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

Primary Progressive Apasia and Aluminum

Proposed Causes and Treatment of Primary Progressive Aphasia (PPA)

Dennis N. Crouse

February 16, 2021

Primary Progressive Aphasia (PPA) is a type of neurodegenerative condition that symptomatically is a slow deterioration of language ability (i.e., aphasia). PPA is associated with other neurodegenerative diseases such as Alzheimer’s (i.e., 1/3 of PPA cases) and frontotemporal lobar degeneration (i.e., 2/3 of PPA cases). PPA is therefore called a neurological syndrome.

The primary symptom of PPA is slowly progressing aphasia occurring as the dominate feature and lasting for at least the first two years of the disease. The first symptoms of PPA are declining speech and language capability followed later by memory loss manifesting itself as difficulty with word finding and object identification (i.e., anomia) and in many cases, finally progressing to a nearly total inability to speak (i.e., mutism). PPA is slowly progressive unlike other forms of aphasia that arise suddenly from stroke or brain injury. PPA is also unlike Alzheimer’s disease as PPA patients have aphasia as the dominant symptom before memory loss and can take care of themselves, maintain their daily living skills, and even remain employed. 

Bird Watching as a Test for PPA

In later life I have resumed the hobby of bird watching that I first began in my early teens. Warblers are my favorite group of birds as they can be easily identified by their plumage and nuanced songs. The art of being a successful warbler watcher hinges on the ability to spot the bird either visually and/or audibly (i.e., sensory processing), identify the name of the warbler from a memorized lexicon of key features (i.e., semantic processing), and finally call out the name of the warbler to others (i.e., articulation). In my teens this three-step process could be carried out in less than a second. But as I have grown older it has been slowed by what is called a “tip-of-tongue delay” caused by temporary anomia. If this delay becomes progressively longer and more frequent over a two-year period it could be a symptom of PPA.

 Brain Atrophy as a Causal Factor of PPA

Brain atrophy (e.g., cortical thinning) of specific areas of the brain is correlated with different symptomology in both patients with PPA and language variants of frontotemporal lobar degeneration (FTLD) as shown in table 1^1,2.

Table 1. Variants of PPA and FTLD, Symptoms, and Location of Brain Atrophy1,2
PPA Variant	Primary Symptom	Location of Brain Atrophy
Agrammatical (PNFA)	Effortful and Halting Speech	Left inf. frontal lobe & ins. cortex
Semantic (SemD)	Anomia	Bilaterally in ant. temporal lobes
Logopenic	Impaired Single Word Retrieval	Left pos. temporal & parietal lobes

PNFA = Progressive Nonfluent Aphasia; SemD = Semantic Dementia; inf. = inferior; ins. = insular; ant. = anterior; pos. = posterior

As PPA or language variants of FTLD progress, brain atrophy extends to other lobes of the brain following a distinct pattern that depends upon the variant². Brain atrophy is also a characteristic of AD, with brain atrophy observed in the frontal and entorhinal cortexes and hippocampus³.

 Brain atrophy in AD is due to the programmed death of neurons during what is called neuronal cell cycle events (CCEs)⁴. The cause of this programmed death is a cytokine modulated cascade that starts with a xenobiotic chemical or pathogen infecting the brain and causing inflammation. Tumor necrosis factor (TNF-alpha) is the primary cytokine responsible for CCEs⁴.  TNF-alpha is a cytokine released by both some white blood cells, called macrophages, and microglial cells in the brain to alert the immune system of an infective agent, such as a toxic metal or pathogen, and induce the process of inflammation.

Higher than normal levels of microglial derived TNF-alpha may play a central role in pathogenesis of Alzheimer’s disease^4,5, late stage dementia⁶, and have been documented in the cerebrospinal fluid of patients with frontotemporal dementia⁷. Therefore, because PPA is associated with both Alzheimer’s and frontotemporal dementia, excess TNF-alpha is also likely involved with brain atrophy observed in PPA^1,2.

Blood-Brain Barrier as the Brain’s Leaky Roof

The blood-brain barrier acts as a protective roof over the brain to keep environmental factors, such as toxic metals and pathogens, from leaking into the brain. This roof becomes leaky due to chemically or physically induced trauma(s). Chemical trauma includes environmental toxins and oxygen deprivation (i.e., hypoxia) caused by stroke or white matter hyperintensities. Physical trauma includes traumatic brain injury due to a blow to the head. Leaks are sporadic and result in localized brain atrophy due to chronic exposure to leaking toxins. 

  

Aluminum Induces TNF-alpha Expression

TNF-alpha is deadly to neurons because with the enzyme JNK a self-amplifying loop is created that induces the generation of reactive oxygen species (ROS) that kills neurons⁸. Toxic metals also induce the production of reactive oxygen species (ROS) in microglial cells of the brain that can kill neurons. The metal that tops the list for ROS production in microglial cells is aluminum as shown in table 2⁹.

Table 2 - Metal Ion Induction of ROS in Human Microglial Cells9
Metal Sulfate	Relative Induction of ROS
Aluminum	10
Iron	6
Manganese	4.5
Zinc	4
Nickel	3.5
Lead	3.5
Gallium	3
Copper	3
Cadmium	3
Tin	2
Mercury	1.5
Magnesium	0
Sodium	0

 

In 1999 it was discovered that aluminum in drinking water (i.e., 0, 5, 25, and 125ppm) for one month enhances the expression of TNF-alpha in mice in a dose-dependent manner .This increased expression due to aluminum was only observed in the cerebrum not in peripheral cells suggesting that microglial cells were the source of increased TNF-alpha¹⁰. Five years later in 2004 this discovery was duplicated by another group. Aluminum lactate in drinking water (i.e., 0.27, 2.7, and 27ppm of aluminum)  for 10 weeks up-regulated TNF-alpha expression, and enhanced reactive microglia in the striatum of mice¹¹. Therefore, aluminum induces the production of TNF-alpha and ROS resulting in a deadly cocktail for neurons causing PPA, AD, and frontotemporal lobar degeneration.   

 

Aluminum Induces Brain Atrophy in AD

Aluminum hotspots in the AD brain were first observed in 1973¹². Aluminum hotspots in the brain are dependent upon where aluminum leakage across the blood-brain-barrier occurs. The location of these hotspots can be random making PPA, AD, and frontotemporal lobar degeneration all primarily sporadic diseases. The sporadic location of aluminum hotspots can account for the variability in symptoms and disease diagnosis of PPA as shown in table 1. Likewise, the locations of aluminum hotspots coincide with the locations of brain atrophy in AD as shown in tables 3 and 4^3,13.

Table 3. Brain Atrophy in Humans with AD and Non-demented Controls During 1 Year3
Regions of Brain Analyzed	AD Longitudinal                  % Change	Controls Longitudinal            % Change
Entorhinal Cortex	-2.42	-0.55
Hippocampus	-3.75	-0.84
Frontal Cortex (caudal)	-1.60	-0.40
Frontal Cortex (ventral)	-1.06	-0.38

 

Table 4. Brain Aluminum in Humans with AD and Non-demented Controls13
Regions of Brain Analyzed	AD                                      (Al mcg/g of brain tissue)	Controls                                 (Al mcg/g brain tissue)
Entorhinal Cortex	10.2 + 9.0	1.5 + 0.6
Hippocampus	4.9 + 3.0	1.4 + 0.6
Frontal Cortex (caudal)	6.8 + 4.3	1.8 + 0.6
Frontal Cortex (basal/ventral)	6.4 + 2.9	2.5 + 0.7

 

Autopsy and analysis of 242 brains of people diagnosed with AD, as reported in six studies, have revealed that in all cases AD brains have higher than normal levels of aluminum^13,14,15-18. Autopsy and analysis of brains from people with early^13,14,18 or late onset AD^13,14,15-17 and with familial^15,16, sporadic^13,14,17 or occupational AD¹⁸ all had higher than normal levels of aluminum. Because of the role played by aluminum in brain atrophy, it could be theorized that it may also play a role in PPA and frontotemporal dementia. However, there are no studies of aluminum in the brains of patients who had been diagnosed with either frontotemporal dementia or PPA prior to death.

Synaptic Loss in PPA

The loss of synapses in neurodegenerative diseases, such as AD, is better correlated with cognitive decline than is neuronal loss^19,20. Synaptic loss impairs the ability of neurons to communicate and underlies the cognitive deficits seen in those with PPA²¹. This loss of synapses was observed in Broca’s area of the brain in a patient with PPA²¹. Impaired cortical synaptic connections in the part of Broca’s area with synaptic loss could account for the symptoms of PPA seen in the patient²¹.

The loss of synapses (e.g., synaptic integrity) is correlated with the loss of synaptophysin, a major synaptic vesical protein. The pathological severity of AD is negatively correlated with the amount of synaptophysin mRNA in temporal cortex neurons²². In addition, the amount of synaptophysin was reduced by 30% of normal levels in the prefrontal cortex of those with severe AD^23,24. Synaptic vesicle formation in vitro and therefore the amount of synaptophysin at synapses is inhibited by aluminum fluoride commonly found in fluoridated drinking water²⁵.

Therefore, aluminum not only causes the loss of neurons but also aluminum bonded to fluoride causes the loss of synapses by inhibiting synaptic vesicle formation as seen in those with PPA^21,25.    

Treatment of PPA

Because of the role played by TNF-alpha in brain atrophy, it has been suggested that TNF-alpha inhibitors, such as Etanercept, could be used to treat PPA^26,27 and Alzheimer’s disease²⁸.  Although published results in 2008 looked good on the basis of a single case of PPA²⁶, there has not been a published duplication of this case study on a larger number of PPA cases with controls.

Aluminum accumulation in the brains of those with PPA could be targeted for detox with orthosilicic acid (OSA) in drinking water²⁹. There are no published studies of OSA treatment of patients with PPA. However, OSA in drinking water has been shown to improve cognition in some AD patients and has been shown to remove aluminum from the brains of rats^30-32. In addition, drinking OSA rich water is correlated with a lower risk of AD as shown in an epidemiological study³³.

Conclusion

Primary Progressive Aphasia (PPA) is a neurological syndrome associated with either Alzheimer’s disease (AD) or frontotemporal lobar degeneration (FTLD). Neuronal and synapse atrophy, along with higher-than-normal levels of the cytokine tumor necrosis factor (TNF-alpha), has been observed in patients with PPA, AD and FTLD symptoms. Aluminum in drinking water enhances the expression of TNF-alpha in mice and is a putative causative factor of AD. Both aluminum and TNF-alpha are associated with increased ROS generation in glial cells of the brain that can result in neuronal and synapse atrophy. Since orthosilicic acid (OSA) in drinking water facilitates the removal of aluminum in rat brains and can improve cognition in AD patients, it is hypothesized that OSA in drinking water can also decrease symptomology in PPA patients.     

References

1.      Matias-Guiu, J.A. and Garcia-Ramos, R.; Primary progressive aphasia: From syndrome to disease; Neurologia; 28(60:366-74 (2013)

2.      Rohrer, J.D., et al.; Patterns of cortical thinning in the language variants of frontotemporal lobar degeneration; Neurology; May; 72:1562-9 (2009)  

3.      Fjell, A.M., et al.; One-year brain atrophy evident in healthy aging; J. Neurosci.; Dec.; 29(48):15223-31 (2009)

4.      Bhaskar, K., et al.; Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cell cycle events; Neurobiol. Dis.; Feb.; 62:1-29 (2013)

5.      Fillit, H., et al.; Elevated circulating tumor necrosis factor levels in Alzheimer’s disease; Neurosci. Lett.; Aug.; 129(2):318-20 (1991)

6.      Bruunsgaard, H., et al.; A high plasma concentration of TNF-alpha is associated with dementia in centenarians; J. Gerontology; Medical Sciences; 54A(7):M357-M364 (1999)

7.      Sjogren, M., et al.; Increased intrathecal inflammatory activity in frontotemporal dementia: pathophysiological implications; J. Neurosurg. Psychiatry; 75:1107-11 (2004)

8.      Blaser, H., et al.; TNF and ROS crosstalk in inflammation; Trends Cell Biol.; Apr.; 26(4):249-61 (2016)    

9.      Pogue, A.I., et al.; Metal-sulfate induced generation of ROS in human brain cells: detection using an isomeric mixture of 5- and 6-carboxy-2’,7’-dichlorofluoresein diacetate (carboxy-DCFDA) as a cell permeant tracer, Int. J. Mol.; 13:9615-26 (2012)  

10.  Tsunoda, M., and Sharma, R.P.; Modulation of tumor necrosis factor alpha expression in mouse brain after exposure to aluminum in drinking water; Arch. Toxicol.; Nov.; 73(8-9):419-26 (1999)

11.  Campbell, A., et al.; Chronic exposure to aluminum in drinking water increases inflammatory parameters selectively in the brain; J. Neurosci. Res.; Feb.; 75(4):565-72 (2004)

12.  Crapper, D.R., Krishnan, S.S., Dalton, A.J.; Brain aluminum distribution in Alzheimer’s disease and experimental neurofibrillary degeneration; Science, May, 180(4085):511-3 (1973)

13.  Andrassi, E., et al.; Brain Al, Mg, an P contents or control and Alzheimer-diseased patients; J. Alzheimer’s Dis.; 7:273-84 (2005)

14.  Rusina, R., et al.; Higher aluminum concentrations in Alzheimer’s disease after Box-Cox data transformation; Neurotox. Res.; 20, 329-33 (2011)

15.  Mirza, A., et al.; Aluminum in brain tissue in familial Alzheimer’s disease; J. Trace Elements in Medicine and Biology; Mar.; 40:30-36 (2017)

16.  Mold, M.; et al.; Aluminum and amyloid-B in familial Alzheimer’s disease; J. Alz. Dis.; 1:1-8 (2019)

17.  McLachlan, D.R.C., et al.; Aluminum in neurological disease – a 36 year multicenter study; J. Alzheimer’s Dis. Parkinsonism; 8: 457 (2018)

18.  Exley, C., and Vickers, T.; Elevated brain aluminum and early onset Alzheimer’s disease in an individual occupationally exposed to aluminum: a case report; J. Med. Case Reports; 8:41 (2014)

19.  Terry, R.D., at al.; Physical basis of cognitive alterations in Alzheimer’s disease: Synaptic loss if the major correlate of cognitive impairment; Ann. Neurol.; Oct.; 30(4):572-80 (1991)

20.  Masliah, E., et al.; Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer’s disease; Neurosci. Lett.; Aug.; 103(2):234-9 (1989)

21.  Lippa, C.F. and Rosso, A.L.; Loss of synaptophysin immunoexpression in primary progressive aphasia; Am. J. Alzheimer’s Dis. Other Dementias; 27(4):250-3 (2012)

22.   Heffernan, J.M., et al.; Temporal cortex synaptophysin mRNA is reducted in Alzheimer’s disease and is negatively correlated with the severity of dementia; Exp. Neurol.; Apr.; 150(2):23509 (1998)

23.  Shimohama, S., et al.; Differential involvement of synaptic vesicle and presynaptic plasma membrane proteins in Alzheimer’s disease; Biochem. Biophys. Res. Commun.; Jul.; 236(2):239-42 (1997)

24.  Minger, S.L., et al.; Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer’s disease; J. Neuropath. Exp. Neurol.; Oct.; 60(10):929-36 (2001)

25.   Cleves, A.E., et al.; ATP-dependent formation of free synaptic vesicles from PC₁₂ membranes in vitro; Neurochem. Res.; Aug.; 22(8):933-40 (1997)

26.  Tobinick, E.; Perispinal Etanercept produces rapid improvement in primary progressive aphasia: Identification of a novel, rapidly reversible TNF-mediated pathophysiologic mechanism; Medscape J. Med.; Jun.; 10(6):135 (2008)

27.  Griffin, W.S.T.; Perispinal Etanercept: Potential as an Alzheimere therapeutic; J. Neuroinflammation; Jan.; 5:3 (2008)

28.  Chang, R., et al.; Tumor necrosis factor alpha inhibition for Alzheimer’s disease; J. Central Nerv. Sys. Dis.; 9:1-5 (2017)

29.   Crouse, D.N.; Increasing IQ, cognition and COVID-19 cure rate with essential nutrients; Etiological Publishing (2021)

30.  Exley, C., at. al.; Non-invasive therapy to reduce the body burden of aluminum in Alzheimer’s disease; J. Alzheimer’s Dis.; Sept., 10(1):17-24 (2006)

31.   Davenward, S., et al.; Silicon-rich mineral water as a non-invasive test of the ‘aluminum hypothesis’ in Alzheimer’s disease; J. Alzheimer’s Dis.; 33(2):423-30 (2013)

32.  Belles, M., et al.; Silicon reduces aluminum accumulation in rats: Relevance to the aluminum hypothesis of Alzheimer’s disease; Alzheimer Disease Associated Disorders; 12(2):83-87 (1998)

33.   Rondeau, V., et al.; Aluminum and silica in drinking water and the risk of Alzheimer’s disease or cognitive decline: findings from 15-year follow-up of the PAQUID cohort, Am. J. Epidemiol. 169:489-96 (2009)