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.