Chapter 1 Part 6 The Case for Aluminum Being the Cause of AD

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:  

1)      Strength of association between aluminum and AD

2)      Consistency of association between aluminum and AD

3)      Specificity of association between aluminum and AD

4)      Temporality of aluminum accumulation occurring before AD

5)      Biological gradient with dose-response effects of aluminum on AD risk

6)      Biological plausibility of aluminum neurotoxicity causing AD

7)      Coherence of what we know about how aluminum causes AD

8)      Analogy of metal neurotoxicity to diseases similar to AD

9)      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.

 1)      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/L^75,76. 

·         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.

2)      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.  

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.   

3)      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 AD^89-92. 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.

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:

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.  

Chapter 1 Part 5 Conclusion of the Case of the Cloaked Assassin

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:

o   AB-plaques

o   NFTs

·         Aluminum causes two symptoms of AD:

o   Mitochondrial disease

o   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 inoculations^65,66. 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.

Chapter 1 Part 4 How does Aluminum get into our bodies and brains ?

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 brain^36-38.  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 bulbs^39-41.  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 brain^43,47,48.  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 aluminum^3,49.  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 others^3,51. 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 brains^28,29. 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 production^56,57. 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 production^56,57.  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.

Chapter 1 Part 3 How are Neurofibertangles formed in the brain ?

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 (PO₃^2-) 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 (PO₃^2-) 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 general^28,29. 

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 oligomers^16,17.  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 degradation^30,31.

·         Aluminum lowers gene expression of the LDL receptor LRP1, required for Aβ peptide clearance and the importation of cholesterol to neurons^30,32.

·         Aluminum increases gene expression of BACE1, the β-secretase enzyme that cleaves the amyloid precursor protein (APP) to the precursor of Aβ peptides^30,31.

·         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.