Chapter 1 Part 8 The Case for Aluminum Being the Cause of AD - continued

8)      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.   

9)      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.  

 

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. 

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.