Chapter 1 Part 7 The Case for Aluminum Being the Cause of AD - continued

4)      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 age^{28,49,113,114}.      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 2010^117,118. 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.

5)      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.

6)      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 AD^16,17,24,25. 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 LTP^{16,101,123,126-129}. 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.

7)      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 blood^118,130,131.  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.

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 age^86,94.

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 tau^22,133. 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 depletion^44,138. This explains why humans with AD have impaired axonal transport^139,140.

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.         

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.