ALZHEIMER’S: AN OVERVIEW

WHAT IS ALZHEIMER’S DISEASE?

Alzheimer’s disease is a slow process of cognitive decline, which takes three to four decades to develop.
It is thought to be due to functional isolation of the neurons (brain cells) by progressive accumulation of mis-folded (twisted) “Beta-Amyloid” in the junctions between the cells and to disorganization and “tangling” of supportive tau protein strands in and around the “microtubules”, the transport channels inside the neurons.

About Beta-Amyloid: – we don’t know exactly what beta-amyloid does, but according to Wikipedia, normal beta-amyloid may activate kinase enzymes, reduce oxidative stress, regulate cholesterol transport and protect against infection.
We don’t know either, why beta-amyloid is ejected from the neurons: all we know is that ejected beta-amyloid isn’t normal: it is mis-folded and some of it is soluble, while some is not.

The glymphatic flow (see below): Waste material ejected by the neurons is normally carried away by the constant flow of “glymphatic” fluid around the brain cells and no one can explain why beta-amyloid waste isn’t washed away.
All we can say so far, is that Beta-Amyloid accumulation around neurons may occur either by overproduction of waste by the cells, or that there is a failure in “house cleaning”: in any event, in Alzheimer’s disease, beta-amyloid accumulates in plaques (lumps) around the neurons and progressively clogs the system.

What is Tau protein? – According to Wikipedia, tau (Tubulin-Associated Unit), a group of six soluble proteins, form a filmy scaffolding which maintains the stability of tiny microtubules in neurons and their axons. Tau protein serves a similar purpose in astrocytes, oligodendrocytes and nerve cells outside of the CNS, but are most important in the CNS neurons. In Alzheimer’s, tau filaments become twisted and tangled, no longer supporting the microtubules.
The reason for tangling of tau protein strands in and around the all-important microtubules has not been explained, to date.

Alzheimer’s disease: Alzheimer’s disease, the cause of perhaps 70% of cases of dementia, results from accumulation of beta-amyloid outside of, and disorganization of the tau protein framework inside, neurons.
Axons are destroyed and neurons die, in no particular area or pattern, across the brain.
Affected areas of the brain shrink and cognitive function slows and deteriorates.
Alzheimer’s sufferers exhibit memory loss and aberration of reasoning, temporal and spatial disorientation, psychological effects and mood disorders, and eventual loss of balance and coordination.
All of these vary in timing and degree, from person to person.

The difference between a normal and an Alzheimer’s brain is shown in figure 1.

Figure 1
Normal, vs. Alzheimer’s brain – https://en.wikipedia.org/wiki/Alzheimer%27s_disease

Inheritance: 1–2% of Alzheimer’s cases are inherited; affected individuals show changes at a much younger age and the disease progresses more quickly.
Three single-gene mutations are associated with this condition: a chromosome 21 gene for “amyloid precursor protein” (APP), a chromosome 14 gene for “presenelin1” and a gene for “presenelin2”, on chromosome #1.
However, while age-related Alzheimer’s tends to run in families, it is not possible to predict its occurrence in the majority of cases.

THE HOUSEKEEPERS:

Water management in the body as a whole: As the blood flows around the body, a little water leaks out through holes the capillaries, into the space between the cells
(the interstitial space). This Interstitial fluid, called “lymph”, travels through tiny “lymphatic” tubes to the lymph glands and then through similar, larger tubes to empty into the bloodstream at the base of the neck. This system serves the entire body, including the scalp, face and skull, but the brain has its own “waterways”.

The glymphatic system: Most of the brain’s fluid (“glymphatic”) flow, comes from active production of cerebro- spinal fluid (CSF), secreted by the “Choroid” plexus of micro-blood vessels.
The choroid plexus is a collection of modified ependymal cells, surrounding a core of capillaries and loose connective tissue , in each of the four ventricles of the brain.
(Do click the link, to see Wikipedia’s beautiful depiction of the ventricles.)
The rate of CSF formation by the choroid is only 0.3 – 0.4 ml minute, but there is also a bi-directional, pulsatile flow of fluid across the blood-brain barrier, more rapid than the CSF flow, which occurs with every heartbeat, as the arterial pressure drives blood through the capillaries which supply the brain’s oxygen and nutrients.
To this is added Lymph produced In the brain, by leakage from the capillaries which deliver blood to the brain cells. However it only amounts to about 20% of the brain’s total “Glymphatic”, fluid flow and it mixes immediately with the CSF.

Fluid from the choroid plexus exits through four little holes in the fourth ventricle.
From there, it circulates through the brain tissue to the sub-arachnoid space.
Much of it is reabsorbed by the “arachnoid“, a diaphanous tissue like spiderweb which covers the surface of the brain, but some exits through the periarterial and perivenus spaces (see figure 3).

So let’s talk about brain housekeeping: There are 4 methods by which waste products are thought to be eliminated from the brain:
(1) Enzymes dissolve the waste, for transport through the blood-brain barrier (the BBB) to the bloodstream. (2) Waste product fragments are washed out: “Glymphatic” fluid enters the periarterial spaces from the subarachnoid area and flows to the ends of the arteries, where the sheath of the artery is “fenestrated” (leaky). There, it passes into the brain channels and flows by the brain cells.
Eventually entering the perivenous* spaces, it carries Beta Amyloid fragments away and, travelling along the veins via the perivenous channels to the outside of the brain, it finally empties into the lymphatic system (see figure 3).
(3) By direct transfer of fluid to the “Meningeal” lymphatic system [“Meninges” is the name for the thin bag which the brain sits in], dissolved waste leaves the nervous system via regular lymphatics, to join the bloodstream in the neck.
(4) Glymphatic fluid carrying Amyloid and Tau fragments also passes along the cranial nerves, in the perineural channels*, in the same fashion as in (2).
* “perivenous” means “around the veins” and “perineural” means “around the nerves”.

Of these three fluid production and drainage systems, the major route is across the blood-brain barrier and into the meningeal lymphatics. This has been demonstrated experimentally.

The importance of sleep: during sleep, the brain and glial cells contract, thus enlarging the spaces between the cells, through which the interstitial fluid flows: this facilitates more rapid flow of fluid.
In mice, this space has been observed to increase by 60%, during sleep.
In addition, transfer of Glymphatic fluid through the blood-brain barrier also increases during sleep.

It is reasonable to assume that the root cause of beta-amyloid accumulation is failure to clear waste material, rather than an increased rate of production of waste.
Accumulation therefore must result from either
(1) Failure of the Arachnoid to produce enough CSF, so that the flow rate is reduced (observed in old age): this must be a minor factor however, since as noted above, the CSF constitutes only 20% of total cerebral fluid flow.
(2) Reduced duration and/or rate of interstitial fluid flow at night, due to poor sleep: this is probably significant, especially since sleep patterns deteriorate with age.
(3) Obstruction of the Glymphatic channels (not a likely scenario).
(4) Progesterone deficiency, leading to underproduction of Allopregnanolone.
(5) Allopregnanolone/melatonin deficieny: in my opinion, this is likely the major problem: allopurinol and melatonin put us to sleep, promote brain cell shrinkage during sleep and thereby improve “cleanup” of the spaces between the cells.

Is Alzheimer’s disease worsened by other conditions? …. Yes ! … Here’s a list:

(1) Deficiency of DHEA, Testosterone, Oestrogen, Progesterone, Melatonin, Vitamin D, Magnesium, Tryptophan, selenium, iodine, iron, zinc, other minerals and vitamins,
(2) Diabetes, kidney or liver disease, chronic inflammatory cytokine production,
(3) THC overdose, smoking, alcoholism,
(4) Severe concussion, or multiple minor concussions,
(5) Mercury, Lead, Copper, Nickel and other metal overloads,
(6) Other toxins, including phthalates, BPA (etc.) and artificial sweeteners
(6) Inflammation, and/or oxidative stress, of the brain,
(7) Chronic stress, due to poverty, or other social conditions
(8) Chronic psychological stress, due to schizophrenia, depression, PTSD etc.
(9) True hypothyroidism, or stress-related intracellular (functional) hypothyroidism
(10) Maternal Hypothyroidism, “true” or “IC”, causing fetal brain maldevelopment

THE BRAIN’S DRAINAGE SYSTEM ISN’T SO COMPLICATED, REALLY !

In the fabulous diagram by Verheggen, VanBoxtel, Verhey, Jansen, Backes. (Figure 3, below), the purple cells are brain cells (Neurons), the bright green ones are “Astrocytes” and the light greens are glial cells.  The brown granules are Tau and Beta-Amyloid waste.
Figure 2 shows the GLIAL cells (oligodendrocytes, astrocytes, ependymal cells, and microglia,in the brain and Schwann cells and satellite cells in the peripheral nervous system.
Glial cells have four main functions:
(1) to surround neurons and hold them in place;
(2) to supply nutrients and oxygen to neurons;
(3) to insulate one neuron from another;
(4) to destroy pathogens and remove dead neurons.

Figure 2: GLIAL CELLS

Glial Cell Types.png

In the large graphic below, Tau and Beta-Amyloid granules are being broken up into tiny bits and pushed down the feet of the astrocytes into a space around each artery or vein, where fluid flow carries them along the surface of the vessel, to be dumped into the glymphatics and from there, into the blood. I call this process, maximised by dilation of the channels during sleep, “brain housekeeping”.

Figure 3:“Interaction between blood-brain barrier and glymphatic system in solute clearance”, by Verheggen, VanBoxtel, Verhey, Jansen, Backes.

Maintenance and repair: ALLOPREGNANOLONE, made from PROGESTERONE, is the brain’s repair hormone.
Progesterone converts to Allopregnanolone with good dose-to-serum-level correlation.

Along with MTHF, vitamin B12, DHEA, Testosterone, T3, Melatonin, Magnesium (etc.), Allopregnanolone “does” brain maintenance and repair, including remyelination of denuded axons in MS and synapse repair in other neurological diseases.
Allopregnanolone enhances self-esteem, relieves and reduces anxiety, helps produce endorphins and fine-tunes the GABA system. Thus it is neurogenic, neuroprotective, antidepressant, anti-aggressive, pro-sexual, sedative and pro-cognitive.
Wikipedia refers to Allopregnanolone as “stress reducing, rewarding, prosocial, anti-aggressive, pro-sexual, sedative, sleep facilitating, pro-cognitive, memory enhancing, analgesic, anticonvulsant, neuroprotective and neurogenic”.

Figure 4: Allopregnanolone: An overview on its synthesis and effects,
S Diviccaro, L Cioffi, E Falvo, S Giatti…
in J Neuroendocrinol. 2022 Feb; 34(2): e12996, 2021Jun29, doi: 10.1111/jne.12996
Neuroprotective effects of allopregnanolone. Treatment with this neuroactive steroid shows: (A) beneficial effects on spinal cord trauma, (B) prevention of neuronal death, (C) reduction of cholesterol accumulation and stroke, (D) decrease in epileptic events, (E) beneficial effects in nervous damage induced by diabetes mellitus, (F) protective effects on neurodegenerative diseases (eg, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis), (G) anxiolytic and anti‐stress actions, (H) effects against the neurotoxicity exerted by human immunodeficiency virus (HIV), (I) protective effects in an experimental model of Niemann‐Pick type C and in (J) neuroinflammatory conditions (eg, multiple sclerosis and experimental autoimmune encephalomyelitis), and (K) analgesic effects against neuropathic pain.
………………………………………………………………………………………………………………………………….
Allopregnanolone takes an active role in the majntenance and repair of “Axons”, the long extensions of nerve cells which connect to other cells; but perhaps its most important function is to facilitate brain cell shrinkage, thus opening up the channels for lavage, during sleep. This is an all-important hedge against Alzheimer’s, because the rate of clearance of Tau and beta-amyloid from the interstitial space in the brain depends on fluid flow.

Fluid flow increases during sleep, when the brain cells (Neurons, Astrocytes and Glial cells) shrink and the passages between the cells open up. It decreases during the day, when the cells are at full volume and the passages shrink.
Therefore fluid flow depends on sleeping well enough and sleeping long enough.

REMEMBER: by ensuring deep sleep, Allopregnanolone, Melatonin and Magnesium facilitate brain cleanup, reduce stress and encourage synapses (links) between brain cells, thus maintaining cognitive function.
Hopefully (this is unproven), enhancing brain hygiene in this way will reduce our liability to Alzheimer’s disease.

PROGESTERONE produces ALLOPREGNANOLONE, so Progesterone deficiency causes Allopregnanolone deficiency.

WHAT SPOILS SLEEP PATTERNS?

(1) Progesterone deficiency, with resultant Allopregnanolone deficiency.
(2) Melatonin deficiency.
(3) Hypothyroidism and/or Intracellular Hypothyroidism: deficiency of “T3″ (thyroid hormone #3) inside the brain cells slows cognition, causing “fuzzy thinking”, “brain fog”, confusion, anxiety, depression and poor sleep patterns.
(4) Magnesium deficiency: Magnesium participates in approximately 300 chemical processes in the body and among its effects is facilitation of sleep and enhancement of sleep patterns.
(5) DHEA/Testosterone deficiency: Testosterone enhances self-confidence, thereby reducing anxiety and depression.
(6) Vitamin D deficiency.
(7) Hyperthyroidism.
(8) PTSD/Depression/Anxiety.
(9) Stimulants (coffee, tea, et cetera) and late-night alcohol intake.
(10) Habit, especially late-night reading and/or TV watching.
(11) Shift work, or light (especially blue light) in your sleeping area, which lowers your Melatonin level.
(12) Pain or discomfort, either due to injury or to inflammatory conditions such as Fibromyalgia and Polymyalgia.
(13) Bowel inflammation, such as “SIBO“*, IBD and Diverticulitis.
(14) Brain inflammation due to oxidative stress, which can be eliminated with oral antioxidants.
(15) Psychological stress.
*SIBO – Small Intestinal Bacterial Overgrowth ( Small Bowel Infection).

SLOWING DOWN? FUZZYHEADED? CONFUSED? – SHOULD YOU SEE YOUR DOCTOR?

MDs tend to wait, to treat full-blown Alzheimer’s, or patients confirmed to be in the early stages of disease. 
Doctors/Investigators/research people, seemingly oblivious to the idea that our systems are dependent on an interactive, orchestrated, cooperative interplay between multiple mineral, vitamin and hormonal players, tend to focus on one factor at a time, with a sort of fuzzy-headed faith in “designer” medications.
In a condition like Alzheimer’s, which manifests 30 or 40 years after it begins, this is a mistake.

To apply the analogy of an aging automobile, would you spend billions of dollars to develop a single fuel additive to correct simultaneously failing ignition coils, spark plugs, headlamp connectors, fuel lines, brake lines, electrically operated windows, computer circuits and Generalized Rattling?
Wouldn’t it be better to do regular maintenance and repair defects as soon as they are found, so that you never have to face a total breakdown ?

Obviously, it would be better to begin surveillance of hormonal, vitamin, mineral and oxidative balances while we are young, beginning to supplement Melatonin, DHEA, Testosterone, Progesterone, Oestrogen, Vitamins, T3, Magnesium, Selenium, Iodine and other essentials as soon as deficiency begins.
CAVEAT: surveillance should include education for everyone.
Our doctors and other health professionals should advise re. diet and exercise, watch carefully for symptoms and do physical examination and blood tests as necessary.
The ” yearly physical” should include hormonal and thyroid balance tests and should be tailored to the individual: it should not be a mechanistic, regimented routine.

Q: SO WHAT CAN YOU DO WHILE WAITING FOR THE MEDICAL PROFESSION TO ARRIVE AT THIS LOGICAL CONCLUSION?
A: Try this ANTI-ALZHEIMER’S PROTOCOL (based on Dr. Bredesen’s principles):
Check your hormone, vitamin and mineral balances* once a year and check for heavy metal overload every five years, with a view to oral chelation if necessary.
Test the hormones: DHEA, Testosterone, Oestradiol, Progesterone, Thyroid3, Thyroid4, reverse Thyroid 3, TSH.
Test the Vitamins: B12, Folate (B9), Vitamin D, etc.
Test the Minerals, especially Iron, Calcium, Magnesium and Zinc.
Check Cholesterol and Glucose management.
Check for heavy metal load.
Test for inflammation: ESR, HSCRP: especially, check Homocysteine, which goes up with brain inflammation……
Correct any deficiencies on an ongoing basis, so as to provide your brain with the metabolic mileiu it needs for efficient housekeeping.

* See “Benefits of Blood Testing for Nutritional Deficiencies“, at https://www.myonemedicalsource.com/2020/06/18/nutritional-testing/
Follow the Guru: Read, “The End Of Alzheimer’s”, by Dr Dale Bredesen and
DHEA in Human Health and Aging“, by Ronald Ross Watson, PhD.
Destress: meditate twice a day, do yoga to reduce stress and sleep seven to eight hours per night.
Sleep, exercise and eat well: eliminate simple carbohydrates, gluten and processed food, eat more vegetables, fruits and non-farmed fish.
Be proactive: it’s better to avoid problems, than to correct them: take DHEA 50 mg, progesterone 100 mg (men), progesterone 2 – 300 mg (women), Melatonin, Vit B-12, Vit D3, Vit K2, Vit C, Vit B2, Vit B6, fish oil, MTHF, NAC, IC3 and CoQ10 each day………… see the “anti-Alzheimer’s protocol” on the final page of this paper. *****
Optimize oral hygiene using an electric toothbrush/flosser, to avoid inflammation from migrating mouth germs.
Fast for 12 hours after dinner, have a fruit and coffee or tea for breakfast, have just a light snack at lunchtime and then don’t eat until dinnertime.
Don’t overuse alcohol.
Exercise for 15-30 minutes, 3 to 6 days per week.
– Consult with a functional medicine or bioidentical hormone restoration professional for assessment, correction and maintenance of your hormonal balance regardless of your current age, and ask specific questions based on the information in this article and your learning from the books by Dr Bredesen and Dr. Watson.

***** Most people who have a “normal” diet, including “veggies”” and fruit, moderate protein, eggs, milk etc. don’t NEED supplemental vitamins for maintenance purposes. However it’s smart to add the above list to the diet. Just don’t take the full dose as recommended on the bottle if you are healthy and fit. For example the dose of MTHF (Vitamin B9) for someone with Alzheimer’s brain inflammation and a high Homocysteine is 3-5 mg per day: for a healthy person just 1 mg per day is enough to correct any small dietary deficiency.

ABOUT SUPPLEMENTS which help to prevent Alzheimer’s disease:

Melatonin is chronobiotic, hypnotic, anxiolytic, analgesic, pro-cognitive and antidepressant. It runs our biological clock, dictating hormone release times. Production falls 10% per decade, so at 50, it is ½ and at 80, it’s 1/10, of what it was at age 20.
Take 1 – 10 mg of melatonin: if it makes you groggy in the morning, take less.
Webber’s “super sleep” contains just 1.5 mg of melatonin and works very well for sleep.

Vitamin B12 (Methyl Cobalamin) supports brain and nerve function. It enhances immune system function, helps to control homocysteine levels, boosts energy and helps memory. It is in fish, meat, poultry, eggs, and dairy products.
It should be tested, because it can go too high: if you don’t need it, don’t take it.
Take 1 mg (1000 µg) of Methylcobalamin daily, if you need it.

Vitamin C, from fruit and vegetables, works with Vitamin D to block infections.
It is necessary for wound healing and many other maintenance jobs in the body.
The VitC guru, Linus Pauling (Scotland) recommended 9 G/day and present-day Naturopaths give up to 50G intravenously, for influenza.
Dogs and other “lower” animals make VitC naturally, but we don’t.
Also, it is excreted quickly in the urine, so we need to get it from our food every day.
Take one gram twice a day and double the dose if you get a cold, a large wound or a surgical operation.

Vitamin D3 is a fat-soluble hormone made by the skin (up to 40,000 units in 24 hours).
It regulates calcium, phosphorus and bone maintenance, helps the immune system, produces Cathelicidin and Defensin (natural antibiotics) and is an anticancer agent. Fish oil contains large amounts of D3.
Take 3000 (? 5000) iu of Vitamin D3 daily.

Vitamin K2 is fat-soluble and is best combined with vitamin D. It is produced by gut bacteria from “leafy greens” and is in fatty foods, like egg yolks and high-fat dairy from grass-fed cows. It is essential for blood clotting, bone maintenance and heart health and it reduces blood vessel calcification. It reduces spinal fractures by 60%, hip fractures by 77% and other fractures by 81%.
Take 150 µg of Vitamin K2, daily.

Vitamin B9, Folic acid is best taken as MTHF (Methyl Tetrahydrofolate). It is needed to make red and white blood cells in the bone marrow, convert carbohydrates into energy, and produce DNA and RNA. However the “biggie” is that It soothes brain inflammation, and we can tell that it is working because it reduces the Homocysteine level in the blood.
MTHF is in fruit, Leafy greens, beans and seeds, seafood, but not in meats, except liver.
Take 1µg of MTHF (Methyl Tetrahydrofolate) daily: if Homocysteine is high, take 3 µg.

NAC (N-Acetyl Cysteine) stimulates glutathione, increasing the efficiency of the Mitochondria.
Take 900 µg of NAC daily (the full dose, if needed, is 1800mg).

I3C (Indole-3-carbinol) is anticarcinogenic, antioxidant, and anti-atherogenic.
Take 200 mg of I3C daily.

Coenzyme Q 10 is a nutrient that occurs naturally in the body and in many foods we eat. CoQ10 acts as an antioxidant, is needed for heart maintenance, delays Alzheimer’s disease, and is anti-inflammatory.
Anticholesterol drugs destroy CoQ10: if they are prescribed you MUST take it.
Take 200 mg of CoQ10 daily.

Vitamin B6 is water-soluble, helps with more than 100 enzyme reactions and is necessary for haemoglobin manufacture, brain health and lowering homocysteine.
It repels mosquitoes, in some people.
Take 25 mg of vitamin B6 daily.

Vitamin B2 (riboflavin) is water-soluble. It is necessary for energy production, maintenance of brain and nerves, absorbing other vitamins from food, hormone production and other functions. Take 10 mg of vitamin B2, daily.

HORMONES:
Everyone over 30 years of age needs DHEA, 50mg daily (protects the heart from dysrhythmia and infarction, prevents or retards many cancers, treats sexual dysfunction in the female, helps with self-confidence and reduces anxiety).
Men over 50 need Progesterone, 50-100 mg at bedtime: women may need 200-300mg.
Every postmenopausal woman needs Oestradiol and Oestriol (requirement is variable, from individual to individual).

NOTE: “Multivite” pills contain combinations of the above: check on this and
“mix & match”, to take fewer pills.

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