Chapter 1

Alzheimer’s Disease

“… anatomically it provided a result which departed from all previously known disease pathology.”  L. Alzheimer 19071

What Causes Alzheimer’s Disease?

The book begins as I did, searching for the cause of Alzheimer’s. I initiated this search when simultaneously my mother and a friend’s mother began having panic attacks due to short term memory failure at age 85. The progression of short term memory loss had been slow and steady and was just beginning to impact their daily living skills.  Routine things they had done on a daily basis, such as grocery shopping, balancing the checkbook, and sewing, had become impossible tasks. I hoped that learning what was known about the cause of Alzheimer’s would allow me to help these women slow the progression of the disease and possibly prevent further erosion of their memories.

I quickly discovered that finding the cause versus symptom of a disease like Alzheimer’s is a tricky business.  It takes a sleuth with the knowledge and cunning of Sherlock Holmes.  Being a chemist I have always had a fascination with Mr. Holmes, probably because he was portrayed as a chemist by Sir Arthur Conan Doyle. Young Stamford said Holmes was a “first-class chemist” when he first introduced Watson to Holmes in “A Study in Scarlet”.  In order to understand my search for a cause of Alzheimer’s (AD) please follow Mr. Holmes and Doctor Watson and read “The Case of the Cloaked Assassin”.


The Case of the Cloaked Assassin

Watson we may have a killer loose on the streets!  I just read on the internet in the Journal of Medical Case Reports 8:41 (2014) of the strange death of a 58 year old man with no prior medical history who was diagnosed with early-onset AD.  Ten years prior to his diagnosis he began working on a daily basis handling alum dust in order to develop a new insulation for the nuclear and space industry.  He was working with minimal respiratory protection.  After six years performing this work he began suffering from memory loss and depression.  In 2011, after his death due to AD at age 66, the frontal lobe of his brain was analyzed for aluminum.  It contained approximately 3mcg (3 micrograms) of aluminum per gram of dried brain tissue (3mcg/gr. dry wt.)2.  This is more than three times higher than the median concentration of aluminum (e.g. 0.87mcg/gr. dry wt.) found after death in the frontal lobes of people 60-70 years old3.  In addition, an abundance of beta-amyloid (Aβ) plaque and a profusion of neurofibrillary tangles (NFTs), hallmarks of AD, were found in his frontal cortex.

So Watson what is coincidence and what caused AD in this case of strange death?  There are four possibilities:

  • The victim was genetically predisposed toward AD
  • Aβ plaques were the cause of AD
  • NFTs were the cause of AD
  • Alum was the cause of AD

The first question – what are Aβ plaques and NFTs? These plaques and NFTs are insoluble protein molecules that are three dimensional aggregates of smaller soluble molecules called peptides and oligomers that are comprised of amino acids.  An amino acid is a molecule with at least one each of an amine and acid.


Amyloid beta (Aβ) plaques are made from Aβ oligomers that are aggregates of Aβ peptides that are in turn fragments enzymatically cleaved from a larger protein called amyloid precursor protein (APP).


NFTs are filaments of a phosphoprotein called tau that stabilizes structural elements in neurons called microtubules. Tau has 79 potential sites for phosphorylation. Thirty of these sites are usually phosphorylated in normal tau proteins giving them an overcoat of phosphorus, oxygen and hydrogen. The tau in NFTs is more highly phosphorylated than normal and is called hyper-phosphorylated tau.


The second question – what is in alum?  Alum is a combination of aluminum and sulfate ions making a salt. In some cases alum salts also include other ions such as in ammonium alum (a.k.a. ammonium aluminum sulfate), and potassium alum (a.k.a. potassium aluminum sulfate, potash alum).


After hearing this definition of alum as being a salt of aluminum sulfate, Doctor Watson became agitated and said: “Wait just a minute Holmes, as a medical doctor I believe aluminum should not be on the list of suspects for AD!” Watson pointed out that according to the Alzheimer’s Association “… studies have failed to confirm any role for aluminum in causing Alzheimer’s”4. Holmes turned to Watson and replied: I applaud you, your profession, and the Alzheimer’s Association for their dedication to caring for and supporting those with illnesses and their mission to eliminate Alzheimer’s disease through the advancement of research and the promotion of brain health. But historically there have been examples when the medical profession has not been sufficiently open-minded to explore all the potential causes of a disease.


One such example of a missed opportunity to save lives was the prevention of pellagra. Pellagra results in dementia, painful disfigurement, and death and is now known to be caused by a lack of niacin in the diet.  Niacin is concentrated in the outer-most layer of the endosperm and germ layers of the corn kernel that are removed by milling. In 1901 the Beall Degerminator was patented that could mill the corn removing the outer endosperm and germ layers from the kernels for improved storage. In the southern part of the U.S. between 1906 and 1940 mechanical corn milling resulted in 3 million people sickened by pellagra and more than 100,000 deaths due to pellagra. In 1913 Casmir Funk wrote an article suggested that the new procedure for corn milling was causing pellagra, but he was ignored5. The medical profession in the U.S. firmly believed a toxin in rancid unripe corn was the cause of pellagra6. It took a number of years after the connection between niacin deficiency and pellagra was discovered for the medical profession to finally abandon their toxin theory.  So as you can see Watson we should remain open-minded and leave aluminum on the list of suspects for AD so we do not repeat any missed opportunities to save lives.

Watson, who was still pondering this dilemma regarding aluminum as a suspect, responded: “I am all for saving lives and I know that aluminum is a proven to be toxic to neurons but I have read and believe the following:”

  • Aluminum compounds are inert or insoluble preventing entry into the body.
  • Any aluminum that does get into the body is immediately excreted.
  • Any aluminum that is not excreted is deposited in biologically inert stores such as bone.

Dear Watson we may find comfort in believing this dogma but these are untrue myths that give us a false sense of security.  Aluminum can cloak itself in a variety of chemical disguises and enter the body through the gut, skin, lung, and nose.  Acidification of aluminum compounds in the environment by acid rain and in the gut by stomach acid solubilizes these compounds and allows aluminum the freedom to change its chemical disguise. Once in the body some of the disguised aluminum finds its way to the brain and accumulates in our brain during our lifetime.   I know these facts are unpleasant to deal with, but facing reality is better than keeping our heads in the sand.  So Watson let’s proceed ahead with aluminum on the suspect list and see where this investigation takes us.



The third question that begs an answer is how old is Alzheimer’s disease?  Is AD an ancient disease that happened to finally get a diagnosis or is it a modern disease?  At age 35 in 1901 Doctor Alois Alzheimer began observing a patient named Auguste Deter in a Frankfort Germany asylum.  She had strange behavioral symptoms and had lost her short term memory.  After she died in 1906 her brain was autopsied by Dr. Alzheimer. Using special stains he found amyloid plaques and neurofibrillary tangles. So let’s ask the doctor himself if AD is a modern disease.  After an exchange of letters, Holmes had the answer. In a translation of Dr. Alzheimer’s words:


The case presented even in the clinic such a different picture, that it could not be categorized under known disease headings, and also anatomically it provided a result which departed from all previously known disease pathology1.

Doctor Alzheimer believed AD is a modern disease but did anyone else share his opinion?  The mental health of older people living between 1886 and 1889 is described in the monograph “Old Age” published in Cambridge England in 18897.  The monograph summarizes the results of British general practitioners studying the mental health of their oldest patients during the mid-1880s.  The study group was 900 subjects who were 80 or older including 74 centenarians.  The monograph’s author concludes that dementia:

“… was witnessed only in two of our centenarians … indeed the brain held out as well or better than other organs” 

This 3% rate of dementia among centenarians in the mid-1880s can be compared with a study 111 years later.  In 2000 a study was done of people in three Dutch towns with populations greater than 250,000.  Of the 17 centenarians found in this more recent study 15 had dementia for an 88% rate of dementia.  The other 2 centenarians could not be examined8.

From Doctor Alzheimer’s comments in 1907 and comparing these two studies of dementia among centenarians done 111 years apart, it is obvious Watson that AD is a modern disease that is between 110 and 180 years old. So now Watson let us look at the first suspect: genetics.

Is there a genetic defect that could be responsible for AD?  Yes Watson, there are two types of AD: familial and sporadic. Familial AD is believed to have a genetic link but accounts for only 1-2% of AD cases9.  Sporadic AD accounts for the remaining 98-99% of AD cases and after extensive searching only the apoE4 gene has been found to increase the risk for sporadic AD9.  Carriers of the apoE4 gene, about 20% of the population, have a 60% chance over age 80 of having AD versus a 10% overall risk of AD over age 80 in the general population.  Therefore the difference in risk for AD between carriers and non-carriers of this gene is 50%. In 2002 there were 9 million people in the U.S. who were 80 years of age or older10.  A 50% chance of AD in the 20% of those over 80 with the apoE4 gene corresponds to 10% of 9 million people or 0.9 million cases of AD.  There were 2.7 million AD cases in the U.S. in 200211.  This means approximately 1/3 (33%) of the sporadic AD cases in the U.S. could be due to genetics involving the apoE4 gene.

Carriers of the apoE4 gene are more vulnerable to AD because they have higher than normal levels of Aβ peptides that can result in higher levels of Aβ oligomers and Aβ plaques. ApoE proteins are chaperones that complex with Aβ peptides and facilitate there transfer across the blood-brain-barrier and out the brain.  Carriers of the apoE4 gene may be more vulnerable to AD because they produce an Aβ peptide chaperone molecule apolipoprotein E4 (apoE4).  This chaperone works with a slow receptor that slows Aβ peptide clearance from the brain12.  Also carriers of the apoE4 gene produce have less apoE protein in their serum and this also slows Aβ peptide clearance from the brain9. Therefore carriers of the apoE4 gene have higher than normal levels of Aβ peptides in their brains that can result in higher levels of Aβ oligomers and plaques in their brains.

Is there any other indication that AD is caused by a genetic defect? In 1987 L.E. Nee, et al. reported a clinical and family study of 22 twin pairs in which one or both twins had AD.    In approximately 40% of the cases, AD affects both twins showing that about 40% of cases in the U.S. could be due to genetics (i.e. the apoE4 gene) 13.  Within experimental errors this 40% agrees with the 33% derived from the math based upon the frequency of the apoE4 gene in the U.S. population.

So as you can see Watson with the data agreeing from a risk analysis and a study of twin pairs we can conclude that greater than 50% of AD is not related to genetics and more than likely caused by environmental factors.  But before turning our back on genetics, could it be possible there is a gene other than the apoe4 gene responsible for AD?

Could any dominant gene or genes spread through the population and cause a modern disease? If a dominant gene is inherited from either parent it is always expressed in that parent’s children. For a recessive gene to be passed on, both parents must have it, so dominant genes spread more quickly through a population than recessive genes.    

As we now know Watson, Alzheimer’s disease is a modern disease first observed 110 years ago in a person 56 years old at the time of death. Since Alzheimer’s is a modern disease, a mutation, such as the apoE4 gene, that could cause Alzheimer’s would have had to occur approximately 180 years ago. A human generation lasted, on average, 30 years during the last 200 years14.  A period of 180 years corresponds to 6 generations.  But how many generations did this gene have to spread through the population by the time people were born who are currently over 80 years old? The 9 million people in the U.S. over 80 were born after approximately 3 of those 6 generations.  Therefore the gene carrying the mutation would have had only 3 generations to spread through the population before those people currently over 80 were born.

Watson asked: “How many people can potentially carry a dominant gene three generations after the single mutation that created the gene?” Holmes answered: “If there was a single mutant and every one of the three succeeding generations had both a dominant gene and eight children, there would be only 512 carriers of the gene worldwide after three generations.  As already mentioned there are 9 million people over age 80 in the U.S. and 20% (1.8 million) of them are carriers of the apo4 gene. The calculated 512 carriers are not even close to the estimated 1.8 million carriers of this gene in the U.S. population over age 80.  So a mutation 180 years ago of the apo4 gene, or for that matter any gene, could not be the cause of AD”.

At this point Holmes turned and noticed that Watson was madly calculating 8 x 8 x 8 = 512 on a sheet of scratch paper and looking confused.  Watson looked up and asked: “So can a modern disease as common as AD be due to a recent mutation?”  Holmes replied: “No, it takes thousands of years to spread even a dominant mutation to a significant percentage of the population”.

Since AD is a modern disease and not an ancient disease we now know three important facts from which we can draw a conclusion:

  • Because of its prevalence the apoE4 gene as it exists today is an ancient gene not a modern gene
  • Twenty percent of humans who have the apoE4gene have been living with higher than normal levels of Aβ peptides in their brains for thousands of years and did not get AD.
  • Only one third of those with AD in the U.S. have the apoE4 gene.

This is the first crux of the case Watson! Because the apoE4 gene is ancient it alone can’t be the cause of a modern disease like AD. Since the apoE4 gene causes higher than normal levels of Aβ peptides, a good percentage of people have lived with these high levels of Aβ peptides for thousands of years and not gotten AD. Therefore excessive levels of these Aβ peptides can’t cause a modern disease like AD.

Watson looked startled and said: “Amazing Holmes this proves that AD is not caused by the ancient apoE4 gene or a recent genetic mutation or even higher than normal levels of Aβ peptides in the brain. So if not genetics and Aβ peptides, then what is the cause of AD?”

Is AD caused by high levels of plaque?

Watson noted: “Aβ plaque is a hallmark of AD and it is found in higher than normal levels in the brain of the case of strange death.  This puts Aβ plaque on the list of suspects. But is there any evidence that Aβ plaque is harmful to the brain?” Holmes replied: “No, AD-related neuron loss and dementia are mediated by Aβ oligomers, not Aβ plaque536.  This is because Aβ oligomers inhibit neuronal viability ten times more that Aβ plaque and forty times more than Aβ peptides15.  Soluble Aβ oligomers (e.g. clusters of soluble Aβ peptides) are converted in the brain to insoluble Aβ plaque16.  Metals, such as aluminum, facilitate the conversion of Aβ peptides to Aβ oligomers and then to Aβ plaque16,17.   Aβ oligomers have been isolated from the cerebral cortex and cerebrospinal fluid in concentrations six times higher than normal in the brains of AD patients18”.

Watson then suggested: “Since these findings suggest that Aβ oligomers rather than Aβ plaque might be a cause of AD, we should add Aβ oligomers to our list of suspects. After all it would appear that Aβ oligomers had to be present in order to make Aβ plaque observed in the brain of the case of strange death.”

Holmes replied: “Excellent deduction Watson, our new list of suspects now includes:

  • NFTs
  • Aβ oligomers
  • Aluminum”

 How are NFTs formed in the brain?

NFTs are insoluble tangles of soluble phosphoproteins called tau.  Because these tangles start forming inside neurons they are called neurofibrillary tangles or NFTs. The appearance in the brain of these NFTs as “tombstones” or “ghosts” is one of the hallmarks of AD. NFT formation requires two things:

  • An above normal amount of phosphoryl groups (PO32-) coated on the tau proteins. This phosphoryl coated tau protein is called hyper-phosphorylated tau.
  • Metal ions that facilitate the formation and pairing of hyper-phosphorylated tau to form paired helical filaments (PHFt) called NFTs.

Lesions in the brain caused by NFTs are better correlated with cognitive decline in AD than intracellular Aβ oligomer and extracellular Aβ plaque formation19.  

Does aluminum cause NFTs or does aluminum complex with NFTs after they form?

Some metal cations inhibit numerous key enzymes in the brain.  One of these key enzymes is PP2A that keeps tau from being covered with too many phosphoryl (PO32-) groups (i.e. over-phosphorylated).  When PP2A is inhibited by zinc20, mercury21, or aluminum22 ions the result is over-phosphorylation of tau leading to PHFt formation, neuronal death, and ultimately neurofibrillary tangles in place of former neurons.  Of the three cations that are known to inhibit PP2A, zinc is a neurotransmitter that is required by our brains and zinc and mercury are not on the list of suspects in the case of strange death as they are not contained in alum. Therefore Watson, zinc and mercury are “red-herrings” and this leaves aluminum in alum on the suspect list.

In 1988 aluminum chloride added to rat brain cells resulted in NFTs that were “distinct” immunochemically from human Alzheimer NFTs23.  This resulted in more controversy but was resolved in 1998 when aluminum chloride was injected into the cerebrospinal fluid in the brains of New Zealand white rabbits24.    The resulting NFTs were immunochemically identical to NFTs found in the brains of AD patients. In 1992 it was found that aluminum stimulates the interaction between filaments of hyper-phosphorylated tau. This interaction results in paired helical filaments of tau (PHFt) and NFT formation25.

Is aluminum linked to NFTs in neurons?

In 1973 levels of aluminum were found to be higher than normal in some regions of the brains of Alzheimer patients26. This finding remained controversial until 1980 when a combination scanning electron microscope and x-ray spectrometer analysis showed there was aluminum in neurons with NFTs in the brains of both Alzheimer and elderly non-Alzheimer patients and no aluminum in adjacent neurons without NFTs27.  Since NFTs are a hallmark of AD, this finding was the first to link aluminum to AD at the neuronal level.  Even more disturbing was the fact that aluminum and NFTs are in the neurons of the elderly in general not just those with an AD diagnosis.  These findings are consistent with research that finds aluminum in the brains of the elderly in general28,29.

Aluminum is a non-essential cation in our brains and an unwanted intruder.  It is obvious Watson, since aluminum promotes the formation of paired helical filaments of tau and NFTs, NFTs are at best only a secondary cause or symptom and not the primary cause of Alzheimer’s.

But Watson was looking skeptical and asked: “Since aluminum is looking more and more like the culprit in the case of strange death, why do people with the apoE4 gene have a 50% higher chance of getting AD than people without this gene?”

Holmes replied: Carriers of the apoE4 gene have lived with higher levels of Aβ peptides, oligomers, and plaque for thousands of years and not had AD.  There must be an environmental factor that facilitates the formation of Aβ peptides, oligomers, or plaque to cause AD”.

Watson asked: “Could this environmental factor be aluminum?”

Yes Watson aluminum is a likely environmental casual factor of AD. Metal cations such as aluminum, copper, zinc, and iron are known to complex with Aβ peptides to form Aβ oligomers16,17.  However, only aluminum complexes of Aβ oligomers are neurotoxic16.  Aluminum makes the degree of neurotoxicity worse because it has the unique property of “freezing” Aβ peptides in the oligomeric state, resulting in high concentrations of Aβ oligomers16. When these Aβ oligomers are complexed with aluminum they cause excess calcium to diffuse into neurons which can ultimately kill them.  Therefore aluminum can cause AD both with and without the apoE4 gene but is 50% more likely to cause AD in carriers of the apoE4 gene. This is due to the carriers having higher levels of Aβ peptides in their brains making it possible for aluminum to freeze more Aβ peptides in the neurotoxic oligomeric state.


Aluminum acts in five ways to increase the accumulation of Aβ oligomers in the brain putting carriers of the apoE4 gene at greater risk of getting AD:


  • Aluminum freezes Aβ peptides in the neurotoxic oligomeric state16.
  • Aluminum lowers gene expression of neprilysin, an enzyme that is the rate limiting step in Aβ peptide and oligomer degradation30,31.
  • Aluminum lowers gene expression of the LDL receptor LRP1, required for Aβ peptide clearance and the importation of cholesterol to neurons30,32.
  • Aluminum increases gene expression of BACE1, the β-secretase enzyme that cleaves the amyloid precursor protein (APP) to the precursor of Aβ peptides30,31.
  • Aluminum increases gene expression for the production of APP, the precursor of Aβ peptides31.


Those with the apoE4 gene are also more likely to get AD due to head trauma or aluminum accumulation leading to an ischemic event, such as stroke.  Ischemia occurs when blood flow is temporarily suspended to some regions of the brain. Sporadic AD is believed to be associated in some cases with an ischemic event33.  Post mortem analysis of the brains of those with AD has shown that 30% have evidence of an ischemic event33.  Shortly after an ischemic event there is increased genetic expression of an apoE protein, such as apoE433.  Also there is both an increased genetic expression of amyloid precursor protein (APP) and the enzyme β-secretase (BACE1) that cleaves APP to the precursor of Aβ peptides33.  Those with the apoE4 gene have slower Aβ peptide clearance than normal.  Because of this, after an ischemic event there is even less clearance than normal in the brains of those with the apoE4 gene and more production of Aβ peptides and Aβ oligomers.


Accumulation of aluminum in the brain increases the toxicity of Aβ oligomers, the amount of aluminum-complexed Aβ oligomers, and the likelihood of an ischemic event (see Chapter 2).   Aluminum is a likely environmental causal factor for both toxic Aβ oligomers and ischemic events and puts people with the apoE4 gene at greater risk than normal for AD.



Watson, this is the second crux of the case. Since Aβ oligomers are only a facilitating factor for AD they can be removed from our list of suspects.


Watson looked alarmed for the first time and asked:  “Is there aluminum in my brain that is ‘freezing’ neurotoxic Aβ peptides in the oligomeric state?”  Holmes replied “I am afraid that we are all suffering from some frozen neurotoxic Aβ oligomers. But luckily we can control the amount of aluminum we ingest, absorb, and excrete. As you have sensed Watson, the sum total of this research has now reached a tipping point”.

Aluminum is the only remaining suspect for causing the case of strange death.  But before we can be certain that aluminum is the culprit we need to find if aluminum has the means and motive to cause AD in the case of strange death.

How does aluminum get into our bodies and brains?

Aluminum salts began to be used as a food preservative in the mid-1880’s and that may be a reason why the first case of AD was discovered approximately 20 years later in 1907 by Doctor Alzheimer. The commercialization of aluminum salts, and products containing aluminum, has resulted in more aluminum being refined and made available every year. Currently we use aluminum in reduced metal, oxidized metal, and ionic chemical forms, such as salts. The ionic chemical forms of aluminum are neurotoxic. The reduced metal form of aluminum must be converted first by corrosion to the oxidized metal form and then by acidic conditions to the ionic form in order to become neurotoxic. The oxidized metal and ionic chemical forms of aluminum are found in a variety of pharmaceuticals, such as antacids, vaccines, food products, baking powder, drinking water, sunscreens, cosmetics, antiperspirants, astringents, and fertilizers.

Because of the amount of drinking water we consume daily, any aluminum in drinking water presents an opportunity for its absorption and accumulation in the body.  The ionic form of aluminum is in drinking water due to acid-rain freeing bound aluminum from minerals in the ground, city water departments using alum to clarify drinking water, and mortar lined city water pipes leaching aluminum into drinking water.

There appeared to be no connection between aluminum in drinking water and AD until the data were reevaluated in 1996.  This analysis revealed a correlation between aluminum in drinking water and AD when taking into consideration the concentration of fluoride and silicic acid as well as aluminum in the drinking water34.  Fluoride ions facilitate the transfer of aluminum across the blood-brain barrier increasing aluminum absorption in the brain35, while silicic acid facilitates aluminum removal from the blood by the kidneys decreasing aluminum absorption by the brain36-38.  Therefore, Watson, drinking water is a common way that aluminum is ingested, absorbed by our bodies, and accumulated in our brains and silicic acid slows this accumulation.

The three points of entry for aluminum into the body are oral ingestion, inhalation, and absorption through the skin.  We do not know which pathway was the major source of aluminum in the case of strange death.  Due to the lack of proper respiratory protection, we might assume that inhalation was the point of entry.  Inhaled aluminum can take a shortcut to the brain across the olfactory epithelium cells lining the nasal cavities and then diffusing through olfactory receptor neurons to enter the brain via both olfactory bulbs39-41.  Organic complexes of aluminum have been found to readily enter the brain via this pathway42. The other two pathways require that aluminum crosses the blood-brain barrier in order to enter the brain. Once in the brain, some of the aluminum stays there throughout life43 inhibiting numerous key enzymes and killing neurons44.

Aluminum in the ionic form can form complexes with a wide variety of organic and inorganic ligands. Some of these complexes are optimal for absorption from the gastrointestinal track into the blood and others are optimal for crossing the blood brain barrier. Ionic aluminum is like a cloaked assassin using these ligands as disguises to cross two barriers: between the gut and blood and the blood and brain. The following organic ligands have an affinity for ionic aluminum and have been found to be present in the blood at the approximate concentrations indicated: citrate (ca. 250mM), pyroglutamate (ca. 180mM), glutamate (ca. 10mM), nucleotides ATP, ADP, and AMP (ca. 5mM), and transferrin (ca. 1mM)45.  In addition to these organic ligands there are inorganic ligands that also have an affinity for ionic aluminum including: fluoride, silicic acid, hydroxide, and phosphate.

Transferrin receptors are more numerous in those areas of the brain that have the highest levels of aluminum accumulation46.  For this reason transferrin has been theorized to be the primary (i.e. 90%) transporter of aluminum to the brain43,47,48.  The problem with this theory is the molecular weight of the transferrin aluminum complex is four-fold higher than can be handled by the kidney’s glomerulus45.  This means that the rapid changes in urinary excretion of aluminum seen following exposure to aluminum can’t be accounted for with such a large transporter. The rest of the previously mentioned ligands result in aluminum complexes that are small enough to be handled by the glomerulus of the kidney and are therefore more likely to comprise aluminum’s cloak. But aluminum can change its disguise when reaching the blood-brain barrier and possibly transferrin is the best disguise for successfully crossing this barrier.

Watson had become agitated with worry.  He asked Holmes: “So how long will it take to get the aluminum I consumed at breakfast out of my body? “  Holmes’ answer was discouraging: “Once aluminum is ingested and absorbed 64% will be excreted during the first day but the rest will be slowly excreted and even after 50 years 4% of what you ingested with breakfast this morning will remain in some parts of your body43.”

As you can see Watson, aluminum has the means to get into the brain. But is aluminum normally found in the brain and is a higher level of aluminum in the brain associated with AD?

How much aluminum is in a normal brain?

It is calculated that the human brain accumulates aluminum at a rate of 10-70 billionths of a gram of aluminum per gram dry weight of brain per year during a lifetime.  This amount is consistent with the 0.4 to 5.6mcg aluminum per gram dry weight of brain as observed by autopsy of different regions of human brains after a normal lifetime of exposure to aluminum3,49.  It now appears likely that this slow aluminum accumulation may facilitate an increased incidence of a wide range of neurological diseases including AD50.


Is there more aluminum in brains of those with AD?

Some people absorb and accumulate aluminum at higher rates than others and this may account for why some get AD earlier than others3,51. AD patients younger than 77 years old have a 64% greater gastrointestinal aluminum absorption rate than age-matched non-AD controls52.  However both AD and non-AD people over 77 have similar high rates of gastrointestinal aluminum absorption53.  These high rates of gastrointestinal absorption result in faster aluminum accumulation in elderly brains as compared with middle-age brains28,29. Also aluminum in the brain is not uniformly distributed.  In the elderly, aluminum is highest in the hippocampus (5.6mcg per gram dry wt. of brain) and lowest in the corpus callosum (1.5mcg per gram dry wt. of brain)49.

A meta-analysis of published studies involving 1,208 participants, including 613 AD patients, revealed that aluminum is significantly higher in brains, serum, and cerebrospinal fluid of AD patients compared with non-AD participants54.

Therefore Watson, aluminum as the “cloaked assassin” has the means to get into the brain. But does it have the motive or biochemical motivation to cause mitochondrial disease, a clinical symptom of AD?

How does aluminum cause mitochondrial disease?

Mitochondrial disease occurs when the mitochondria of the cell fail to produce enough energy for cell or organ function. This neuro-metabolic dysfunction has been theorized to be a factor in the causation of AD55. But it is hard to tell the difference between a cause and a symptom of a disease.  Watson, here is why aluminum is the cause of mitochondrial disease and mitochondrial disease is not a cause but a symptom of AD.

Mitochondria are membrane bound organelles inside brain and muscle cells that produce stored energy in the form of ATP generated by combining oxygen with nutrients in food. The brain normally consumes 30% of the total energy produced from these nutrients by the body. This process is called bioenergetics and it requires using nutrients, such as sugar, to make ATP in a series of steps called the Krebs cycle (a.k.a. TCA cycle).  Aluminum lowers the amount and activity of several Krebs cycle enzymes involved in ATP production56,57. So aluminum lowers the efficiency of ATP production in brain.  This lowers the amount of energy available to the brain resulting in mitochondrial disease.

Aluminum facilitates the formation of reactive oxygen species (ROS) by glial cells in the brain that are toxic to mitochondria and neurons58. Aluminum also inhibits two enzymes in the Krebs cycle that are involved in NADH production56,57.  NADH is used in the body for making reduced-glutathione59. Reduced-glutathione reduces cofactors in the body, such as pyrroloquinoline quinone (PQQ), that in turn reduce the reactive oxygen species (ROS) that are harmful to mitochondria and neurons. The inhibition of NADH production by aluminum decreases reduced-glutathione levels allowing ROS to harm mitochondria and neurons resulting in mitochondrial disease60.

Therefore Watson, aluminum can cause mitochondrial disease by decreasing ATP production, increasing ROS production, and preventing cofactors, such as PQQ, from protecting the mitochondria from oxidative harm by ROS.

How does aluminum impair memory?

Some parts of the brain are more prone to absorb aluminum than others, possibly due to some cells having more transferrin receptors46.  The main aluminum-affected brain regions in humans, rats, and rabbits exposed to aluminum in their diet include the entorhinal cortex (EC), hippocampus, and locus coeruleus (LC).  The EC and the hippocampal regions (e.g. CA1 pyramidal cell layer) are the regions with most absorbed aluminum in rats chronically exposed to aluminum in their diet44. These are also regions of the brain most vulnerable to NFT formation and neuronal death in AD61.  In fact the EC is the first area of the brain to be affected by AD62.

The entorhinal cortex (EC) is a neuronal hub linking the hippocampus with the neocortex.  The hippocampus plays a key role in declarative memories such as autobiographical, episodic, and semantic memory and spatial memories including memory formation and consolidation and memory evolution during sleep.  The neocortex is involved with sensory stimuli, generation of motor commands, spatial reasoning, conscious thought, and language.  A region of the EC (e.g. layer III) is connected to all regions of the hippocampal formation including the dentate gyrus, all CA regions, including the CA1 pyramidal cell layer, and subiculum. These connections are called the perforant pathway.  Surgical destruction of the perforant pathway in rats results in memory impairment44 and surgical destruction of the perforant pathway in humans results in impairment of short term memory63.  Aluminum in the diets of rats results in both lesions in the perforant pathway and in memory impairment44.  Therefore Watson, aluminum, like a surgeon’s knife, can cause short term memory loss.

Conclusion of the Case of the Cloaked Assassin

Holmes and Watson, have methodically solved the case of the “Cloaked Assassin” by reaching the following conclusions:

  • Aluminum in alum is the cause of AD in the case of strange death.
  • Aluminum is the only suspect capable of causing AD and has both means and motive to cause AD.
  • Aluminum causes the two hallmarks of AD:
    • AB-plaques
    • NFTs
  • Aluminum causes two symptoms of AD:
    • Mitochondrial disease
    • Memory impairment

Watson, we need to inform Lestrade over at Scotland Yard so the police can regulate this evil monster before more harm is done.

Before leaving on his mission, Watson turned and asked Holmes: Why isn’t aluminum regulated like other toxic chemicals?

Holmes replied: “Even though aluminum adversely influences more than 200 biological reactions and has various neurotoxic effects on the mammalian central nervous system, it has not been regarded as posing a health hazard64.  As a consequence, aluminum compounds are used in food additives, food processing, water purification, pharmaceuticals, and inoculations65,66. These factors may account for why, in the U.S. by the year 2002, 2.7 million people had AD11 and worldwide by the year 2005, 24 million people had AD67. “

The controversy surrounding aluminum being a cause of AD has impacted the regulations regarding aluminum exposure.  In 2010 the World Health Organization (WHO) lowered the provisional tolerable weekly intake (PTWI) of aluminum per person from 7 mg/kg of body weight to 1 mg/kg based upon new data68.  In both 1998 and 2003 WHO stated:

“The positive relationship between aluminum in drinking-water and AD … cannot be totally dismissed.”  World Health Organization 1998 and 2003

Since 2010, the European Aluminum Association with support from the aluminum industry has participated in the Codex process, submitting biased reviews of the scientific literature in order to have the new aluminum limit re-assessed64.  In response to this lobbying by the aluminum industry a joint FAO/WHO Expert Committee on Food Additives recently established a PTWI of 2 mg/kg body weight, superseding the previous WHO PTWI of 1 mg/kg body weight69.

The initial response of government agencies to commonly used substances found to be toxic by scientific researchers usually favors the industries producing the substances70.  For example, in 1979 when lead exposure in children was found to be correlated with low IQ, the credibility of the researcher was questioned by psychologists hired by the tetraethyl lead industry. These psychologists publically accused the researcher of scientific misconduct70.  The parallel between lead and aluminum is very strong as they are both neurotoxins with powerful industrial lobbies backing their continued use.   The only difference is that lead has a much longer history than aluminum (see Chapter 8 for the history of lead poisoning).

Watson looked discouraged and said “If it can’t be better regulated is there any hope for individuals to lower the aluminum levels in their bodies and possibly prevent AD?

Holmes suggested: “One method to lower your body burden of aluminum and possibly prevent AD is to routinely ingest or inject a metal chelator or complexing agent.  Ideally this agent will only attach itself to aluminum and thereby facilitate the removal of aluminum from the body.”

In 1991 McLachlen, et al. demonstrated for the first time that a chemical called desferrioxamine (DFO), when given by intramuscular injection 5 days a week for 24 months, led to a 50% decrease in the rate of decline of AD patients’ daily living skills71.  In 1998 Savory, et al. demonstrated that DFO could reverse the formation of NFTs in white rabbits from New Zealand that had been previously injected with aluminum24.  DFO removes aluminum from the aluminum/PHFt complex and allows PHFt to be degraded reversing the formation of aluminum-induced neurofibrillary tangles (NFTs)24. The problems with DFO are the number of required injections and its ability to remove not only aluminum but also the required element iron from the body.

A more ideal candidate for preventing or reversing AD would be a complexing agent for aluminum that can be taken orally and does not complex iron.  Such a candidate has been found to be the dissolved mineral orthosilicic acid (OSA) that will be discussed in Chapters 5, 6, and 7.

This concludes the case of the cloaked assassin.



The Case for Aluminum Being the Cause of AD

Proving that aluminum is the cause of AD and not just correlated with AD has been the subject of a long-term debate among scientists. In order to prove causality, established epidemiological and experimental criteria for causality must be met.  These criteria were originally set out by Sir Austin Bradford Hill72.  In addition, the application of Bradford’s criteria to neuropsychiatric conditions, such as AD, has been further developed by Robert Van Reekum73.  Briefly stated these criteria for causality are:

  • Strength of association between aluminum and AD
  • Consistency of association between aluminum and AD
  • Specificity of association between aluminum and AD
  • Temporality of aluminum accumulation occurring before AD
  • Biological gradient with dose-response effects of aluminum on AD risk
  • Biological plausibility of aluminum neurotoxicity causing AD
  • Coherence of what we know about how aluminum causes AD
  • Analogy of metal neurotoxicity to diseases similar to AD
  • Experimental evidence showing that AD can be prevented


These nine criteria have been applied by Doctor J. R. Walton to testing the aluminum/AD relationship using data from human and animal studies74.  The conclusions were that AD is caused by aluminum and AD is a human form of chronic aluminum neurotoxicity74.  In this chapter the following 9 criteria have been applied using primarily data from human AD patients and not animal studies, with the same conclusions being reached.




  • Strength of association between aluminum and AD:


Populations exposed to high levels of aluminum in their drinking water have a higher risk of AD than those exposed to lower levels of aluminum in their drinking water.

  • The most extensively controlled study of AD and aluminum in drinking water was based upon autopsy-verified brains from AD patients and non-demented controls donated to the Canadian Brain Bank between 1981 and 199175. These brains were from people who had lived in 162 geographic locations in Ontario with recorded aluminum levels in their drinking water. This study found that the risk of developing AD is 2.6 times higher among those who drank water containing over 100mcg/L for at least 10 years versus those who drank water containing less than 100mcg/L75.


  • A 15 year study of 3,777 people 65 years or older living in France also found that those who drank water containing more than 100mcg/L of aluminum had a 3.3 times greater relative risk of developing AD versus those drinking water containing less than 100mcg/L75,76.


  • Another study of 1,924 people found a 2.7 times greater relative risk of AD after 44 years of exposure to high aluminum levels in drinking water77.

These studies all indicate a strong association between aluminum and AD and also show that the association is dose dependent with 100mcg/L in drinking water increasing the risk of AD by a factor of 2.6 to 3.3.

  • Consistency of association between aluminum and AD:


The relationship between aluminum and AD has been consistently confirmed in independent investigations78.

The consistency of the association between aluminum in drinking water and AD has been demonstrated by a number of epidemiological studies. A 2001 meta-analysis involving a comprehensive literature survey discovered that 9 out of 13 epidemiology studies had found a significant positive correlation between aluminum in municipal drinking water and AD79.  In 1989 a high incidence of AD was reported in areas with a high level of aluminum in the drinking water in England and Wales80.  In 1991 high levels of aluminum in drinking water were linked with high dementia mortality in an area of Norway81.  In 1991 and 1996 a positive relationship between aluminum in drinking water and AD risk was identified in Canada82.

The consistency of these epidemiology studies led the World Health Organization to conclude in 1998 and 2003 drinking water standards: “The positive relationship between aluminum in drinking-water and AD … cannot be totally dismissed”83. WHO recommended a limit of 100mcg/liter of aluminum in drinking water in 1998 and 200383.

Humans have been tested for their rate of aluminum absorption using an isotope of aluminum (e.g. 26Al) that has identical properties to aluminum (e.g. 27Al)84. After ingestion there was a three-fold variation in aluminum retention among those tested51.  AD patients absorb on average 64% more aluminum than non-demented control subjects52.  In 2015 a meta-analysis was performed on 34 published studies involving 1,208 participants, including 613 AD patients.  Aluminum was measured in brain tissue in 20 studies involving 386 participants, serum in 12 studies involving 698 participants, and cerebrospinal fluid (CSF) in 4 studies involving 124 participants. AD sufferers had significantly higher aluminum levels in brain tissue, serum, and CSF than did controls54.  Ferritin is an iron storage protein in the blood that is shaped like a hollow sphere that can hold 4,500 iron atoms.  Aluminum and zinc in the blood compete with iron for binding sites inside ferritin. Serum ferritin of AD patients had on average 62% aluminum versus only 37% aluminum in non-demented controls85.

Measuring aluminum levels in the brain was at first inconsistent and inconclusive.  But recently improved analytical techniques are providing a more consistent picture of how aluminum accumulates in the brains of AD patients. In 2005 inductively-coupled plasma atomic emission spectroscopy was used by Andrasi et al. to measure aluminum levels in specific brain regions in three AD patients and three non-demented controls86.  The data in the following table shows that there are aluminum “hot spots” in the brain where aluminum is preferentially absorbed at higher levels in AD patients than non-demented controls.



Brain Aluminum Measurements from Humans with AD and Non-demented Controls86
Regions of Brain Analyzed AD (mcg/g of brain tissue)    Dry Weight Controls (mcg/g brain tissue) Dry Weight
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


In 2011 Rusina et al. measured both aluminum and mercury in the hippocampus and associated visual cortex of 27 controls and 29 histologically-confirmed AD cases.  There was a four-fold increase in aluminum levels in the hippocampus of the AD cases versus the controls.  There was no difference in mercury levels between the AD cases and controls87. Crapper et al. (1973) were the first to observe “hot spots” of aluminum in the brains of AD cases26.  An amount as high as 8mcg/g of aluminum per gram dry weight of brain tissue has been found in the inferior parietal lobe88. Hot spots in human brains with AD typically are in excess of 4mcg/g dry weight of brain tissue88.  They contain a large number of NFTs or large pyramidal cell with high levels of aluminum.  Hot spots are not found in non-demented age-matched controls88.

  • Specificity of association between aluminum and AD:


This criterion of specificity is based upon old beliefs that each disease results in only one outcome.  As Van Reekum et al. has pointed out this criterion is invalid for exposures to toxic substances like aluminum that can cause a variety of outcomes73.  In fact aluminum is the likely cause of at least five diseases depending upon the age of the patient and the amount of aluminum accumulation.  In the unborn fetus and newly born infant aluminum causes autism. In middle and old age aluminum causes both AD and vascular disease leading to stroke.  Also aluminum may be involved in α-synuclein aggregation that is a hallmark of Lewy Body dementia as described in Appendix I. Aluminum may also be a causal factor in hippocampal sclerosis as described in Appendix III and cerebral amyloid angiopathy as described in Appendix IV.

We have shown that the cause of sporadic AD is environmental and not genetic. Out of all environmental factors considered, only aluminum experimentally triggers all major histopathological events associated with Alzheimer’s67. The “hot spots” in the brain where the highest levels of aluminum were found include the hippocampal complex, entorhinal cortex, and frontal cortex86. These areas of the brain are all important for memory.  Impaired memory is the core clinical feature of AD. The entorhinal cortex had the highest overall aluminum levels, is amongst the earliest regions of the brain to develop NFTs, and is ultimately the most damaged region of the brain in AD89-92. Some brain atrophy in the hippocampal complex and the frontal cortex (i.e. 0.3-0.6%) is common with age in healthy adults93. In 2009 Fjell et al. studied brain atrophy in people 60-91 years old.  The study included 142 healthy participants and 122 with AD.  The four areas of the brain found to significantly atrophy during one year in AD patients were the same areas found to be “hot spots” for aluminum accumulation. Also rate of atrophy is much higher in AD brains than in healthy adult brains as shown in the following table94.  Of course even healthy brains have accumulated some aluminum and that could account for the atrophy observed in the controls.

Brain Atrophy in Humans with AD and Non-demented Controls During 1 Year94
Regions of Brain Analyzed AD Longitudinal                  % Change Controls Longitudinal            % Change
Entorhinal Cortex -3.75 -0.55
Hippocampus -2.42 -0.84
Frontal Cortex (caudal) -1.60 -0.40
Frontal Cortex (ventral) -1.06 -0.38

Note: these are the same brain regions found to be “hot spots” for aluminum accumulation86

In the brains of those with autism it has been found that the brain regions most impacted include the hippocampal complex, entorhinal cortex, and amygdala. These areas of the autistic brain have smaller and less complex neuronal networks than normal suggesting a curtailment of normal neuron development95.   These areas of the brain are also responsible for disturbances of memory, learning, and emotion and behavior that comprise the core clinical features of autism96.  These are the same brain regions found to be “hot spots” for aluminum accumulation86. The specificity of aluminum accumulation in these brain regions may manifest itself as the clinical symptoms of AD in older people and autism in the very young.

The presence of mixed cerebral pathologies becomes more common in individuals with advancing age, particularly in those over 9097. Pathologies associated with dementia were studied in a group of 183 participants of “The  90+ Study”.  This clinical-pathology investigation involved longitudinal follow-up and brain autopsy.  Six of the pathologies studied and the percentage of participants with both dementia and these pathologies were:

  • Alzheimer’s disease (AD) – 23%
  • α-Synuclein aggregation (a.k.a. Lewy body disease – see Appendix I) – 1%
  • Cerebral amyloid angiopathy (cause of some hemorrhagic strokes – see Chapter 2) – 3%
  • Strokes due to 3 or more micro infarcts (see Chapter 2) – 6%
  • White matter disease (a.k.a. leukoaraiosis – see Chapter 2) – 4%
  • Hippocampal sclerosis (see Appendix III) – 4%

All of these pathologies may be linked to aluminum accumulation in the brain. Supporting Van Reekum’s claim that environmental toxins like aluminum can cause a variety of outcomes73, 45% of the cases of dementia in the 90+ study had a multiple number of these pathologies. The presence of multiple pathologies is associated with increased likelihood and severity of dementia. AD as a single pathology is present in 28% without dementia and 23% with dementia. When a single additional pathology in addition to AD is present the chance of dementia is four times higher than with just AD pathology. When any three or more of these pathologies were present, the chance of dementia is 95% in those over 9097.

Environmental factors, such as aluminum, can cause changes in the way genes are expressed.  This process is called epigenetics and it does not involve changes in the genetic information stored as a DNA sequence.  A gene is first expressed by messenger RNA (mRNA) being made from a small portion of the DNA sequence.  Then mRNA is used to make a specific type of protein that may be used as an enzyme or factor in the body.  This two-step process can be either slowed or increased in speed by aluminum binding to the phosphate groups of DNA and mRNA.  Trace amounts of aluminum (i.e. nanomoles) can affect the expression of genes that are responsible for brain function98 resulting in the pathologies summarized in the following table:

Epigenetics of Aluminum (Al)
Epigenetic Effect Epigenetic Outcome Associated Disease
Al Lowers Gene Expression for Protein Phosphatase 2A (PP2A) Hyperphosphorylated Tau & NFTs – Hallmark of AD AD99,100
Al Indirectly Lowers Gene Expression for Brain Derived Neuro Factor (BDNF) Impairs Long Term Memory & Impairs Spatial Learning AD101-103
Al Lowers Gene Expression for Neprilysin and LDL Receptor LRP1 and Increases Gene Expression for BACE1 and the Aβ peptide precursor APP Aβ Oligomers and Plaques – Hallmark of AD AD30,31,104
Al Lowers Gene Expression for Krebs Cycle Enzymes Mitochondrial Disease –  Symptom of AD AD & Autism57
Al Lowers Gene Expression for DNA Repair Factor BRAC1* Broken DNA AD & Cancer105-107
Al Increases Gene Expression for TNF-α that in turn Decreases Gene Expression for the Enzyme MS Increased Homocysteine  Stroke & Autism108,109

*BRAC1 gene mutations are common in AD106 and in breast110, ovarian110, and prostate cancer111

The effect of aluminum accumulation in the brain manifests itself in a variety of pathologies dependent upon age and the amount of aluminum.  Therefore aluminum lacks specificity to cause a single pathology due to its ability to complex with a wide variety of proteins and nucleic acids in the brain resulting in multiple pathologies.

  • Temporality of aluminum accumulation occurring before AD:


This criterion requires that the causative agent occurs prior to the outcome.  Therefore chronic aluminum exposure must precede AD if chronic aluminum intake is the environmental cause of AD.

For the last 125 years we have lived in the “aluminum age” during which there has been a steady increase in our exposure to aluminum. We ingest food, pharmaceuticals, and drink water containing aluminum, we apply aluminum containing products to our skin, we are vaccinated with aluminum containing vaccines, and we inhale air containing aluminum112.  This results in a slow accumulation of aluminum in our brains from the fetal stage to old age28,49,113,114.      Therefore humans living in an industrialized society accumulate aluminum in certain regions of their brains many years before the onset of AD.  There are three sub-cellular changes in brain physiology that occur prior to overt AD in humans and all three lead to AD:

  • Progressive aluminum accumulation in neurons
  • Hyperphosphorylation of tau due to aluminum inhibition of an enzyme
  • Oxidative stress due to aluminum

Increasing aluminum exposure and accumulation is in lock-step with the increasing frequency of AD.  AD was described as a rare disease in The Lancet fifteen years after Alzheimer’s 1911 paper115. The reported number of AD cases rose from one in 1907 to more than 90 by 1935116.  Subsequently the age-adjusted death rate for AD in the U.S. rose from 0.4 per 100,000 in 1979 to 25 per 100,000 in 2010117,118. In the 25 year span from 1980 to 2004 the annual U.S. death rate from AD in those over 65 rose from 1,037 to 65,313 per year117.

It is estimated that in North America the mean aluminum intake is 24mg of aluminum per day, equivalent to more than 8.76 grams per year118.   The demand for aluminum products has increased requiring more and more aluminum be extracted and refined from bauxite deposits.  The current annual global demand for aluminum is 11 kg per person119.  This means approximately 0.08% of the aluminum produced each year is ingested.  Demand for aluminum has increased 30-fold since 1950 and is estimated to increase by 3-fold current levels by 2050119.  Using these data on aluminum demand, it is estimated that human exposure to aluminum has and will continue to increase at a rate of 90 fold over the 100 year period from 1950 to 205039.  This means we only ingested 0.29 grams of aluminum per year in 1950 and by 2050 we will be ingesting more than 26 grams per year.

So temporality exists as aluminum accumulates in our bodies prior to the onset of AD.  In addition the rate of ingestion and accumulation of aluminum is increasing and this accounts for the rising prevalence of AD.

  • Biological Gradient with Dose-response Effects of Aluminum and AD:

In 1996 McLachlan, et al. observed a dose-response in the amount of aluminum in drinking water with the risk of AD in humans75.  Each subject’s residential and drinking water history for the 10-year period prior to death were taken into account.  The drinking water subjects were exposed to varied from less than 100mcg/L to 175mcg/L.  A single pathologist performed a histopathological examination of all 614 brains included in this study. The brains were assigned to AD or control groups based upon clinical history and the presence or absence of plaques and NFTs. The results in the following table demonstrate a dose-response relationship between aluminum in drinking water and AD.

 Dose-response Relationship Between Aluminum in Drinking Water and AD75
Aluminum in Drinking Water (mcg/L) Relative Risk of AD
<100 1
>100 2.6
>125 3.6
>150 4.4
175 7.6

Several other epidemiological studies have also shown a dose-response effect of aluminum and AD risk75-77,82,120.



  • Biological Plausibility of Aluminum Neurotoxicity Causing AD:

It is known that aluminum facilitates the formation of Aβ plaques and NFTs in the brain that are two hallmarks of AD16,17,24,25. Aluminum causes oxidative stress that kills mitochondria and ultimately kills neurons53.  This results in mitochondrial disease and increased atrophy of some brain regions both of which are clinical symptoms of AD. Aluminum also disrupts memory storage that is a behavioral symptom of AD44.

Some metal ions, such as aluminum, act as physiological stressors in the brain by stimulating brain cells to produce oxidizing chemicals (a.k.a. ROS)121,122. This ROS can damage and kill mitochondria and neurons creating inflammation in the brain. Aluminum tops the list of metal ion inducers of ROS in human brain’s glial cells58.

It has been observed from microscopic evidence that aluminum causes lesions in the brain’s perforant pathway that result in short term memory loss44.  Aluminum also acts as individual ions to block the neurochemistry of long and short term memory storage123. This mechanism of action explains why very small amounts of aluminum in the brain (i.e. on the order of several parts per million or micrograms per gram of brain on a dry weight basis) can have a very large impact on memory storage.

Calmodulin is a calcium-binding messenger protein required for memory formation and storage.  Aluminum ions modify its structure thereby inhibiting its function123.  This prevents calmodulin from regulating calcium levels in neurons and also prevents the activation of four key enzymes that control memory formation and storage in neurons.

The neurochemical explanation of how memories are stored in neural networks is still evolving. However considerable detail has already been discovered.  The ground-work was laid by Donald Hebb in 1949124 when he described a theory of neuronal learning as:

“Neurons that fire together – wire together and neurons that are out of sync – do not link”.

The neurochemical mechanism that supports Hebbian Theory involves the synchronized firing of several different types of neuroreceptors at a synapse between two neurons.  When this occurs in synchrony it leads first to stronger or potentiated neuronal connection between the two neurons.  This connection is then made even stronger by several types of neuroreceptors moving their location in order to increase their density at the synapse.  The theory that describes this two- step process of strengthening neuro-circuits is called spike-timing dependent plasticity (STDP)125.  The successful result of this process is called long term potentiation (LTP).  STDP and LTP are theorized to be the way memories are stored.  A lack of synchrony in the process leads to no potentiation and is called long term depression (LTD) or lost memories.  Aluminum ions inhibit calmodulin from activating four key enzymes involved in LTP16,101,123,126-129. Thereby aluminum ions encourage LTD and cause memory loss (see Neurochemistry of Memory Impairment by Aluminum for details on role of these four enzymes in memory storage).

The biological plausibility of aluminum causing AD is well established by those studies that have connected aluminum’s neurotoxicity with the hallmarks and symptoms of AD.

  • Coherence of what we know about how aluminum neurotoxicity causes AD:

Aluminum taken in by ingestion alone is estimated to be 24mg a day of which approximately 0.2% is absorbed into our blood118,130,131.  We know that aluminum accumulates more in some areas of the human brain such as memory processing regions86.  This accumulation likely results in chronic aluminum neurotoxicity and the hallmarks and symptoms of AD.  The cells in these regions have very high energy needs.  The high rate of energy utilization increases the demand for iron.  Transferrin is the molecule that carries iron to these cells.  Therefore these cells have a high density of transferrin receptors on their membrane in order to facilitate iron uptake.  Aluminum and iron ions are almost equivalent in size and can have the same ionic charge.  This allows aluminum to be carried by transferrin into these cells in higher than normal amounts even though the cells have no need for aluminum.

Some metal ions act as physiological stressors in the brain by stimulating brain cells to produce oxidizing chemicals (a.k.a. ROS)121,122. The metal ions stimulate inducible nitric oxide synthase (iNOS) in microglial and astroglial cells of the brain to produce nitric oxide (NO) that reacts to produce ROS122. This ROS can damage and kill neurons creating inflammation in the brain.  The following table shows how much ROS is produced from a cell culture of human glial cells exposed to 50nM aqueous solutions of various common metal ions58.  Aluminum tops the list of metal ion inducers of ROS in human brain’s glial cells.

Metal Ion Induction of ROS in Human Glial Cells58
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


The brain damage caused by aluminum inducing ROS could partially account for the neuronal death that underlies brain atrophy. This atrophy is seen in those areas the brain that are aluminum “hot spots” and it parallels aluminum accumulation in those areas of our brains as we age86,94.

Neurofibrillary tangle (NFT) formation in the brain is a hallmark of AD.  Aluminum has been shown to participate in NFT formation in both pre-tangle and tangle-bearing cells132.   Aluminum inhibits the activity of enzyme PP2A that clips off excess phosphoryl groups on a structural protein of the brain called tau22,133. Aluminum also inhibits the expression of a gene involved in making PP2A100. Aluminum creates a lack of active PP2A that results in tau being coated with more than the normal number of phosphoryl groups. This accounts for low PP2A activity and paired helical filaments (PHFt) found in the brains of AD patients133. In AD brains aluminum secondarily aggregates the PHFt into granules that fuse and grow into cytoplasmic pools of PHFt and aluminum that give rise to NFT filaments132. Aluminum and PHFt give rise to NFTs in brain cells, including large pyramidal and stellate cells, particularly in the brains of those with AD132.   Pyramidal cells are found in many regions of the brain, including the hippocampus, entorhinal, and prefrontal cortex.

Aβ plaque formation in the brain is another hallmark of AD.  Aβ plaques form from Aβ peptides that are cleaved from large Aβ precursor proteins (APP).  This process is called amyloidogenic cleavage and alteration of this process is a key feature of AD134.  Beneficial non-amyloidogenic cleavage of APP leads to a secreted product that is important for promoting neurite growth and maintaining brain tissue.  Protein phosphorylation stimulates the beneficial non-amyloidogenic pathway.  Both protein kinase C (PKC) activity that increases phosphorylation and protein phosphatase 2A (PP2A) activity that decreases phosphorylation are involved in the control of how much of each competing pathway is used for APP cleavage135. Activation of PKC decreases production of Aβ peptides by 50-80% and increases the beneficial non-amyloidogenic cleavage by 30-50%135. Nanomolar concentrations of aluminum reduce PKC activity by 90%136.  Therefore inhibition of PKC activity by aluminum directs APP to the amyloidogenic pathway resulting in more Aβ peptide135.   This situation is partially modulated by aluminum’s inhibition of PP2A135.

Microtubules are important neuronal structural features that are required for strength, rigidity, and transportation of cell constituents between the nucleus of the cell and the synapses.  Human pyramidal cells that contain NFTs and/or high levels of aluminum accumulation are microtubule-depleted44.  Aluminum-induced microtubule depletion is possibly more fundamental to AD neuropathology than AB oligomers, AB plaques, or NFTs74. This is because microtubule depletion is more damaging to neuronal connectivity and function than these hallmarks of AD neuropathology that may represent protective cell responses to aluminum 132,137. Aluminum-induced microtubule depleted cells have axonal and dendritic dieback that is consistent with AD being associated with neuronal disconnection.   In addition aluminum-induced microtubule depletion leads to synapse breakdown and depletion44,138. This explains why humans with AD have impaired axonal transport139,140.

Neuronal death is marked in the brain by ghost NFTs that can be the result of aluminum accumulation in the neuron prior to death.  NFTs inside the pyramidal cells tend to displace the cell nucleus to the periphery resulting in denucleation. The denucleated cell is unable to renew cellular membranes and eventually the cell membrane ruptures74.  This results in an extracellular ghost NFTs that act as tombstones of former neurons and a hallmark of AD.

  • Analogy of metal neurotoxicity to diseases similar to AD:

The two best analogies for a trace metal in the environment causing a disease, such as aluminum causing AD, are the effects of lead or mercury accumulation in our brains. Like aluminum both of these metals slowly accumulate in our bodies over our lifetime and cause mental illness.

Low level lead exposure was common during the Roman Empire.  The people of this period used lead to make water pipes, cookware, and cosmetics.  Corrosion of lead in contact with their drinking water and application of leaded cosmetics to their skin resulted in lead accumulation in their bones and brains141.  Judging from the amount of lead found in their bones, these people suffered from mild to severe lead poisoning resulting in brain swelling that caused severe headaches, confusion, irritability, seizures, and possibly death. Lead exposure continues today as there is lead in drinking water due to lead water pipes and lead pollution in ground water. For more information on the analogy between lead and aluminum exposure see Chapter 8.

Low level mercury exposure is currently common.  Mercury gets into the environment from both human-generated sources, such as coal-burning power plants, and natural sources, such as volcanoes. Consumption of fish is the primary ingestion-related source of mercury in humans.  The mercury in both salt and fresh water organisms is bio-concentrated in the food-chain that ends up in fish and humans. Symptoms of mercury poisoning typically include lack of coordination and sensory impairment, such as vision, hearing, speech, and sensation.  Although these symptoms indicate brain damage, mercury also damages the kidneys and lungs and can lead to death.

  • Experimental evidence showing that AD can be prevented:

The primary goal of this book is to show that diseases caused by aluminum can be prevented by 7 supplements, 7 lifestyle choices, and a dissolved mineral.  For example AD may be prevented by, antioxidants that counteract the oxidative effects of aluminum (Chapter 3), avoidance or minimization of aluminum exposure (Chapter 4), a complexation agent and vitamin that lower brain aluminum accumulation (Chapter 3 and 5), and a combination of aerobic exercise and sleep (Chapter 6).

  • The antioxidant PQQ protects the brain from low level aluminum exposure by inhibiting the formation of reactive oxygen species (ROS) and reducing ROS as they form in the brain due to aluminum accumulation.
  • Avoiding foods and pharmaceuticals, like antacids, that are high in aluminum, filtering drinking water, and cooking in non-aluminum cookware minimizes aluminum exposure.
  • Orthosilicic acid taken orally is absorbed into the blood and complexes with aluminum facilitating its excretion by the kidneys.
  • Vitamin D3 taken orally is converted by the body to vitamin D that facilitates the excretion of aluminum by the kidneys, even in the case of damaged kidneys due to kidney disease.
  • Aerobic exercise and sleep help to cleanse the brain of Aβ peptides and oligomers that are complexed with aluminum.


The best evidence that AD can be prevented is comparing the AD rate in countries with high levels orthosilicic acid in their drinking water, such as Singapore and Malaysia, with countries with low levels of orthosilicic acid in their drinking water, such as the U.S. and Iceland.

Life Expectancy and AD Death Rate by Country
Country Life Expectancy (yrs.)* AD Death  Rate (per 100,000)**
Iceland 83.3 25.1
United States 79.8 24.8
Malaysia 75.7 0.2
Singapore 84 0

*Life expectancy data from WHO 2014, **AD death rate data from

With comparable life expectancy and higher orthosilicic acid in their drinking water, people who live in Malaysia and Singapore have a much lower death rate due to AD.  Since orthosilicic acid facilitates the excretion of aluminum by the kidneys, there is evidence that lowering aluminum will prevent AD.


Conclusion: The nine criteria of causality originally set out by Sir Austin Bradford Hill72 and applied to neuropsychiatric conditions, such as AD, by Robert Van Reekum73 have been applied using primarily human data taken from studying AD patients and controls. The conclusions are that aluminum is the likely cause of AD and AD is a human form of chronic aluminum neurotoxicity.  Given these conclusions we as individuals and a society have a responsibility to take action.  This book proposes what action can and needs to be taken to avoid or lower our exposure to aluminum and prevent diseases caused by aluminum.

Aluminum an Unrequired and Unwanted Intruder

People representing the aluminum industry routinely point to aluminum’s omnipresence in our bodies as a sign of its essentiality. It is true that we all currently have a body-burden of aluminum but there has been no proven benefit of aluminum in our bodies.  In fact aluminum is a neurotoxin and aluminum exposure is the known cause of a number human diseases142.

The brain relies on a delicate balance of monovalent (e.g. potassium and sodium) and divalent (e.g. calcium, magnesium, and zinc) cations in order to function properly.  These cations bind reversibly and not tightly with aminoacids, such as histidine and lysine that are involved in the active sites of key enzymes (e.g. protein phosphatase) or on the backbones of key proteins (e.g. β-amyloid and α-synuclein).  Aluminum is a small trivalent cation that can bind tightly to both key enzymes and proteins in the brain.  For instance magnesium regulates over 300 proteins and aluminum competes for magnesium binding. Aluminum binds to some of these proteins 10 million times stronger and dissociates 10 thousand times slower than magnesium143. This property results in aluminum’s slow accumulation in select areas of the brain and aluminum’s inhibition of enzymes that causes the onset and progression of AD and possibly other forms of dementia. Aluminum is an unrequired neurotoxic element and not a nutrient for normal body function.  This makes aluminum an unwanted intruder.

Prevalence of Alzheimer’s Disease

The 2002 ADAMS study of dementia in the U.S. estimated that 2.7 million people in the U.S. had Alzheimer’s disease (AD)11 and by the year 2005, 24 million people worldwide had AD67.   AD prevalence is the highest in those 80 years of age and older. In 2002 there were 9 million people in the U.S. who are 80 years of age or older10. Therefore in 2002 approximately one in three people 80 years of age or older had AD.  This means almost everyone over 80 will be impacted by AD as they age.  Those of us who live to 80 and beyond will have at least a 1 in 3 chance of getting AD and, if we don’t get AD, we have at least a 1 in 2 chance of caring for a friend or relative with AD.

The prevalence of AD is increasing both as the size of the population in the U.S. over age 65 continues to increase and as our exposure to aluminum continues to increase.  Currently the Alzheimer’s Association estimates that 5.3 million people in the U.S. have AD4.  By 2025 the number of people 65 and older with AD is estimated to reach 7.1 million and by 2050 this number is projected to be 13.8 million, barring adoption of preventive measures, such as those described in this book, or the development of medical cures.



Symptoms of Alzheimer’s Disease

The clinical symptoms that characterize AD are:


  • Mitochondrial disease
  • Decreasing Aβ peptides and Aβ oligomers in cerebrospinal fluid
  • Increasing tau in the cerebrospinal fluid
  • Shrinkage of the brain
  • Olfactory dysfunction*

*Olfactory dysfunction or anosmia (i.e. the inability to smell) is among the first signs of AD and Parkinson’s Disease144,145.

The behavioral symptoms that are a result of cognitive impairment and characterize AD are4:

  • Short term memory loss that disrupts daily life
  • Difficulty in planning and problem solving
  • Difficulty completing familiar tasks
  • Confusion with time and place
  • Confusion with visual and spatial relationships
  • Difficulty with word finding during speaking and writing
  • Increased daytime sleepiness*
  • Changes in mood and personality
  • Withdrawal from work or social activities
  • Decreased or poor judgement

*Sleepiness is measured by timing how long it takes for an individual to fall asleep while laying on a bed in a quite dark room.  The largest difference in sleepiness between non-AD (16min.), mild AD (11min.), and moderate AD (8min.) was observed at 10AM and 12PM146.  In those with dementia, including AD, sleepiness should not be confused with 5 to 20 second long fainting spells, called syncope, that start abruptly and end with spontaneous recovery147,148.

Diagnosis of Alzheimer’s Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease that is a terminal illness with an average life expectancy of three to nine years post diagnosis.  The AD process occurs in stages 5 to 20 years before the first symptom of cognitive impairment is observed. The stages of AD are as follows:

  • The first stage of this process involves aluminum facilitating the formation of small soluble protein fragments from amyloid precursor protein (APP), such as Aβ peptides and Aβ oligomers, and insoluble Aβ plaques between neurons. Aluminum conjugates of Aβ oligomers are much more neurotoxic than any other APP metabolite16. Aluminum’s epigenetic effect of lowering gene expression for both neprilysin and LDL Receptor LRP1, and increasing gene expression for both BACE1 and APP results in more Aβ peptides and Aβ oligomers, and insoluble Aβ plaques30,31 . Aluminum chloride with D-galactose has been found to create predementia in a mouse model for AD104. The first stage of AD can be detected in humans as decreasing levels of Aβ peptides and Aβ oligomers in the cerebrospinal fluid.  These levels decrease as the peptides and oligomers are formed into insoluble Aβ plaques.


  • The second stage of this process involves aluminum facilitating tau protein clumping together in tangles (NFTs). Normally tau protein is used for microtubule assembly and stabilization in neurons. Aluminum’s epigenetic effect of lowering the production of the enzyme PP2A and aluminum’s inhibition of PP2A results in excess phosphoryl groups on tau22,99,100,136. Aluminum also facilitates the formation of NFTs from these over phosphorylated tau proteins24,25. NFT formation results in the death of neurons that are replaced with “tombstones” or “ghosts” of NFTs. The second stage can be detected as increasing levels of tau in cerebrospinal fluid.


  • The third stage is called mild cognitive impairment (MCI) and it occurs 1 to 4 years prior to a person being diagnosed with AD. MCI is characterized by poor decision making and difficulty in remembering recent events and other lapses of memory.  These symptoms are due to aluminum causing microtubule loss, dendritic die-back, and cortical atrophy resulting in slow loss of memory149.  MCI can also be a symptom of metabolic (non-AD) dementia that may be curable (see Appendix II).


  • The fourth stage is called Alzheimer’s disease because it can be diagnosed as a slow loss of cognition with symptoms including difficulties with word recall and disorientation, such as getting lost, mood swings and behavioral issues. These symptoms are due to substantial neuron damage and loss, called lesions, in areas of the brain related to short term and long term memory and decision making.  The severity of this stage can be gauged by performing either volumetric MRI to measure the shrinkages of the brain due to neurons expiring or FDG-PET that gauges the health of mitochondria in neurons.


If you are like me and have one or more aging parents, you may already have witnessed the slow decline of their short term memory. It is disturbing to realize they may have reached the 3rd stage of AD without even being aware their brains have the hallmarks of AD.  Also if you are like me you may worry that your own brain is beginning that downward spiral into AD.  Until recently it was only in the 4th stage that the disease could be diagnosed and called AD.  This late stage diagnosis of AD requires two major symptoms with short term memory loss usually being one of the two symptoms.

According to the Alzheimer’s Association only 45% of those with AD or their caregivers report being told of an AD diagnosis. In part this is due to the difficulty in making the diagnosis. Until recently examination of brain tissue after death was required for a definitive diagnosis of AD.  The two hallmarks of AD histopathology are:

  • Neurofibrillary tangles (NFTs) inside neurons and “tombstones” or “ghosts” of former neurons in between living neurons.
  • Insoluble Aβ plaques formed from Aβ peptides and oligomers in between living neurons.

See sidebar on “Biochemistry and Neurochemistry of AD” for details on these two hallmarks.

One reason it has been difficult to prove what causes AD is that the symptoms of AD become apparent only in the 3rd and 4th stage and a definitive diagnosis of AD has required an autopsy.  A new class of ligands has recently been developed that allows for brain imaging by PET scans of both NFTs150 and Aβ plaques151. This allows researchers to follow the development of the hallmarks of AD histopathology in living patients.  These tests should facilitate our understanding of how aluminum and possibly other environmental toxins cause AD. These tests should also allow faster testing of drugs under development that will provide palliative relief from the symptoms of AD, if not a cure for AD.

Conclusion of Alzheimer’s Disease

For the last 50 years, in spite of excellent research, the cause of Alzheimer’s has remained controversial.  It may be years before all the needed research is performed and the controversy ends. But now a tipping point has been reached and as described in this chapter there is convincing evidence that aluminum accumulation in our brains can cause Alzheimer’s disease.  Aluminum absorption in select areas of the human brain can result in the cognitive deterioration and associated cerebral pathology seen in AD as described in the following list:

  • Increased amyloid plaque formation in the brain that is a hallmark of AD
  • Increased phosphorylation of tau protein leading to neurofibrillary tangles (NFTs) that are a hallmark of AD
  • Inhibition of mitochondrial enzymes resulting in mitochondrial disease that is a clinical symptom of AD
  • Lesions in the perforant neuronal pathway resulting in loss of short term memory that is a behavioral symptom of AD

The presence of mixed cerebral pathologies becomes more common in individuals with advancing age. Forty-five percent of those over 90 with dementia had a multiple number of cerebral pathologies97. The presence of multiple pathologies is associated with increased likelihood and severity of dementia. AD as a single pathology is present in 28% of those over 90 without dementia and 23% with dementia. When a single additional pathology in addition to AD is present the chance of dementia is four times higher than with just AD pathology. When any three or more of these pathologies is present, the chance of dementia is 95% in those over 9097.  In addition to aluminum being a causal factor for AD, it has also been implicated as a casual factor for other cerebral pathologies (see Appendix I, III, and IV). For instance in Chapter 2 aluminum’s role as a causal factor for strokes and white matter disease is discussed. This is not to say that aluminum is the only cause of cerebral pathologies.  There are numerous environmental chemicals and several factors, such as head trauma, that have been implicated in cerebral pathologies (see Appendix I). Future research may find additional chemicals in our environment and additional factors that cause cerebral pathologies.

Since the commercial production of aluminum began, there has been a dramatic increase in AD cases worldwide.  There are cases of accidental and occupational exposure to aluminum that have shown that aluminum can cause both early-onset AD and the hallmarks of AD.

The Alzheimer’s Association finds that Alzheimer’s disease is grossly misunderstood and underestimated.  When they surveyed people in 12 countries they found:

 “59 percent of people surveyed incorrectly believe that Alzheimer’s disease is a typical part of ageing”.


As a society we have made an incorrect assumption:

“Because we now live longer, more of us will die of Alzheimer’s disease”   

This assumption is a self-fulfilling prophecy unless action is taken by individuals to lower their exposure to aluminum and society to improve regulations on the amount of aluminum in food, drink, and pharmaceuticals.  By lowering our aluminum ingestion and absorption we may be able to live longer without developing and suffering from AD.

The people of Malaysia and Singapore have a much lower death rate due to AD than the U.S even though they have a similar life expectancy. Could the people of Malaysia and Singapore be ingesting a dissolved mineral called OSA that increases aluminum excretion by their bodies?  See Chapter 5 for the answers to these questions. In Chapter 4 we will discuss ways to avoid or lower aluminum ingestion and in Chapter 5 we will discuss how to decrease aluminum absorption by your brain after ingesting aluminum.