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From the 12 June 2001 issue of Smart Life News [v8n2]. Copyright (c) 2001, 2002, 2009. All rights reserved.
Smart Life Update:
by Steven Wm. Fowkes
The body of scientific evidence indicating that mercury toxicity underlies Alzheimer's disease (AD) has grown to the point that it must now be considered a primary mechanism. During the last ten years, scientists have connected mercury toxicity to a variety of enzymatic changes that are seen in AD. Now, for the first time, scientists have shown that mercury exposure alone induces the characteristic morphological (visual) changes (i.e., neurofibrillary tangles) that are associated with AD. This article will present the primary evidence supporting the role of mercury toxicity in AD, and discuss how mercury toxicity may be connected to genetic risk factors, oxidative stress and beta-amyloid plaque formation.
Mercury is a medically loaded subject. According to orthodox dental associations, the mercury exposure from silver (mercury amalgam) dental fillings is not, they repeat, not a significant health hazard. However, there is a massive amount of evidence to the contrary. This evidence has prompted many countries to pass laws, restricting or banning its use and even recommending removal of amalgam fillings.
Despite the strong political influence of the American Dental Association (ADA), grass-roots awareness of mercury amalgam risks is growing in the US. Part of this can be atrributed to the educational efforts of the International Academy of Oral and Medical Toxicology, a professional organization promoting mercury-free medicine and dentistry. As criticism of amalgams has increased, so has the political pressure being applied to bolster public confidence in mainstream dental practices.
Mercury is not just a dental issue. The mercury-based preservative thimerosal is commonly used in vaccines. Although US public health officials state that thimerosal toxicity is minimal compared to the benefits of vaccines, use of vaccines is now tied to autism in children. Whether this is related to mercury toxicity or some kind of immune disruption, or both, is not yet known. However, the mechanisms of mercury toxicity in AD may significantly relate to the spectrum of neurological dysfunction seen in autistic children.
As a consequence of official policy on mercury safety, medical regulation has been manipulated for political ends. Dentists have been disciplined (a politically correct term for punished) for counseling patients about mercury toxicity, or (gasp!) actually removing amalgam dental fillings and replacing them with composite materials (usually plastic/ceramic mixtures). Fortunately, medical dysregulators have not been completely effective in suppressing the mercury-toxicity issue and there are an increasing number of dentists that perform amalgam-removal services. There are areas where amalgam removal is still considered heretical or deviant medical practice, so it may be extremely difficult to get mercury-oriented therapy for anybody with AD, let alone anybody merely concerned about reducing their AD risks. Fortunately, there are also self-care options that individuals can consider.
One of the scientific problems delaying acceptance of the idea that Alzheimers disease (AD) relates to mercury toxicity has been a number of studies that show no correlation between amalgam-filling status and AD. Although there is reason to doubt the scientific objectivity of some of these studies due to their sources of funding and their being published in dental journals, blood levels of mercury do correlate with AD (see Figure 1). Mercury blood levels in AD patients were double those of controls [Hock et al., 1998]. In early-onset cases, mercury levels were almost triple.
At autopsy, mercury levels are usually higher in AD brains than control brains. However, in many specific brain locations, the differences do not reach statistical significance [Ehmann et al., 1986; Thompson et al., 1988]. Subcellular organelles (nuclei, microsomes, mitochondria) also have elevated mercury levels in AD, but it only reaches statistical significance in microsomes (cell protein factories) [Wenstrup, 1990].
Although mercury accumulation appears to be much more related to AD than mere exposure, neither can adequately account for AD. Some AD patients have substantially lower levels of mercury than people without AD. There must be other factors involved. Two of these are 1) biological detoxification mechanisms thatmitigate the toxicity of mercury, and 2) pathological processes that augment the toxicity of mercury.
If detoxification mechanisms are robust, the brain can coexist with high levels of mercury. If these mechanisms fail, then dramatically lower levels of mercury are enough to precipitate AD. Detoxification mechanisms for mercury are extremely complicated and not yet fully understood. As a consequence, there is currently no clear consensus on the best way to decrease mercury toxicity. Many clinical techniques in current practice increase mercury-related symptoms in the process of removing mercury from the body.
Some possible aggravating factors are 1) fungal infections that can produce the neurotoxin gliotoxin (see illustration), which independently attacks mercury-sensitive brain enzyme systems, and 2) as-yet-uncharacterized bacterial infections in teeth (root-canal or otherwise) that produce highly potent inhibitors of brain enzyme systems. Some of this toxicity may relate to anaerobic degradation of methionine and cysteine into methanethiol and hydrogen sulfide (see illustration). These low-molecular-weight sulfide species can bind to mercury and increase its toxicity and mobility. Other chemical entities are likely to be involved as well.
This year, researchers from the University of Calgary have finally shown the transformation of a healthy cultured neuron to an AD-like state by the simple addition of nanomolar mercury [Leong et al, 2001] (see the adjacent sidebar for an explanation of nano and molar). For the first time, a single causal influence has produced the characteristic neurofibrillary tangles that are an accepted diagnostic marker of AD. The researchers even made a time-lapse movie of the process. It will be interesting to see how long political pressures will keep the movie from being shown on public television, the Discovery Channel, or network news.
The concentration of mercury in the average human brain varies from 10^-8 to 10^-6 M [Haley, 2001]. This is roughly ten-fold greater than the nanomolar (>10^-9) solutions that produce neurofibrillary tangles in cell culture. The reason that small increases in mercury precipitate AD morphology (structural changes) is that the mercury increase is comparatively sudden. In vivo, brain mercury accumulation is a gradual process in which detoxification mechanisms have time to adjust. Sudden addition of mercury overwhelms the delicate balance between mercury and protective sulfur compounds. This leads to catastrophic consequences.
The effects of nanomolar mercury are not limited to visible changes. Other researchers have previously shown that nanomolar mercury causes the same shifts in brain enzyme function that are seen in AD. These include 1) inhibition of GTP-tubulin interactions [Pendergrass et al., 1987; Khatoon et al., 1989], 2) inhibition of glutamine synthetase [Gunnersen and Haley, 1992; Olivieri, 2000], 3) inhibition of creatine kinase, and 4) increased tau phosphorylation and beta-amyloid secretion [Olivieri, 2000]. Each of these will be discussed individually later.
As with neurofibrillary tangles, the level of mercury necessary to affect these enzymatic changes is a small fraction of the amount that is commonly found in human brains that do not exhibit the signs of AD. In fact, at autopsy, some human brains show levels of mercury in excess of micromolar levels (10^-6 M), without any sign of neurofibrillary tangles. In one person with a particular kind of heart disease (see sidebar file), heart-muscle mercury levels were measured at millimolar (10^-3) levels!
How could somebody have almost a tenth of a percent mercury in a critical body tissue and still be alive? Its obvious that the body has the potential to detoxify very large amounts of mercury. However, mercury toxicity is not just a matter of detoxification. Different chemical forms of mercury have widely differing toxicities. Mercury cloride is very toxic. But mercury selenide is not very toxic at all. This is why mercury researchers often measure selenium at the same time as mercury. Methyl mercury can be even more toxic to the brain than ionic mercury because it easily passes through the blood-brain barrier. Methylthiomercury is even more toxic. So mercurys toxicity depends on the presence or absence of other substances that can bind with it and potentiate or mitigate its toxicity and/or mobility.
Mercury (Hg) and sulfur (S) have a special chemical affinity for each other. This is evidenced not only by mercuric sulfide (HgS) being the primary mercury-containing ore found in the earths crust (and exploited for commercial production of mercury), but by the fact that mercury ions (Hg++) readily bind to sulfhydryl (SH, thiol) groups in biological systems. These sulfhydryl groups are chemically active in a variety of biological capacities. For examples, glutathione (GSH) is a primary antioxidant defending cellular membranes from oxidative damage. Alpha-Lipoic acid is an essential component of dehydrogenase complexes that drive the Krebs citric-acid cycle, which generates the primary energy for the cell. A wide variety of proteins and enzymes contain cysteine-to-cysteine links (disulfide bridges), which link sections of protein chains to each other to determine their final 3-D structures. And many enzymes contain cysteine at their active sites, the sulfhydryl group of which participates in the chemical transformation catalyzed by the enzyme. The chemical reactivity of sulfhydryl groups is essential to the healthy functioning of biological systems.
When mercury ions are present, they bind to sulfhydryl groups and destroy their special reactivity. Enzymes with mercury bound at their active sites do not catalyze their normal reactions. Glutathione (GSH) bound to mercury does not function as an antioxidant.
There are always mercury ions present in biological systems. However, if they are dramatically outnumbered by sulfhydryl groups, the poisoning effect is minimized and normal metabolic functions proceed to a significant degree. So the ratio of sulfhydryl groups to mercury ions is an important aspect of mercury detoxification. This offers one insight into how some people can tolerate higher levels of mercury than others.
Over the last decade, many research teams have focussed on enzyme systems and structural proteins in the brain that are disrupted in AD patients. It turns out that the most seriously impaired systems contain sulfhydryl groups.
One of the most plentiful, and arguably the most important, sulfhydryl compound in the brain is glutathione (GSH). Glutathione has a strong affinity for mercury. In recent experiments, glutathione depletion has been found to be one of the quickest effects of low-level mercury exposure on cultured neurons [Haley, 2001]. Glutathione and vitamin C are the primary water-soluble antioxidants in the brain, and they are absolutely essential to protect neural membranes and protein structures from a wide variety of oxidative stresses. Depletion of glutathione represents a potential mechanism for 1) the observations of oxidative stress in AD, and 2) the catastrophic destabilization of neuron infrastructure that is seen in AD.
Creatine kinase (cree-a-teen kie-naze) is a sulfhydryl enzyme that is highly expressed in the brain and regulates ATP storage. During times of ATP surplus, creatine kinase uses ATP to phosphorylate creatine into creatine phosphate (see Figure 2). During times of ATP demand, creatine kinase performs the reverse reaction, using creatine phosphate to rapidly convert ADP back to ATP. So creatine phosphate is like a back-up battery for peak-energy-use periods, and creatine kinase acts like a battery charger when energy is plentiful and an emergency power generator when it is not.
There has been a lot of research into creatines important role in muscle tissue, specifically relating to peak strength and stamina. However, creatine plays an equally critical role in the central nervous system, where brain proteins and enzymes tend to beamong the most highly phosphorylated structures in the human body. In the AD brain, creatine kinase is over 95% inhibited. It is also rapidly inhibited by nanomolar mercury exposure, although not quite as quickly as glutathione.
Kinases are enzymes that phosphorylate (attach phosphate groups to) other enzymes and proteins. In the process, they modify the properties of those enzymes and proteins. Phosphate groups are bulky and highly electronegative (see Figure 3), so this can shift the physical structure and alter electrical attractive and repulsive forces at the surfaces of proteins, which can change the conformation (shape) and activity of enzymes. In some cases, phosphorylation increases enzyme activity. In other cases, phosphorylation reduces enzyme activity. This means that increasing or decreasing the overall level of phosphorylation can modulate phosphorylation-sensitive enzyme activities in a concerted manner. This capability seems to be extensively utilized by the human brain in the regulation of cytoskeletal growth and function. The latest research indicates that phosphorylation peaks and troughs on a one-minute cycle, which correlates with a tightening and relaxing of the cytoskeleton. The energy demands of maintaining such a high level of phosphorylation may be a primary contributor to the remarkably high metabolic rate of the brain.
Phosphatases operate oppositely to kinases. While kinases attach phosphate groups, phosphatases remove them. Some phosphatases are known to be seriously inhibited in AD.
There are many dozens of kinases and phosphatases that regulate different aspects of phosphorylation. More are being discovered every year. Some specialize in phosphorylation or dephosphorylation of serine and threonine residues (aliphatic amino acids with exposed hydroxy groups), while others operate on tyrosine residues (an aromatic amino acid with an exposed hydroxy group). Some kinases and phosphorylases are quite specific to particular enzymes or enzyme families, while others can have widespread and overlapping activities. One of the latter, protein kinase C (PKC), is more highly expressed in the human brain than in any other tissue.Like creatine kinase, PKC is also strongly inhibited by mercury ions.
Our understanding of the specifics of feedback control mechanisms involving phosphorylation is still rudimentary. Given 1) the large numbers of proteins and enzymes that are being phosphorylated and dephosphorylated, 2) the large numbers of kinases and phosphatases that are competing against each other, 3) the kinases (or phosphatases) with overlapping activities, and 4) the possibility of inverse enzymatic response to changes in phosphorylation, it may be decades before we have it all figured out.
Neurofibrillary tangles are one of the hallmarks of Alzheimers disease (AD). They consist of paired helical fillaments, which are composed of the microtubule-associated protein tau (see next section for discussion of microtubules). The tau in neurofibrillary tangles is different from normal tau; it is heavily over-phosphorylated. This appears to be the result of inhibition of protein phosphatases. Recently, researchers have provided evidence that protein phosphatases PP-1 and PP-2A, and phosphotyrosyl-protein phosphatase (PTP), are significantly inhibited in the AD brain. Furthermore, in vitro, the addition of PP-2A and PP-2B restores tau to normal levels of phosphorylation [Pei et al., 1998]. This inhibition of phosphatase activity is not related to any decrease in the production of PP-1, PP-2A or PTP. In fact, levels appear to be slightly higher in the AD brains than in controls, possibly indicating an unsuccessful attempt to compensate for the phosphatase defect.
There are numerous protein polymers in neural cells that serve a wide variety of structural functions. Collectively, these protein polymers are referred to as the cytoskeleton, which, among other things, is responsible for creating and maintaining the complicated three-dimensional structures of neurons. Cytoskeletal development controls 1) neuron growth, 2) neural branching, and 3) neural migration patterns, which ultimately determine the hard wiring of the brain. The development and maintenance of the cytoskeleton is regulated by changes in phosphorylation.
The cytoskeleton is made up of neurofilaments, microfilaments and microtubules. Neurofillaments and microfillaments are smaller diameter fibers. Neurofillaments (10 nanometers (nm) in diameter) have side arms that allow attachment to other cytoskeletal structures. They seem to specialize in branched structures that may serve a scaffolding purpose. Microfillaments (5-12 nm diameter) are extensively used in muscle fibers to pull structures together. They also help regulate the conformation of the outer cell membrane in cells that move which include neurons. And they may regulate cytoplasmic fluidity.
Microtubules (MTs) are of special interest in AD because they are seriously disrupted. In healthy brain, MTs are long, rigid, linear structures with a larger diameter (20 nm) than both neurofillaments and microfillaments. MTs do not branch, although they are often bound by numerous neurofillament linkages to the rest of the cytoskeleton. In cell cultures, MTs are readily disrupted by nanomolar mercury exposure.
Microtubules (MTs) are formed from tubulin proteins, which come in alpha, beta and gamma forms. The role of gamma-tubulin appears to be limited to MT initiation. Once initiated, alpha-tubulin and beta-tubulin are used to elongate the MTs.
The first step in the MT assembly process (see Figure 4) is the formation of a heterodimer, consisting of one alpha-tubulin protein joined to one beta-tubulin protein (hetero means different). This dimer requires a molecule of GTP for its assembly. GTP (guanosine triphosphate) is a close chemical cousin of ATP (adenosine triphosphate), which is the primary energy currency of the cell. GTP is produced from ATP, so it is a special form of energy currency that is used to power the building and maintenance of the cytoskeleton.
The alpha-tubulin beta-tubulin dimers then assemble into long chains or protofilaments, also requiring GTP. Thirteen of these protofilaments then bind together to form the wall of a MT (see Figure 4). The MT is hollow inside, like a straw.
The beta-tubulin protein contains more than a dozen sulfhydryl groups. Two of these sulfhydryl groups are located near the GTP binding site. When mercury binds to these two sulfhydryl groups, GTP binding is seriously inhibited, which prevents tubulin polymerization. The mercury-mediated disintegration of MT infrastructure causes gross neural dysfunction.
Because the tubulin dimers are electrically polarized, they can only join alpha-unit to beta-unit. Alpha-tubulin will not polymerize by itself. Neither will beta-tubulin. It takes both, and they necessarily end up in an alternating (alpha-beta-alpha-beta) sequence.
Because of this electrical polarity, microtubules (MTs) are inherently directional! They start at one place in the cell (usually near the cell nucleus) and grow in a straight line 1) towards the cell periphery, 2) down an axon or dendrite, and/or 3) to a nerve terminus, where neurotransmitters and receptors are located. The directionality of the MT is then exploited by motor proteins (transporters) that bind to the MTs and move in only one direction (i.e., outward or inward). The motor protein kinesin moves outward (towards the positive end of the MT), and will carry vessicles (membrane-bound sacks of biological material) from the nucleus to the cell periphery. The motor protein dynein moves inward (towards the negative end of the MT). It carries material from the cell periphery back to the nucleus. Thus, MTs function as two-way highways, on which motor proteins travel to bring their cargo to some kind of cellular destination.
This transport function of MTs is especially critical to the proper functioning of neurons. Unlike the vast majority of cells that tend to be globular, neurons grow long, thin extensions with multiple branchings. If a microtubule (20 nm width) were the size of a highway (approx. 20 feet lane width), the distance between a nucleus and its nerve terminus in a 1 inch long (2.54 cm) dendrite would be almost 5000 miles (8000 km). Imagine contemplating such a trip without roads or motor vehicles. Axons can be an order of magnitude longer than dendrites. Given such immense distances, it is easy to see how the central nervous system is critically dependent on MT infrastructure.
There is very good evidence that the risks of Alzheimers disease (AD) are genetically related (see SDN v3n2p1). Several research teams have demonstrated that variations in apolipoprotein (A-poe-lie-poe-pro-teen) E, a cholesterol-carrying blood protein, are related to age of onset of AD (see Figure 5). The association of ApoE4 with increased risk has become widely accepted. However, until recently, nobody has been able to offer an explanation as to how ApoE variants might actually influence AD pathology. Moreover, individuals with protective ApoE alleles (genes) still get AD. They just get it a few years later in life than people who carry the alleles associated with increased risk. Clearly, ApoE is not a cause of AD. It is merely influencing or modulating a deeper mechanism.
ApoE is also produced in neural cells for housekeeping purposes that have not yet been made clear. It travels from the cell into cerebrospinal fluid, which is then flushed out into the body.
In humans, ApoE comes in three different forms, ApoE2, ApoE3 and ApoE4. ApoE4 is associated with increased risk of early onset Alzheimers disease (see Figure 5). ApoE3 is the most common form in humans. The rarest is ApoE2, which seems to offer significant protection from Alzheimers disease. Is ApoE connected to mercury?
Dr. Boyd Haley and colleagues think it is. The genetic differences between ApoE alleles involve substitutions between arginine and cysteine at positions 112 and 158 of the proteins. All the other amino acids in the ApoE protein are identical. The protective form (ApoE2) has two cysteines at those positions, the common form (ApoE3) has one cysteine and one arginine, and the increased-risk form (ApoE4) has two arginines. Since cysteine can bind mercury and arginine cannot, the cellular production of ApoE2, and ApoE3 to a lesser extent, can carry mercury from brain neurons into the cerebrospinal fluid and dump it into the body. This explanation easily integrates ApoE genetics into the mercury model. The number of cysteine residues in ApoE correlates perfectly with the observed age of AD onset (Figure 5) and AD risks (Figure 6).
Glutamine synthetase (GS, glue-tah-mean sin-theh-taze) is another sulfhydryl enzyme that is seriously inhibited in AD. GS is important for 1) ammonia detoxification in the brain, and 2) termination of the glutamate signal in excitatory synapses [Gunnersen & Haley, 1992]. It converts glutamate (an excitatory neurotransmitter) to glutamine (which is not excitatory) using ammonia and ATP. It is found in large amounts in astrocytes, which surround and protect excitatory neurons.
Activation of excitatory receptors by glutamate (or aspartate) triggers calcium influx into the neuron. This flow of calcium ions across the neural membrane causes a shift in electrical polarity, which triggers nerve electrical firing. The calcium is then pumped back out of the neuron to get ready for the next firing.
Excessive stimulation of excitatory receptors produces a calcium-influx burden in excitatory neurons. This is called excitotoxicity. If calcium cant be pumped out fast enough and exceeds a threshold level, it triggers apoptosis (cell suicide). So it is very important to be able to modulate excitatory activity to avoid apoptosis (a-poe-toe-sis).
Glutamine synthetase is found in the cerebrospinal fluid of AD patients, but not normal controls [Gunnersen & Haley, 1992; Tunami et al., 1999]. Its function is inhibited by mercury ions, and its production is increased by mercury exposure. Perhaps excitotoxicity is responsible for the loss of neurons in AD.
The central role of mercury in these AD-associated processes suggests that anybody concerned about the possibility of AD should now focus on 1) minimizing environmental mercury exposure, 2) reducing accumulated mercury stores in body tissues, especially the brain, 3) supporting antioxidant defenses, especially those that relate to mercury detoxification, 4) supplementing minerals that mitigate mercury toxicity, especially when deficient, and 5) avoiding metals and unnecessary minerals that may exacerbate mercury toxicity. Although such strategies make sense, none of these options has been systematically evaluated for its efficacy in reducing the toxicity of mercury to brain enzyme systems.The issue of therapy for AD is further complicated by the fact that existing mercury detoxification protocols often produce an increase in symptoms in people suffering from mercury toxicity. The spectre of getting worse before you can get better is daunting when the worse is loss of mind. Ideally, we need a reliable way to remove mercury from the body without increasing mercury toxicity to the brain. Well be looking at this issue for future updates.
Melatonin seems to offer significant protection from mercury toxicity. In a neuroblastoma cell culture exposed to mercury (HgCl2), pretreatment with 10^-6 M melatonin 1) protected cells from loss of glutathione (GSH), 2) prevented over-phosphorylation of tau, and 3) attenuated beta-amyloid secretion [Olivieri et al., 2000].
In a clinical study, 9 mg doses of melatonin before bed provided sleeping benefits and prevented further deterioration in 14 Alzheimers patients over a period of 22-35 months [Brusco et al., 2000].
The mercury sensitivity of brain enzyme systems is modulated by the presence or absence of other ionic species. Magnesium is closely associated with ATP and GTP complexes, and magnesium deficiency increases symptoms of mercury toxicity. It is possible that magnesium supplementation may significantly decrease mercury toxicity in a general manner. It is important to remember that inexpensive supplements based on magnesium oxide or dolomite depend on robust stomach-acid production for their efficient absorption. Well chelated supplements, like magnesium citrate, aspartate, orotate or ascorbate, are bioavailable even in achlorhydric people.
Even though magnesium aspartate is efficiently absorbed, aspartate is an excitatory neurotranmsmitter that may pose a slight excitotoxic risk. Since there are other chelating agents available, it may be best to avoid all aspartate chelates.
There are two minerals, cadmium and zinc, that are chemically related to mercury: cadmium is just above mercury on the periodic table, and zinc is just above cadmium (see Figure 8). The presence of cadmium increases mercury toxicity. Zinc may also increase mercury toxicity. Is it a good idea to avoid zinc supplements in AD? There is some evidence to justify that position.
The ability of relatively low doses of zinc chloride to increase mercury toxicity towards beta-tubulin in brain homogenates is dramatic at the lowest levels of mercury exposure (see Figure 7). Zinc chloride alone, at 10 mcM and 20 mcM, inhibited beta-tubulins ability to bind GTP by approximately 18% and 27%, respectively (see black diamonds). At this level, zinc chloride is significantly toxic.
Mercury (white circles) is more than ten times more toxic. GTP binding is about 30% inhibited by 1.25 mcM mercury, which is comparable to zinc at 20 mcM.
At the lowest level of mercury, 0.625 mcM, GTP binding is only 4% inhibited. But when this low level of mercury (4% inhibition) is combined with 10 mcM of zinc (18% inhibition), the GTP binding is 50% inhibited (see gray circles). With 20 mcM of zinc (27% inhibition), GTP binding is 75% inhibited. Although this synergistic effect of zinc on mercury toxicity lessens at higher levels of mercury, it is still observed.
This in vitro (test-tube) experiment deals with adding zinc chloride (ZnCl2) to brain homogenates, which is not the way zinc would be delivered to a living brain. So are these data an artifact of the unnatural circumstances of the experiment? That is certainly possible, and maybe even likely. This is not a clinical finding. Nevertheless, it might be wise to closely monitor cognitive function for adverse changes with any increase in zinc supplementation during AD therapy.
Copper, which often competes with zinc for enzyme sites, also aggravates mercury toxicity to brain enzyme systems.
The brains fundamental reliance on microtubules (MTs) and phosphorylation make it more sensitive to mercury than other tissues. The human brains greater reliance on neural branching gives it greater intellectual abilities than the brains of other mammal species, but also more sensitivity to mercury toxicity. Mercury-mediated disruption of MTs, phosphorylation and sulfhydryl enzyme systems produces the characteristic enzymatic and morphological changes that are seen in Alzheimers disease (AD). The evidence connecting mercury to AD is now robust and well integrated. It is now time to focus our energies on clinical research to learn how to deal with mercury toxicity, to find a cure for AD. There are already a plethora of clinical techniques to accomplish this end. All we need is the will to undertake the process.
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