ALZHEIMER’S: A LOGICAL 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 brain cells by progressive accumulation of waste (“Tau” and “Beta-Amyloid”) molecules in the junctions between the cells.
This accumulation may occur either by overproduction of Tau and Beta-Amyloid waste products, or by failure of the system to clear those molecules from the intercellular spaces.
However It is more likely that the cause is a failure in “house cleaning”, so that naturally produced waste material accumulates and aggregates, progressively clogging the system and eventually, slowing cognitive function to the point of total shutdown.
Allopregnanolone and Melatonin facilitate beta-amyloid and tau removal from the brain and the disease may be related to their deficiency.

An inherited tendency (not a hard-and-fast, inevitable, progressive process) to Alzheimer’s disease has been demonstrated. However, while Alzheimer’s tends to run in families, it is not possible to predict its occurrence in the vast majority of cases. It is likely however that maintenance of mental, physical and metabolic health would lead to a reduction of the incidence of Alzheimer’s disease.

PROBABLE MECHANISM OF HOUSEKEEPING ACTIVITY:

THE LYMPHATIC SYSTEM:

As the blood flows around the body, small amounts of water get squeezed out of the capillaries into the space between the cells (the interstitial space). This “Interstitial fluid” eventually enters the “Lymphatic system”, traveling through tiny tubes to the lymph glands and then through similar, larger tubes to empty into the bloodstream at the base of the neck.

THE GLYMPHATIC SYSTEM:

A similar interstitial fluid is produced In the brain: we call it “Glymphatic”, not “Lymphatic”.
However It only amounts to about 20% of the brain’s total flow: Most of the brain’s fluid flow is from active production of cerebro- spinal fluid (CSF), which is secreted by the “Choroid” plexus of micro-blood vessels. This is a col which lection 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 CSF exits through four little holes in the fourth ventricle, circulates through the brain tissue to the sub-arachnoid space and is reabsorbed by the “arachnoid“, a diaphanous tissue like spiderweb which covers the surface of the brain.
The rate of CSF formation in humans is only 0.3 – 0.4 ml minute.
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.

BRAIN HOUSEKEEPING

There are 4 methods by which waste products are thought to be eliminated:
(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 Tau and 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 diagram).
(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.

It has been observed that during sleep, the brain and glial (supportive) cells contract, thus enlarging the spaces through which the interstitial fluid flows and facilitating 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 BBB also increases during sleep.

It is reasonable to assume that the root cause of Alzheimer’s disease 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),
(2) Reduced duration and/or rate of interstitial fluid flow at night, due to poor sleep patterns,
(3) Obstruction of the Glymphatic channels,
(4) Progesterone deficiency, leading to underproduction of Allopregnanolone. Allopregnanolone deficieny causes poor sleep, less brain cell shrinkage during sleep and reduced “cleanup” of the spaces between the cells.

IS “ALZHEIMER’S” WORSENED BY OTHER CONDITIONS? ………………. yes ! …… Here’s a short list:

(1) Deficiency of DHEA, Testosterone, Oestrogen, Progesterone, Melatonin, Vitamin D, Magnesium, Tryptophan. (2) Diabetes, severe kidney or liver disease, alcoholism, THC overdose and metal overload, Inflammation and oxidative stress, Concussion, Mercury, Lead, Copper and other toxins.
(3) Inflammation, and/or oxidative stress, of the brain, from (1) and (2), or other causes.
(4) Hypothyroidism, either “true” or “functional”, which results in slowing of all body functions, including cognition.

THE BRAIN’S DRAINAGE SYSTEM IS NOT SO COMPLICATED, REALLY !

In the fabulous diagram by Verheggen, VanBoxtel, Verhey, Jansen, Backes. (second graphic, 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.
The graphic above 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.

First Graphic: GLIAL CELLS

Glial Cell Types.png

In the large graphic below, The 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”.

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

THE BRAIN’S HOUSEKEEPER:

ALLOPREGNANOLONE, made from PROGESTERONE, is the brain’s most important hormone.
Progesterone elevates Allopregnanolone levels with good dose-to-serum-level correlation.

Working with DHEA, Testosterone, T3, Melatonin and Magnesium, Allopregnanolone “does” brain maintenance and repair, possibly including remyelination of denuded axons in MS and synapse repair in other neurological diseases.
It 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”.

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 and Thyroid.
Test the Vitamins: B12, Folate (B9), Vitamin D, etc.
Test the Minerals, especially Iron, Calcium, Magnesium and Zinc.
Check Cholesterol and Glucose management.
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 is better to avoid health issues, than to correct them – take Melatonin, Methylcobalamin, Vitamin D3, Vitamin K2, Vitamin C, Vitamin B2 And Vitamin B6, fish oil, 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 lunch and then don’t eat until dinnertime.
Don’t overuse alcohol.
Exercise for 30 minutes, 4 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. 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 (best taken as MTHF (Methyl Tetrahydrofolate), 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 1 µg 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.
Men over 50 need Progesterone, 50 mg at bedtime: women may need up to 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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