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.