combination with vitamin K, Lysine, Citric Acid (Lime or Lemon Juice) and Magnesium, it facilitates chelation (removal) of calcium deposits from the walls of the Arteries and Arterioles. *

It is recognised as an invaluable hormonal supplement, in those parts of the world where climate restricts natural “D” production by the skin.

HOW YOUR SKIN MAKES VITAMIN D

The Vitmin D saga is complicated: The lower layers of the skin use UVB from sunlight, to convert Cholesterol into an inactive prohormone called Cholecalciferol.
The blood takes the Cholecalciferol to the liver, where it is changed into Calcifediol.
Calcifediol is transported in the blood, from the liver to the kidneys and the Kidneys turn it into Calcitriol (D3), the active Vitamin D hormone…..

OKAY, OKAY! …… so it’s your kidneys that make vitamin D (!).

Finally, Calcitriol travels from the kidneys via the bloodstream to every cell of every organ, to do its work.
 

WHERE DOES VITAMIN D WORK, MOSTLY?

Vitamin D is active, everywhere in the body.
It is most famous for its special care of the bones (remember the story about all the poor kids in London getting rickets because windows were taxed?) …… People bricked up their windows to save on tax and sunlight couldn’t get in, so all the children were Vitamin D deficient…… The kids didn’t grow to full height and their bones were too soft, so they developed bow legs.

Anyway …… Vitamin D is essential. It takes part in most chemical reactions inside the cells, so it takes an active part in almost all our functions.

Deficiency of vitamin D is associated with increased risks of cancer, heart disease, MS, rheumatoid arthritis, type 1 diabetes and many other diseases and malfunctions.

WHAT’S D3’S MOST IMPORTANT JOB?

That’s hard to say: Vitamin D is active everywhere you look (even in the brain). But
perhaps the most important) work done by Vitamin D is regulation of so-called “Antimicrobial Peptide Genes”. These genes produce “Histatins, “Cathelicidins” and “Defensins”, internal antibiotics which target bacteria, viruses and funguses **, but also function as signalling molecules which activate the immune system, attracting white blood cells to sites of infection.

Without Vitamin D, we run short of Antimicrobial Peptides

We “catch a cold” when there isn’t enough sunshine to make Vitamin D: with VitD out of the picture, viruses living in our noses quickly take advantage of the lack of Antimicrobial Peptides, to multiply and attack the mucosal lining of the nasal passages, causing the swelling, “stuffiness” and mucous secretion which we call a “cold”.

So if you feel as though you have “caught a cold”, or if a “runny nose”, which is often the first sign of Covid 19, begins, cut it short with an extra daily 5000iu dose of D3: it works “like a charm”.

VITAMIN D TOXICITY (?)

Much has been said about the “toxicity” of Vitamin D: Vitamin D overdose is rare, but when it happens, it causes hypercalcaemia (high blood calcium), which can produce calcium deposits, or stone formation, in organs like kidneys and saliva glands. Hypercalcemia can cause symptoms, including loss of appetite, nausea and vomiting, then excessive thirst and high urine production, weakness, insomnia, nervousness, itching and rarely, kidney failure.

Because of this possibility, plus the ever present spectre of litigation, doctors are reluctant to encourage supplementation with more than token doses of this supremely important vitamin. However the current consensus is that everyone should take 3,000 to 5,000 (some say 6.000) international units of VitD3 , 6,000iu) per day (according to some authorities, you would haveto take 50,000 units of Vitamin D daily for 6 months, to run into severe side effects).

Message

Q: Why don’t you catch cold on sunny days?
A: Because your body makes Vitamin D!

Opinion

In my opinion, taking Vitamin D is essential. Everyone (every adult) should take between 3,000 and 5,000 international units of vitamin D3 daily *** year-round. ****
(For doses in kids, consult a reliable website, such as the Cleveland clinic site).

* Arteriosclerosis, a major cause of erectile dysfunction, takes decades to develop, so not surprisingly, it can take a year or more to get rid of it by chelation.

** Defensins and Cathelicidins are chemical attractants for white blood cells and in addition, they promote production of “cytokines” and “chemokines” which attack germs. Particularly, they are active against Covid 19.

*** I find that taking D3 at bedtime relieves nasal congestion: I go to sleep more easily, but you can take it at any time of day. It is fat-soluble, so you need fat or oil in the diet, to encourage absorption (Vegetarian diets contain little fat, so vegetarians are more prone to deficiency).

**** I say “year-round” because we get no direct sunshine in Winter and in Summer light-skinned people, whose skin absorbs more UVB and makes more Vit. D, avoid the sun, while dark-skinned people, whose melanin blocks UVB, need stronger sunshine than we get in Canada.

Covid 19

Special note, Re Histatins, Cathelicidins and Defensins: this is where COVID 19 comes in: please see the 2005 paper, “Human Antimicrobial Peptides: Defensins, Cathelicidins and Histatins”, by Kris De Smet  1 , Roland Contreras, PMID: 16215847DOI: 10.1007/s10529-005-0936-5, at https://pubmed.ncbi.nlm.nih.gov/16215847/

Please see, also, “Perspectives for clinical use of engineered human host defense antimicrobial peptides”, at https://pubmed.ncbi.nlm.nih.gov/28521337/ – hopefully, engineered human antimicrobial peptides will prove effective and with any luck, will become available within the next decade.

DHEA prevents cancer

Excepting in rats’ livers

I just got the prompt below, from SUBSTACK: it sounds like a good idea, so here it is !
THE PROMPT READS……. “You originally published “DHEA prevents cancer” 3 years ago. Consider sharing it again with your readers. Sharing relevant old posts is a great way to engage your audience who might not have seen them already without having to create new content.”

The Post should perhaps have been titled ”DHEA HELPS to PREVENT CANCER”

TP53 and DHEA

This note was inspired by a very well-written, easy-to-read, but very long and complicated dissertation on how DHEA prevents cancer, entitled “Detection of a novel, primate-specific, ‘kill switch’ – a tumor-suppression mechanism that may fundamentally control cancer risk in humans: an unexpected twist in the basic biology of TP53”, by Jonathan W Nyce, In: Endocr Relat Cancer. 2018 Nov; 25(11): R497–R517. Published online 2018 Jun 25. Doi: 10.1530/ERC-18-0241, PMCID: PMC6106910, PMID: 29941676 , at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106910/   

DNA DAMAGE AND MALIGNANT TRANSFORMATION

Our cells are constantly exposed to a variety of cellular stressors and are prone to DNA damage, which can lead to mutation, formation of abnormal genes and eventually, cancer.

Cancer development is a complicated sequence.

To protect organs from malignant transformation, the cells’ nuclei carry a gene called TP53. When DNA is damaged, TP53 is converted into its active form: it accumulates in the cell nucleus and turns on “KILLER GENES”, which can arrest cell metabolism and kill the abnormal cell, by generation of “reactive oxygen species” (ROS). In layman’s terms, the cell is “burned” with oxygen. This is a natural process, called apoptosis, which is good because cells with cancerous potential are destroyed.

The cells carry tiny quantities of TP53 and it exists in a dormant, inactive form. If the damage is mild, cell metabolic slowdown permits DNA repair. Only when the situation is bad enough, is TP53 activated, to trigger the killer genes. ROS is generated and the abnormal cell dies, in a process called apoptosis. In this way, dangerously damaged cells are prevented from cloning themselves and producing daughter cells with damaged DNA and cancer potential.

When cellular injury involves damage to the TP53 gene itself, it mutates and an abnormal gene is born, which activates an enzyme, called Glucose-6-Phosphate Dehydrogenase (G6PD, present in all cells). G6PD prevents the formation of damaging free oxygen radicals by triggering production of an antioxidant, NADP (nicotinamide adenine dinucleotide phosphate). NADP cancels ROS formation by any normal TP53 which may be present in the cell, so the cell survives and multiplies, and a cancer begins.

HOW DOES DHEA PREVENT CANCER?

(1) Many years ago (BACK IN THE ’80S), DHEA, the “mother hormone” made by our adrenal glands and our brains, was observed to inhibit spontaneous breast cancer and chemically induced tumors of the lung and colon, in mice.
The mice were given a carcinogen named DMBA and another called TPA: without DHEA, they grew cancers; but if they were given DHEA, it stopped tumour formation! In fact, DHEA proved to be effective in stopping cancer formation in all species of animals tested, excepting rats: in rats, it promoted liver cancer, (that anomaly is still a mystery).

DHEA inactivates G6PD

The action of DHEA in preventing cancer formation was unexplained for decades, but in 2018, a breakthrough was reported in the article I mentioned above:

Now, we know that cancer-forming mutations prevent activation of TP53 and also increase production of G6PD: the G6PD prevents ROS formation, allowing the cell to develop, multiply and produce a cancer. We also have an explanation of the fact that people under 25 don’t usually get cancers: in youth, while our bodies are still producing large amounts of DHEA, the DHEA blocks G6PD, stopping NADP formation. Without NADP, ROS are produced and the cancer cell dies.

(2) To put it another way, under normal circumstances, when a cancer cell forms, TP53 is activated: the TP53 generates ROS, to kill the abnormal cell. However some cells generate G6PD, which blocks the formation of ROS (Reactive Oxygen Species), so the cell survives, multiplies and forms a cancer ………….. if this process starts in a young person who is still producing large amounts of DHEA, the DHEA acts like a policeman and arrests the G6PD, as a result of which ROS production goes ahead and the abnormal cell dies. …………

(3) But we don’t make DHEA throughout our lifetime: we begin to lose production at a rate of 1% per year, at age 26!

DHEA prevents cancer, but it falls 1% yearly, from age 26

DHEA prevents cancer by shutting off G6PD, thus allowing a lethal rise of oxygen species inside the cell which kills the cancer cell. But our production of DHEA is reduced by 1% every year from the age of 26 and due to this, our protection from cancer-producing mutations gets lower as we get older!

Some cancer mutations include mutation of the TP53 gene, itself and the mutated TP53 gene is unable to shut off G6PD. So in those who don’t have enough DHEA to block it, active G6PD keeps the ROS low in cancer cells, which grow and multiply.

So what I am talking about is using DHEA to prevent cancer. However DHEA may not be effective against all developing cancer cells and I am not suggesting prescribing it as a cure for an existing tumour.

DHEA reduction, in aging

Other long-lived mammals make DHEA only in the brain: they utilise alternative disease preventatives. Humans make DHEA in the adrenal glands and we make more of it, weight for weight, than all our other hormones put together. However our DHEA production is maintained only to age 25. Thereafter, we progressively reduce that shield, by 1% per year (see the diagram below): is that why we don’t last?

Caveats

– DHEA production is reduced by 1% every year from age 26, so our protection from cancer-producing mutations falls as we get older!
– Many of us fail to produce normal amounts of DHEA from the teen years, perhaps because of PTSD in childhood, so when DHEA production starts going down at age 26, high producers start from normal and low producers, from whatever they had at age 20. So by age 80, the highest DHEA producers are down to 10-20% of their original level and the lowest producers are down to zero.
– Shouldn’t we all keep or DHEA levels up?
– In my practice of hormone restoration therapy between 2006 and 2021, I tested 685 people for DHEA levels: the vast majority had a serum DHEAS of <6. I concluded that supplementation is good for everyone, over the age of 25, or before, if necessary.
Figure 4, DHEA: NATURAL production levels in humans, vs. long-lived mammals.

Recap: cancer suppression systems targeting G6PD.

In humans, the DHEAS level peaks between age 20 and 25. Therefore, DHEA’s protection from cancers and other noncommunicable diseases only covers us efficiently for the first 25 years; our original, prehistoric life expectancy. From age 26, it declines by 1% per year, until the adrenals stop making DHEA in the 80s or 90s. Thereafter, the only source of DHEA is the brain, whose production is insufficient to supply the rest of the body with adequate amounts of DHEA.

Long-lived species such as the elephant, the whale, the moose and the naked mole rat, which employ tumor suppression systems that do not decline with age, experience little or no increased risk of cancer as they age.

Dr.J W Nyce’s graphic, modified from dePeretti & Forest, 1976

For details, please see the following URLs:
Cancer incidence by age, in the UK: (http://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/age).
Human Lifetime cancer risk of 38.4% (https://www.cancer.gov/about-cancer/understanding/statistics).
Cancer risk of most long-lived mammals = 4%, from Abegglen et al. (2015).
Circulating DHEAS levels (dePeretti & Forest 1976, Parker & Odell 1980, Vermuelen 1980, Orentreich et al. 1984, Labrie et al. 1997).

The effect of oral DHEA on liability to cancer: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106910/   

MESSAGE

So here is an idea: maintain optimum DHEAS levels for life, by taking side-effect-free, inexpensive DHEA, beginning at age 26, or whenever your serum DHEAS falls below 6 µmol per litre. DHEA will certainly do no harm: all body parts, your brain and your personality will benefit from normalized DHEA availability and perhaps, cancer formation may be prevented.

Remember

DHEA is freely and inexpensively available (in the USA). It has been OTC since 1995 and there have been no reports of serious side effects. In Canada, thanks to our omniscient ministry of health, it is on the “DANGROUS DRUGS” list.

FAQ:

Q: Do we get cancers because we don’t make enough DHEA?  
A: In some cases, yes.
Q: If I have a cancer, will DHEA stop it?                                            
A: Possibly (it won’t encourage it, but cure is not guaranteed).
Q: Why don’t all doctors know about this?                                         
A: Ask the doctor’s professors and advisors that question.
Q: Why is DHEA on the “dangerous drugs list” in Canada?            
A: Citizens’ lobbies are not as effective in Canada, as they are in the USA and on this particular subject, our ministry of health and are medical “colleges” are misinformed. This is a pity, because people on DHEA tend not to get depressed, or sick.

REFERENCES

(1) Role of p53 in Cell Death and Human Cancers: Toshinori Ozaki1 and Akira Nakagawara , Cancers (Basel). 2011 Mar; 3(1): 994–1013.Published online 2011 Mar 3. doi: 10.3390/cancers3010994, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756401/

(2) Detection of a novel, primate-specific ‘kill switch’ tumor suppression mechanism that may fundamentally control cancer risk in humans: an unexpected twist in the basic biology of TP53, Jonathan W Nyce,
2018 Nov;25(11):R497-R517., oi: 10.1530/ERC-18-0241. Epub 2018 Jun 25.
PMID: 29941676, PMCID: PMC6106910, DOI: 10.1530/ERC-18-0241, https://pubmed.ncbi.nlm.nih.gov/29941676/

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