"Finding a Cause and Potential Cures for Alzheimer’s Disease Climbing the Ladder of AD Causation" Introduction to my 4th book

Finding a Cause and Potential Cures for Alzheimer’s Disease

Climbing the Ladder of AD Causation

Publication Spring 2022 available on Amazon

 

 

Author:  Dr. Dennis N. Crouse, BSc Biochemistry, - Harvard College, Ph.D. Organic Chemistry - Harvard University Chemistry Department, Post-graduate courses:  Understanding Dementia - Wicking Faculty of Health, University of Tasmania, Fundamentals of Neuroscience - Harvard.

 

Introduction

Alzheimer’s disease (AD) is prevalent in the U.S. with an estimated 6.2 million people age 65 and older currently living with AD. Unfortunately, my mother is one of those people. Her short-term memory was going from bad to worse when she was 85. Her doctor was following this trend with the mini-mental state exam (MMSE) and reported that she had MCI that could lead to AD. Several years later, magnetic resonance imaging (MRI) of her brain indicated she had “accelerated brain atrophy” that is a characteristic biomarker of AD used to diagnose AD.

Being trained in biochemistry and chemistry at Harvard College and Harvard University, respectively, I decided to take action with the goal of identifying causal factors of AD so a cure for mom might be found. After several years of researching the scientific literature on AD, a causal factor of AD was identified and a potential cure for mom was tried with some success! Mom’s MMSE score improved and thankfully by age 89 she could describe the daily news she read or heard. This potential cure for some symptomologies of AD is also a preventative as documented in my 2016 book titled: “Prevent Alzheimer’s, Autism, and Stroke with 7 Supplements, 7 Lifestyle Choices, and a Dissolved Mineral”²¹¹.

Most AD cases are sporadic and result from hereditary and environmental causes. A subset (i.e., 66%) of sporadic AD cases, that are usually diagnosed before age 70, are associated with a specific genotype (i.e., ApoE e4 allele) increasing the risk of AD and amount of cerebral beta-amyloid protein (Ab-42)¹⁷⁸. Less than 2% of total AD cases are familial early-onset AD (EOAD) that is associated with mutations in presenilin 1 and 2 genes. EOAD is usually diagnosed before age 65 and is also characterized as having an increased amount of Ab-42¹⁷⁹. At least one third of AD patients do not have an ApoE e4 allele. In addition, half of those with two copies of the ApoE e4 allele, do not get AD and survive to age 80¹⁷⁸. Also, 24% of people with high levels of Ab-42 do not have in vivo biomarkers of AD^180,181. Therefore, logically there must be one or more environmental causes of sporadic AD that are made worse by increased amounts of cerebral beta-amyloid Ab-42. 

My mother has the ApoE e3/e4 alleles and I have the ApoE e2/e4 alleles. I got the ApoE e4 allele from my mother and the ApoE e2 allele from my father who had ApoE e2/e3 alleles . Carriers of the ApoE e4 allele have increased odds of getting AD as compared to carriers of two ApoE e3 alleles, like my sister who has ApoE e3/e3 alleles.

The odds of getting sporadic AD are based upon environmental factors, age and sex of the carrier, and if the carrier has one or two copies of the ApoE e4 allele (see two graphs below)¹⁷⁸. At age 65 I had approximately 2-fold greater odds of getting AD due to my genetics as compared with my sister¹⁷⁸. My mother’s odds of getting AD at age 65 were 4.5-fold greater than my sister¹⁷⁸. Men and women with ApoE e4/e4 alleles at age 60 have 11-fold and 12-fold greater odds of getting AD, respectively¹⁷⁸. But in spite of these greater odds, studies of twin pairs have demonstrated the ApoE e4 allele accounts for only 10.7% of the variance in Ab-42 accumulation, suggesting significant environmental factor(s) as cause(s) of sporadic AD^315-318.

Relative odds of getting AD based upon Caucasian subjects in clinical and autopsy studies¹⁷⁸

When I began researching AD in 2012 it became apparent that the field had become dominated by some very large and financially powerful players (e.g., aluminum industry, pharmaceutical industry and their partner the Alzheimer’s Organization) They had decided for their own financial gain that scientists in the U.S. and U.K. should play by their rule: if you are not working on decreasing beta-amyloid protein (Ab-42) you are not working on AD. In spite of their rule there are three proposed theories, not just one, on the cause of AD:

·       Aluminum Accumulation

·       Beta-amyloid Accumulation

·       Calcium  Dyshomeostasis

Playing by their rule required that you ignore two of these theories and don’t work on hypothesizing a fourth or fifth theory. Being close-minded does not facilitate finding cure(s) for a disease. Ironically at an Alzheimer’s Organization talk in 2015 by Claudia Kawas on the 90+ study it was pointed out those with just neuronal beta-amyloid accumulation do not have a high risk of AD dementia. Two other cerebral pathologies are required to significantly increase odds of AD dementia. A significant number of people are resilient to beta-amyloid accumulation¹⁸¹.     

Even before Claudia’s talk, I decided to not play by their rule. I read research papers on all three proposed theories with the goal of building a unified theory of AD.

Molecular epidemiological data is available that can be used to find causal factors of AD and cures for AD.  Looking for correlations in this data, revealed a causal factor of AD. I found that there is molecular epidemiological data providing convincing evidence that aluminum is both a causal factor of AD and drinking silica rich water is a preventative intervention for AD and a potential cure for some symptomology of AD.

Finding the cause of a disease facilitates finding the cure and finding factors that mediate or modulate the disease can reveal the cause of a disease. A literature search for modulators of AD uncovered two independent French epidemiology studies published in 2005 and 2008 that used two different data sets and surprisingly found drinking water containing greater than 4mg/day of silica as orthosilicic acid (OSA) or drinking water greater than 12mg/liter of OSA significantly lowered the odds of getting AD^200,209. With further searching I found a small 2006 study where 3 out of 15 patients with AD had an improvement in cognition after just 12 weeks of daily drinking OSA rich water^42,43. The 2008 French epidemiology study also found that aluminum levels in drinking water of 100mcg/liter or more significantly increased the odds of getting AD²⁰⁰. These studies were the primary inspiration for my first book²¹¹. My second book looked at the health of people who drank OSA rich water for their entire life²³⁹.

Does drinking OSA rich water significantly lower the odds of getting AD in those, like my mother and I, who are carriers of the ApoE e4 allele? This question was answered during the writing of my second book when I discovered Ibadan, Nigeria. The drinking water of Ibadan has a high level of OSA (i.e., 35ppm) compared with average level in the U.S. (i.e., 11ppm)^319,320.

From 1992 to 2006 a cohort of 2,245 elderly Nigerians living in Ibadan were genotyped and clinically diagnosed. Also, a cohort of 2,147 elderly African Americans living in Indianapolis, Indiana, were genotyped and diagnosed. In this latter cohort, people with the ApoE e4 allele had increased odds of getting AD. In general people living in Ibadan have 2-fold less risk of AD that those living in Indianapolis^321,322. Importantly, unlike the cohort of African Americans living in Indianapolis, the cohort of people with the ApoE e4 allele living in Ibadan did not have increased odds of getting AD^321,322. Therefore, drinking OSA rich water is an environmental factor that significantly lowers the odds of getting AD even in those with the ApoE e4 allele.

Based upon these studies I began in September of 2015 drinking 4 cups a day of OSA rich water (i.e., Silicade) spaced throughout the day. After 6 years I had my body burden of accumulated aluminum tested and it was found to be in the range of a healthy 22-year-old. These test results made me feel much younger than my 75 years and also made me confident that even with the ApoE e4 allele I would not get AD.

In addition to aluminum there are many environmental factors that negatively impact cognitive health. These environmental factors could also be potential causal factors of AD. The scientific literature was searched without success for links between these “brain drainers” and AD. This search revealed that essential nutrients could be used to detoxify these brain drainers as summarized in my third book titled “Increased IQ, Cognition, and Covid 19 Cure Rate with Essential Nutrients”⁴⁰.  

In 2018 I began reading about the new science of cause and effect called “causal inference” and applying it to finding causes, mediators, and modulators of AD. Having acquired a large amount of data on causal factors of AD, I found it could be logically organized as a “ladder of AD causation” inspired by causal inference. The result is a data-based logical argument for aluminum being the cause of AD based upon the current scientific literature and is the subject of this my fourth book.   

  

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mTOR is higher than normal in Alzheimer’s disease (AD) brains making it a risk factor for AD

 

mTOR Activity Increases in AD Brains Due to Inhibition of PP2A by Aluminum

Dennis N. Crouse

mTOR Complex 1 (mTORC1) includes mTOR a serine/threonine kinase that is found in all eukaryotic cells, phosphorylates several targets, and acts as a master regulator of protein synthesis and degradation. The activity of mTOR is higher than normal in Alzheimer’s disease (AD) brains making it a risk factor for AD that is independent of the ApoE status of patients. (Yates 2013) mTOR activation is a biomarker of autoimmune disorders, cancer, obesity, aging, and possibly AD. (Perl 2015) The activation of mTOR results in an AD associated increase in phosphorylation of both mTOR and downstream targets of mTOR in neurons of AD brains:

·         mTOR phosphorylated at Ser2481 (3-fold higher than normal) and Ser2448 (2.6-fold higher in those with AD than normal) (Pei 2008,  Li 2005, Griffin 2005)

·         p70S6K, a downstream target of mTOR, phosphorylated at Thr421 and Ser424 (phosphorylation is 4-fold higher in those with AD than normal) (An 2003)

·         eIF4E eukaryotic translation factor 4E a downstream target of mTOR 28 (eIF4E’s phosphorylation level is 100-fold higher in those with AD than normal) (Li 2004)

The phosphorylated forms of mTOR and p70S6K may represent putative indicators of cognitive impairments in AD. (Pei 2008) This higher mTOR activity is likely due to higher-than-normal phosphorylation of mTOR at Ser2481 and Ser2448. (Li 2005, Griffin 2005) Also, higher-than-normal levels of phosphorylation of p70S6K and eIF4E were significantly increased in AD brains and correlated with Baark’s stage and the levels of p-tau a biomarker of AD. (An 2003, Li 2004) Also, levels of phosphorylated p70S6K are higher in neurons that later develop NFTs a biomarker of AD. (An 2003)

The enzyme PP2A lowers the phosphorylation level of the mTORC1 complex and by doing so suppresses activity of mTORC1 complex. (Apostolidis 2016) However, aluminum inhibits PP2A in the AD brain thereby preventing suppression of mTORC1 and increasing the activity of the mTORC1 complex. (Yamamoto 1990)  Therefore, aluminum, a biomarker of AD, inhibits PP2A causing both increased mTORC1 activity and increased risk of AD. Facilitating aluminum excretion by drinking OSA rich water will likely allow PP2A to suppress mTORC1 activity and decreased the risk of AD.

Sirolimus (a.k.a. rapamycin) is a macrolide that both lowers mTORC1’s activity and inhibits cell proliferation and growth by interaction with FK506-binding protein. Sirolimus functions as an immunosuppressant and is used to prevent organ transplant rejection by inhibiting the activation of T-cells and B-cells required  by the immune system. (Mukherjee 2009) Taking sirolimus can lower the bodies resistance to bacterial and viral infection, such as COVID-19. Sirolimus can also cause lung toxicity as interstitial pneumonitis. (Chhajed 2006) Therefore, drinking OSA rich water to facilitate the elimination of aluminum and lower mTOR activity is safer than taking sirolimus.

References

An, W.-L., et al.; Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer’s disease; Am. J. Pathol.; Aug.; 163(2):591-607 (2003)

Chhajed, P.N., et al.; Patterns of pulmonary complications associated with sirolimus; Respriation; 73:367-74 (2006)

Griffin, R.J., et al.; Acrivation of Akt/PKB, increased phosphorylation of Akt substrates and loss and altered distribution of Akt and PTEN are features of Alzheimer’s disease pathology; J. Neurochem. 93:105-17 (2005) 

Li, X., et al.; Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain; Neuroreport; Oct.; 15(14):2237-40 (2004) 

Li, X., et al.; Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer’s disease brain; FEBS J.; 272:4211-20 (2005)

Mukherjee, S., and Mukherjee, U.; A comprehensive review of immunosuppression used for liver transplantation; J. Transplantation; Article ID 701464 p1-20 (2009)

Pei, J.-J., and Hugon, J.; mTOR-dependent signalling in Alzheimer’s disease; J. Cell. Mol. Med.; 12(6B):2525-32 (2008)

Perl, A.; mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging; Ann. N. Y. Acad. Sci.; June; 1346(1):33-44 (2015)

Yamamoto, H., et al.; Dephosphorylation of tau factor by protein phosphatase 2A in synaptosomal cytosol fractions, and inhibition by aluminum; J. Neuroscience; 55:683-90 (1990)

Yates, S.C., et al.; Dysfunction of the mTOR pathway is a risk factor for Alzheimer’s disease; Acta Neuropath. Comm.; 1:3 (2013)

Why Drinking Silica Water Is An Alternative To Following A Keto Diet

 

Why Drinking Silica Water Is An Alternative To Following A Keto Diet

There are two primary energy sources for the body:

·  Carbohydrates in the form of sugars (i.e. glucose) produce energy by glycolysis to make acetyl CoA for the citric acid cycle.
·  Fats in the form of triglycerides produce energy by beta-oxidation to make acetyl CoA for the citric acid cycle.

Carbohydrates and fats are converted to energy in cellular organelles called mitochondria. Energy is produced by both glycolysis and the citric acid cycle.  Environmental toxins can inhibit the production of energy from both carbohydrates and stored fats resulting in obesity. For instance aluminum at a concentration of some drinking water in the U.S. inhibits glycolysis.

Since development of the Bayer process for aluminum purification from bauxite in 1888, there has been a steady increase in the amount of aluminum humans ingest and accumulate.  Aluminum, at levels found in some drinking water (108ppb,108mcg/liter, 4mcM), inhibits hexokinase, an enzyme that catalyzes the first step in carbohydrate  metabolism (i.e. glycolysis)1.  The biochemical response to the inhibition of glycolysis is the conversion of carbohydrates to fat as triglycerides comprised of long chain fatty acids2.  This fat can be stored in adipose tissue or metabolized for energy.  However, aluminum also inhibits the production of L-carnitine required for movement of long chain fatty acids in stored fat to the mitochondria for conversion to energy3-6.   Therefore aluminum inhibits two key steps in metabolizing carbohydrates and fats for energy generation:

·      Aluminum inhibits the first step of carbohydrate metabolism called glycolysis1. Inhibition of glycolysis promotes the conversion of carbohydrates to stored fats (e.g. lipogenesis)2.
·      Aluminum inhibits the biosynthesis of L-carnitine3-6. L-carnitine is required for mobilizing stored fat as long chain triglycerides for mitochondrial energy production7.

The result of aluminum ingestion is therefore, more fat from carbohydrate, more fat being stored, and less fat being utilized for energy, resulting in obesity that does not respond to dieting.

Ketogenic Diet of Medium Chain Triglycerides for Coping with Aluminum Toxicity

Switching from a low fat – moderate carbohydrate diet to a high fat – low carbohydrate diet results in higher than normal levels of chemicals called ketones in the blood.  For this reason the high fat diet is called a ketogenic diet.  The source of fat on a ketogenic diet can be from plant and/or animal sources, such as canola oil, coconut oil, and/or beef tallow.  All fats are primarily triglycerides comprised of fatty acids of varying chain length and unsaturation that are esterified to glycerol. These fatty acids are of three types: 
·         Long chain essential fatty acids (e.g. linoleic and alpha-linolenic acids)
·         Long chain non-essential fatty acids (i.e. EPA and 22C DHA)
·         Medium chain fatty acids  (i.e. lauric acid found as 50% of coconut oil)

History of the Ketogenic Diet

The fact that the human body can switch from carbohydrates to triglycerides as its primary source of energy is called the “Schwatka Imperative”.  This is named after Lieutenant Frederick Schwatka who volunteered for a 19 month 3,000 mile Arctic mission, taking with him only enough carbohydrate to last 10 months8.  On June 15th of 1879 he ate his last hard bread and then it became imperative that his body switch to a diet of primarily fresh-killed reindeer meat with occasional fish. For the first two or three weeks on the ketogenic diet he felt “… an apparent weakness and inability to perform severe exertive, fatiguing journeys.”  Then miraculously after two to three weeks on the ketogenic diet his strength and stamina returned to normal. For example, during the last two days of the expedition he hiked 75 miles.

Lieutenant Schwatka was looking for information on why the men of the Franklin Expedition perished in the Arctic a quarter century earlier. Schwatka was lucky he traveled ten years before the Bayer Process for aluminum purification from bauxite was developed in 1888. Since 1888 people in general have been dosed with ever increasing levels of aluminum that is impacting how their mitochondria generate energy. 

           
Moderate Carbohydrate Diet with Supplements for Losing Weight and Aluminum

Johnston in 2006 compared 10 overweight people on a low fat and moderate carbohydrate diet with 9 overweight people on a ketogenic diet with high fat and low carbohydrate diet.  The groups were fed diets providing the following percentages of energy:

Moderate Carbohydrate Diet:    30% fat   –   40% carbohydrate   –   30% protein
Ketogenic Diet:   60% fat   –     5% carbohydrate   –   35% protein

After eight weeks the moderate carbohydrate dieters lost more weight than the ketogenic dieters.  The researchers concluded that the ketogenic diet did not offer any significant metabolic advantage over the moderate carbohydrate diet12.There are supplements of biochemicals naturally found in your body that taken daily will result in improved stored fat utilization and weight loss.  These supplements are:

·         Dissolved silica (a.k.a. OSA) for lowering your body-burden of aluminum13-15
·         CoQ10 for improving your energy and cognition16
·         PQQ for increasing mitochondrial biogenesis and cognition16-18
 

By lowering aluminum levels in your body, glycolysis and fat metabolism will return to normal.  This coupled with new mitochondria will allow you to metabolize or “burn” stored fat resulting in dieting with weight loss.

 There are also supplements of biochemicals naturally found in your body that will lower LDL and triglycerides, both of which are linked to an increased risk of vascular disease, such as stroke and heart attack: 
·         EPA (eicosapentaenoic acid) for reducing triglycerides by 5 to 10%19
·         PA (palmitoleic acid) for reducing triglycerides by 15% and LDL by 8%20
·         Vitamin D for reducing triglycerides by 23%21

Lowering triglycerides and LDL decreases the risk of vascular disease, heart attack, and stroke.  For more details on these supplements see my book “Prevent Alzheimer’s, Autism, and Stroke”22.

Ketogenic Diet with Fat from Medium Chain Triglycerides

Medium chain triglycerides (MCT), as opposed to long chain (i.e. 18 carbon atoms) triglycerides (LCT), do not require L-carnitine for mobilization and conversion into energy by the mitochondria10.  Therefore the metabolism of MCT is not inhibited by aluminum. Also the oxidative utilization (sum of digestion, absorption, and oxidation) of MCT can be 3 to 4 times greater than for LCT10.  These results were obtained with animals preconditioned to survive, like Lieutenant Schwatka, on a ketogenic diet10.  Therefore the modern equivalent of the “Schwatka Imperative” is to either:

·         Remain obese while surviving on a diet of medium chain triglycerides or
·         Lose some weight by decreasing aluminum accumulation and eating a moderate carbohydrate diet.  

Many people are opting for the MCT diet, such as coconut oil, without lowering aluminum.  This will provide more energy and improved cognition. Unfortunately it will not result in weight loss since aluminum is still inhibiting the mobilization and conversion of stored long chain fatty acids to energy. Also:·         

MCT or Coconut oil does not contain essential fatty acids (e.g. linoleic and alpha-linolenic acid)
·         Lauric acid, comprising 50% of coconut oil, increases LDL by 16% in humans and LDL is linked to vascular disease, such as stroke and heart attack11

References
1. Lai, J.C., and Blass, J.P.; Inhibition of brain glycolysis by aluminum; J. Neurochem.; Feb.; 42(2):438-46 (1984)
2. Mailloux, R.J., et al.; Hepatic response to aluminum toxicity: Dsylipidemia and liver diseases; Exper. Cell Res.; 317:2231-2238 (2011)
3. Gaballa, I.F., et al.; Dyslipidemia and disruption of L-carnitine in aluminm exposed workers; Egyptian J. Occup. Med.; 37(1):33-46 (2013)
4. Lemire, J., et al.; The disruption of L-carnitine metabolism by aluminum toxicity and oxidative stress promotes dyslipemia in human astrocytes and hepatic cells; Toxicol. Lett.; Jun.; 203(3):219-26 (2011)
5. Waly, M. I-A., et al.; Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal; Mol. Psychiatry; 9:358-70 (2004)
6. Waly, M. I-A., and Deth, R.; Neurodevelopmental toxins deplete glutathione and inhibit folate and vitamin B12-dependent methionine synthase activity – a link between oxidative stress and autism, FASEB J.; 22:894 1 (2008)
7. Fritz, I.B., Kaplan, E., Yue, K.T.; Specificity of carnitine action on fatty acid oxidation by heart muscle; Am. J. Physiol.; Jan.; 202:117-21 (1962)
8. Schwatka, F.; The Long Arctic Search; Stackpole, E.A., Editor; No. 44; The Marine Historical Association, Inc.; Mystic, CT (1965)
9. Beattie, O., and Geiger, J.; Frozen in time – The fate of the Franklin Expedition; Bloomsbury (2004)
10. Heo, K.N., et al.; Medium-chain fatty acids but not L-carnitine accelerate the kinetics of [14C]triacylglycerol utilization by colostrum-deprived newborn pigs; J. Nutr.; 132:1989-1994 (2002)
11. Tsai, Y.H., et al.; Mechanisms mediating lipoprotein responses to diets with medium chain triglyceride and lauric acid; Lipids; Sep.; 34(9):895-905 (1999)
12. Johnston, C.S., et al.; Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets; Am. J. Clin. Nutr.; 83:1055-61 (2006)
13. Edwardson, J.A., et al.; Effect of silicon on gastrointestinal absorption of aluminum; The Lancet; 342(8865):211-12 (1993)
14. Carlisle, E.M., and Curran, M.J.; Effect of dietary silicon and aluminum on silicon and aluminum levels in rat brain; Alzheimer Dis. Assoc. Disord.; 1(2):423-30 (2013)
15. Davenward, S,, et al.; Silicon-rich mineral water as a non-invasive test of the ‘aluminum hypothesis’ in Alzheimers disease; J. Alzheimer’s Dis.; 33(2):423-30 (2013)
16. Nakani, M., et al.; Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons; Food Style; 21 13(7):50-3 (2009)
17. Chowanadisai, W., et al.; Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1 alpha expression; J. Biol. Chem.; Jan.; 285(1):142-52 (2010)
18. Onyango, I.G., et al.; Regulation of neuron mitochondrial biogenesis and relevance to brain heath; Biochim Biophys Acta; jan.; 1802(1):228-34 (2010)
19. Bernstein, A.M., et al.; Purified palmitoleic acid for the reduction of high-sensitivity C-reactive protein and serum lipids: a double blinded, placebo controlled study; J.Clin. Lipidol.; 8(6):612-7 (2014)
20. Harris, W.S.; n-3 Fatty acids and serum lipoproteins: human studies; A. J. Clin. Nutr.; 65(suppl.):1645S-54S (1997)
21. Rejnmark, L., et al.; Simvastatin does not affect vitamin D status, but low vitamin D levels are associated with dyslipidemia; Results from a randomized, contolled trial: Internat. J. Endrocrin.; Article ID 957174 (2010)
22. Crouse, D.N.; Prevent Alzheimer’s, autism, and stroke, with 7 supplements, 7 life-style choices, and a dissolved mineral; Etiological Publishing (2016)

Aricept (Donepezil) and Cholinesterase Inhibitors facilitate the progression to dementia quicker than no treatment

 Excerpt from  the book "Increasing IQ, Cognition and COVID-19 Cure Rate with Essential Nutrients .....  Targeted Detox Improves Children’s IQ, ADHD Behavior, and Adult Cognition by Dennis N Crouse    

Chapter 11. Crouse Protocol for Reversing MCI and AD

                                    Efficacy of Cholinesterase Inhibitors and Memantine

Many people with mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD) are prescribed a cholinesterase inhibitor (ChEI). Those with moderate to severe AD (e.g., Mini-Mental State Examination [MMSE] scores below 15) are prescribed memantine, with in some cases a ChEI. Administration of a ChEI increases the concentration of acetylcholine by inhibiting its breakdown. These drugs treat some of the symptoms of MCI, such as memory loss, agitation, apathy, and psychotic symptoms including delusions, hallucinations, and disordered thought. Examples of ChEIs are: 

·         Galantamine (trade name Razadyne) is approved by the FDA for treatment of vascular dementia and mild to moderate AD. It enhances memory in brain-damaged adults⁵⁴⁴.

·         Rivastigmine (trade name Excelon) is approved to for mild and moderate AD.

·         Donepezil (trade name Aricept) is approved to treat all stages of AD.   

A study was published in 2011 on the efficacy of these three ChEIs and memantine taken by patients diagnosed with MCI or mild AD. Approximately one-half of 392 MCI patients and two-thirds of 188 mild AD patients were APOE-4 carriers. Among the MCI patients 33.4% received only ChEIs, 11.7% received ChEIs and memantine, and 54.9% received neither. Among the 188 AD patients 38.9% received ChEIs, 45.7% ChEIs and memantine, and 15.4% neither⁸¹⁷.

The patients with MCI were divided into three groups, only 22% of the non-treated group progressed to dementia, 43% of the ChEI treated group progressed to dementia, and 56% of the group treated with both memantine and ChEI progressed to dementia. Therefore, there is a greater  risk of dementia among people taking these drugs. The mean time to dementia was 30% quicker in the ChEI treated group than the untreated group and 42% quicker for the memantine and ChEI treated group than the untreated group. Both MCI patients and AD patients who received ChEI treatment had a more severe decline in cognition than untreated patients. Therefore, these drugs may reduce symptomology of MCI and AD but both increase the risk of dementia and hasten the progression to dementia when compared with un-treated people⁸¹⁷.

I have an acquaintance with MCI who was prescribed Aricept to improve her short-term memory but had trouble sleeping once she began taking the drug. The doctor then recommended a sleeping pill with the side effect of memory impairment. This is an example of a doctor being uniformed on the negative side effects of a prescribed drug.

Although these drugs are FDA-approved for those with MCI and AD, they are not efficacious for slowing the progression to dementia. In fact, they significantly increase the risk and speed the progression to dementia. These drugs will facilitate the progression to dementia quicker than no treatment. 

Review of my book Prevent Alzheimer's Autism and Stroke

This review can be found in the Spring 2021 edition of  the journal 'Wise Traditions' a Publication of The Weston Price Foundation 

This book can be purchased on Amazon.

https://www.amazon.com/Dennis-N.-Crouse-Ph.D./e/B01LFW4782%3Fref=dbs_a_mng_rwt_scns_share

How to test for Aluminum, Lead, Mercury, and Arsenic in the Body

 Measuring the Body Burden of Toxic Trace Metals in Humans

Dennis N. Crouse

3/24/2021

 

Aluminum – Drinking water containing orthosilicic acid (OSA) has been proven to remove aluminum from most organs of the body including bone and brain. Therefore, the best way to measure your body burden of aluminum is to drink a liter of Fiji water or Silicade that contains 124ppm of OSA and then collect your urine for 24 hours. Measure the total volume of the collected urine and have total aluminum concentration (in units of nanomolar) and total creatinine (in units of micromolar) both quantified in the collected urine. The ratio of aluminum to creatinine concentrations reflects the urine aluminum through-out the body over a 24-hour period. This is more representative of your aluminum body burden than a blood sample that is only representative of the time and place where the blood sample is taken. It is also more reliable than hair samples as some shampoo and hair colorants have aluminum as an ingredient.

Based upon the color of your urine you know that it is sometimes more dilute than at other times. This can be due to inhibition of diuretic hormone by substances, such as alcohol, that reduce the reabsorption of water from the urine resulting in dilute urine. Both aluminum and creatinine once in the kidney are not reabsorbed back into the blood, unlike water. Creatinine is a breakdown waste product from muscle and is present in a narrow concentration range in urine. Therefore, a ratio of aluminum to creatinine concentrations minimizes the effect of urine dilution.

For 10 healthy adults who had not consumed 1 liter of OSA rich water the mean of urinary aluminum (nM/mM creatinine) is 43 and silicon (mcM/mM creatinine) is 32. These numbers are dependent upon the health of an individual and amount of aluminum and silicon in their diet and drinking water. For instance, secondary progressive multiple sclerosis (SPMS) is a disease in which aluminum accumulates in the brain at levels higher than normal. Patients with SPMS who drank 1 to 1.5 liters per day of OSA rich water for twelve weeks had mean urinary aluminum levels of 135 (nM/mM creatinine) before drinking OSA rich water and 349 (nM/mM creatinine) after 12 weeks or drinking OSA rich water.

Here is a link to a lab that does this type of testing.  https://requestatest.com/aluminum-urine-test

If you are outside the US here is what you need to look for when choosing a lab.   

Measuring Accumulated Aluminum – The best way to measure your body burden of accumulated aluminum is to have your urine tested for total aluminum excreted in 24 hours. This test can be performed by a laboratory, such as LabCorp (test no. 071555)³⁴. The 24-hour total aluminum test has three requirements:

·       Aluminum must be measured in units of mg/L or mM/L by the laboratory

·       Aluminum must be detected down to a level of 3mg/L that is equivalent to 0.11 mM/L

·       The total volume of urine must be measured in liters (L)

There are laboratories that only report aluminum/creatinine ratios and/or can’t detect aluminum at sufficiently low levels. Check with the laboratory first before submitting your urine for testing. 

The 24-hour aluminum test is usually performed by collecting your urine for 24 hours in a container provided by the testing laboratory. Do not pour anything but urine into the container and do not pour anything out of the container. The  container should be kept at a cool temperature throughout the collection period and during travel to the laboratory. Follow these instructions for collecting your 24-hour urine specimen:

1.     Upon arising in the morning, urinate into the toilet, emptying your bladder completely. Do not collect this sample. Note the exact time and print it on the container.

2.     Collect in the provided container, optionally using a plastic collection pan, all urine voided for 24 hours after this time, including urine passed during bowel movements. 

3.     At exactly the same time the following morning, void completely again after awakening. This completes the 24-hour urine specimen that must be taken to the lab.

Test results can indicate “Aluminum, Urine 24 Hr.”  as the number of micrograms of aluminum excreted in 24 hours (mg/24hr). Divide mg/24hr by 27 to get micromoles of aluminum excreted in 24 hours (mM/24hr). If your test results are in units of mg/L or mM/L, multiply by the number of liters of urine that was collected in order to get total 24-hour aluminum in units of mg/24hr or mM/24hr. For interpreting your test results see table 4 where the units of measure are mM/24hr.

 

Lead – Exposure to lead can be measured with a whole blood test. However, the blood lead level (BLL) is not a reliable indicator of prior or cumulative dose or total body burden of lead. An indicator of prior lead exposure is a buildup of erythrocyte protoporphyrin in red blood cells. Tests are used to measure free erythrocyte protoporphyrin (FEP) and zinc protoporphyrin (ZPP) in the blood. When BLLs reach or exceed 25mcg/dL an increase in FEP and/or ZPP can be detected. These increases in FEP and ZPP usually lag increases in BLL by two to six weeks.  When BLLs reach 40mcg/dL the FEP or ZPP levels increase abruptly and stay elevated for 3-4 months which is the average life span of a red blood cell.

·       Elevated BLL and Normal FEP/ZPP = Recent exposure to lead in last 2-6 weeks

·       Elevated BLL and Elevated FEP/ZPP = Chronic/ongoing exposure to lead

There is no safe level of lead and all adults have some body burden of lead. The U.S. National Institute for Occupational Health and Safety (NIOSH) in 2015 indicated 5mcg/dL as a reference BLL above which action should be taken to target the detox of lead.

Mercury – Mercury in the body can be in three chemical forms: organic mercury, such as methylmercury from eating fish, inorganic mercury, such as mercuric ion and mercury selenide, and metallic mercury, such as the mercury in dental fillings and some thermometers.

·       Methylmercury is measured in a whole blood sample taken from a vein.

·       Inorganic mercury and metallic mercury are measured in a random or 24-hour urine sample.

A hair sample can be measured to indicate exposure to increased levels of methyl mercury. However, hair samples are rarely used due to hair exposure to mercury containing dyes, bleach, and shampoo.

The Centers for Disease Control and Prevention (CDC) define the laboratory criteria for a diagnosis of excessive mercury exposure is blood mercury level greater than 10mcg/L. Most people have hair mercury levels well below 1mcg/gr (ppm). Adults with average hair mercury level of 4.2mcg/gr have neuropsychological function deficits.  Maternal hair mercury levels of 0.3 to 1.2mcg/gr have been associated with prenatal neurodevelopmental effects. If you have levels over these limits, stop eating fish and begin augmenting your diet with L-selenomethionine.

 

Arsenic – Significant exposure to arsenic results in greater than 12nanograms/ml in blood taken 4 to 6 hours after exposure. Blood concentration of arsenic are elevated for only a short period of time after exposure. This is because arsenic has a high affinity for tissue proteins. The body treats arsenic like phosphate and incorporates it in place of phosphate.  Arsenic is excreted at the same rate as phosphate with an excretion half-life of 12 days because most of ingested arsenic is in tissues, not in the blood where it has a half-life of 4 to 6 hours. Therefore, 24-hour total urine samples, not blood samples, are most useful for measuring the body burden of arsenic. The concentration of inorganic arsenic and its metabolites (i.e., MMA and DMA) in urine reflects the body burden of absorbed arsenic due to acute or chronic arsenic exposure.

Hair analysis can only be used as a screening tool for arsenic intoxication as there can be arsenic deposition in hair due to hair exposure to arsenic containing dyes, bleach, and shampoo. Also, there are uncertainties about the normal levels of arsenic in hair.     

Safety of Fiji Water

 

How Safe is Bottled Fiji Water

Dennis N. Crouse

March 15, 2021

 

Fiji water is sold in recyclable polyethylene terephthalate (PET) bottles¹. Fiji water is a unique bottled water because the bottle is made of 100% PET that is more economic to recycle than bottles made of mixed plastics¹. Both glass and PET bottles were used to store water from the same spring and in both cases no endocrine disrupters were released into the water^2,3. This suggests that known endocrine disruptors, such as di-2-ethyhexyl phthalate (DEP)⁴, optionally added to some PET as a plasticizer, may be the cause of endocrine disruption seen with water stored in some non-Fiji PET bottles². Fiji water has been tested and found to contain no detectable DEP⁵. Also, it is claimed the PET Fiji uses, does not contain phthalate plasticizers¹.

Fiji water is also a unique bottled water because of its high concentration of orthosilicic acid (OSA) which is a water-soluble form of silica. OSA exists as single molecules [i.e., Si(OH)₄] at a concentration of 124-149ppm⁶. Drinking water containing less than 160ppm of OSA (equivalent to 100ppm of dissolved silica) is generally regarded as safe (GRAS) by the U.S. FDA⁷.

In addition to OSA, Fiji water also contains bicarbonate, calcium, chloride, magnesium, sodium, and sulfate, all of which are considered harmless⁵. In addition, Fiji water contains the following trace metals including arsenic (1.2ppb), and fluoride (0.24ppm)^5,8 that are well below the maximum contaminant levels [MCL or SMCL set by the U.S. EPA]. Also, Fiji water was filtered through a 0.45micron filter and then the filter was examined using a 45x power microscope to reveal 12 particles of unknown composition/liter⁹.

·       Aluminum: 0 ppb¹⁰ (levels of aluminum over 100ppb have been linked to Alzheimer’s)¹⁰

·       Antimony: 0 ppb⁵ (6 ppb MCL)^{Note 1}

·       Arsenic: 1.2ppb⁵ (10ppb MCL)

·       Fluoride: 0.24ppm^5,8 (2.0ppm SMCL)

·       Lead: 0 ppb⁵ (0ppb MCL)

·       Mercury: 0 ppb⁵ (2ppb MCL)

·       Particles: 12/liter⁹ where usually 1 in 3000 is a microplastic particle^{Note 2}

Therefore, Fiji water is safe to drink. 

 

Note 1: An insignificant amount antimony is leached out of PET into bottled water after 3 months of storage at 22^oC (71.6^oF)¹¹. However, storage of drinking water in PET containers at greater than 70^oC (the glass transition temperature of PET) has been shown to add antimony to the stored water¹¹.

Note 2: Fiji water is “micron-filtered” prior to bottling in order to remove particles⁵. A study that found 12 particles larger than 0.45 microns per liter of Fiji water, used a microscope that could not identify the composition of the particles⁹. When looking at small particles with just a microscope it is impossible to discern their composition¹².   People who use equipment that can discern composition of particles (e.g., Raman spectrometer) have not examined the particles in Fiji water. However, they have found that only 1 particle in 3000 particles in river water is microplastic¹². The toxicology of microplastic particles is currently unknown but in spite of this, plastic microbeads were used for a number of years in some toothpastes and cosmetics. Because microbeads may be mistaken as food by fish, the Microbead Free Waters Act of 2015 by the U.S. FDA outlaws the manufacture, delivery, and sale of any rinse-off products (e.g., toothpastes, cosmetics, and over the counter drugs) containing microbeads smaller than 5 millimeters¹³. 

References

1. Lynch, I., et al.; Fiji water A sustainability report; University of Vermont (2010)

2. Wagner, M., and Oehlmann, J.; Endocrine disruptors in bottled mineral water: total estrogenic burden and migration from plastic bottles; Environ. Sci. Pollut. Res.; 16:278-86 (2009)

 3. Chung, B.Y., et al.; Uterotropic and Hershberger assays for endocrine disruption properties of plastic food contact materials polypropylene (PP) and polyethylene terephthalate (PET); J. Toxicol. Envrion. Health, Part A; 76(10):624-34 (2013)

4. Latini, G., et al.; Di-2-ethylhexyl phthalate and endocrine disruption: a review; Curr. Drug Targets Immune Endocr. Metabol. Disord.; Mar.; 4(1):37-40 (2004)

5. Fiji Water; Bottled water quality report; January (2017)

6. Crouse, D.N.; Silica water the secret of healthy blue zone longevity in the aluminum age, Etiological Publishing (2018)

7. Select committee on GRAS substances – SCOGS-61, NTIS Pb 301-402/AS (1979)

8. Delaney, J. as Client; Tweed Laboratory Centre; NSW Australia; Laboratory report on Fiji water (2019)

9. Barrows, A.P.W., Anthropogenic microparticle contamination in bottled water for human consumption; (2018)

10. Crouse, D.N.; Prevent Alzheimer’s, autism, and stroke with 7 supplements, 7 lifestyle choices, and a dissolved mineral; Etiological Publishing (2016)

11. Westerhoff, P., et al.; Antimony leaching from polyethylene terephthalate (PET) plastic used for bottled drinking water; Water Res.; Feb.; 42(3):551-6 (2018)

12. Ivleva, N.; Technical University Munich; How dangerous is microplastic?  https://phys.org/news/2019-01-dangerous-microplastic.html

13. The microbead-free waters act: FAQs; U.S. FDA (2020) https://www.fda.gov/cosmetics/cosmetics-laws-regulations/microbead-free-waters-act-faqs