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Abstract

The etiology of most cases of Alzheimer's disease (AD) is as yet unknown. Epidemiological studies suggest that environmental factors may be involved beside genetic risk factors. Some studies have shown higher mercury concentrations in brains of deceased and in blood of living patients with Alzheimer's disease. Experimental studies have found that even smallest amounts of mercury but no other metals in low concentrations were able to cause all nerve cell changes, which are typical for Alzheimer's disease. The most important genetic risk factor for sporadic Alzheimer's disease is the presence of the apolipoprotein Ee4 allele whereas the apolipoprotein Ee2 allele reduces the risk of developing Alzheimer's disease. Some investigators have suggested that apolipoprotein Ee4 has a reduced ability to bind metals like mercury and therefore explain the higher risk for Alzheimer's disease. Therapeutic approaches embrace pharmaceuticals which bind metals in the brain of patients with Alzheimer's disease. In sum, both the findings from epidemiological and demographical studies, the frequency of amalgam application in industrialized countries, clinical studies, experimental studies and the dental state of AD patients in comparison to controls suggest a decisive role for inorganic mercury in the etiology of AD.
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Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Neuroendocrinology Letters No.5 October Vol.25, 2004
Copyright © 2004 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Alzheimer Disease: Mercury as pathogenetic factor and
apolipoprotein E as a moderator
Joachim Mutter*, Johannes Naumann*, Catharina Sadaghiani*,
Rainer Schneider*
1
& Harald Walach*
1
*Institute for Environmental Medicine and Hospital Epidemiology, University Hospital Freiburg,
GERMANY.
1
Samueli Institute, European Ofce, Freiburg, GERMANY.
Correspondence to: Joachim Mutter, MD
Institute for Environmental Medicine and Hospital Epidemiology
University Hospital Freiburg,
Hugstetter Str. 55
79106 Freiburg, GERMANY
PHONE: +49 761-270-5489
FAX: +49 761-270-5440
EMAIL: jmutter@iuk3.ukl.uni-freiburg.de
Submitted: July 26, 2004 Accepted: August 4, 2004
Key words:
mercury; amalgam; Alzheimer’s disease; neurotoxicity;
neurodegeneration; neurobrillary tangles; Apolipoprotein E;
metals
Neuroendocrinol Lett 2004; 25(5):331–339 NEL250504R01 Copyright © Neuroendocrinology Letters www.nel.edu
Abstract
The etiology of most cases of Alzheimer’s disease (AD) is as yet unknown.
Epidemiological studies suggest that environmental factors may be involved
beside genetic risk factors. Some studies have shown higher mercury concen-
trations in brains of deceased and in blood of living patients with Alzheimer’s
disease. Experimental studies have found that even smallest amounts of mer-
cury but no other metals in low concentrations were able to cause all nerve cell
changes, which are typical for Alzheimer’s disease. The most important genetic
risk factor for sporadic Alzheimer’s disease is the presence of the apolipopro-
tein Ee4 allele whereas the apolipoprotein Ee2 allele reduces the risk of devel-
oping Alzheimer’s disease. Some investigators have suggested that apolipopro-
tein Ee4 has a reduced ability to bind metals like mercury and therefore explain
the higher risk for Alzheimer’s disease. Therapeutic approaches embrace phar-
maceuticals which bind metals in the brain of patients with Alzheimer’s disease.
In sum, both the ndings from epidemiological and demographical studies, the
frequency of amalgam application in industrialized countries, clinical studies,
experimental studies and the dental state of AD patients in comparison to con-
trols suggest a decisive role for inorganic mercury in the etiology of AD.
R E V I E W A R T I C L E
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Abbreviations
ApoE Apolipoprotein E
AD Alzheimer’s disease
Hg mercury
GS Glutamine Synthetase
CS Creatininkinase
Sulfhydryl group SH
INTRODUCTION
Alzheimer’s disease (AD) rarely occurs in early
forms between the age of 30 and 65 (5–10%), and fre-
quently in late forms above the age of 65. On average
the duration of the disease is 6 to 10 years, although
duration of survival decreases with increasing age. In
the US, Alzheimer’s disease causes costs abounding
to an estimated 90 billion dollars [1]. It ranks fourth
among all death causes, meanwhile infesting 4.5 mil-
lion citizens [2]. According to estimations, a total of 16
million individuals will be affected by the year 2050
[2,3]. In recent years, the incidence of Alzheimer’s dis-
ease has been on the rise. At least 30–50% of all individ-
uals above the age of 85 are affected in industrialized
countries [4]. With ever increasing life-spans Alzheim-
er’s disease will be one of the major public health prob-
lems of coming decades.
The central pathogenetic mechanism is neurode-
generation and inammatory processes, which in turn
produce oxidative stress that accelerates neuron dam-
age. The neuro-degeneration starts with a hyperpho-
sporilization of the tau-protein due to as yet unknown
reasons. This in turn leads to a break-down of microtu-
bules which form the cytoskeleton of the neuron and
are essential for the neuron’s metabolism and func-
tioning. The vital processes of the neuron are dis-
turbed and nally neuron death ensues.
The deposits cannot be adequately removed and
form neurobrillary tangles which in turn acceler-
ate the inammatory cascade and the positive feed-
back circle that leads to the progression of the dis-
ease. Nerve cell degeneration produces damages in
the cholinergic projective systems of the basal prefron-
tal brain, in the entorhinal cortex, and the hippocam-
pus at early stages [5–7]. The neuronal losses are high-
est in the nucleus basalis Meynert (Nbm) and reach
more than 90% at advanced affection stages [8,9]. Due
to the concomitant reduction of the cholinergic activity
of the cerebrum, which normally determines the activ-
ity status of the cortex, memory performance is signif-
icantly impaired despite the fact that the cerebral cor-
tex does not show much damage [5–7]. In the course
of Alzheimer’s disease, considerable and unusual
amounts of extra cellular protein accretions are trace-
able. Fiber mass consists of insoluble b-Amyloid-Pro-
tein (Ab). Therefore, it cannot be removed by antibod-
ies. Accretion of Ab causes induction of inammatory
processes and an increased creation of free oxygen rad-
icals which are further enhanced through elevated ho-
mocysteine and metals [10–14]. This might explain the
neurotoxicity of amyloid accretions.
The cause of Alzheimer’s disease is yet unknown.
About 3–5% of all cases are genetically determined,
suggesting a multi-causal model for the disease. Stud-
ies on migration suggest that exogenous factors might
be responsible for triggering this pathological positive
feedback circle [15–18]. The amount of neurobril-
lary tangles found in eminently affected brain regions
in Alzheimer’s disease correlates with the severity of
Alzheimer’s disease (Figure 1) [19–22]. Minor neuro-
brillary nerve cell changes may occur as early as 50
years before onset of clinical symptoms [19]. Thus, age
is not the cause, but only one factor for its clinical man-
ifestation [20]. Interestingly, neurobrillary tangles in
low amounts are already found in about 20% of indi-
viduals aged 20–30 years without clinical symptoms of
Alzheimer’s disease (Figure 1) [20]. In the age group
70–80 yrs., 90% of the individuals display neurobril-
lary tangles in their brains. In this cohort, 35% have
highest numbers of histological detectable neurobril-
lary tangles and subsequently suffer clinically detect-
able from Alzheimer’s disease (Figure 2) [20]. Thus, if
an exogenous factor contributes to the development of
neurobrillary tangles and consequently Alzheimer’s
disease, this factor must be present in a great portion
of the public only in industrial developed countries. In
the past 20 years, a number of studies were published
suggesting a potential pathogenetic role of inorganic
mercury in Alzheimer’s disease. In this article, we per-
formed a multidisciplinary review of the material pub-
lished so far.
SEARCH STRATEGY
The data base Medline was searched using Ovid
Technologies, Version rel 9.1.0 for 1966–16.1.2004
with the keywords (mercur$) and (neurotoxic$ or al-
zheimer$ or dement$). This search was supplemented
from the bibliography of retrieved articles. Also, we
searched the internet using Google. Additionally, the
current knowledge about Alzheimer’s disease was
screened in literature about neurology. We tried to
come to a fair assessment of the situation by a multi-
disciplinary review of the material by several research-
ers with different leanings and preconceptions, and by
discussing difcult ndings.
APOLIPOPROTEIN E
A well known genetic risk factor for the early and
late forms of Alzheimer’s disease is the polymorphism
of the apolipoprotein E gene (APOE). APOE occurs in
three genetic variants which are determined on chro-
mosome 19: APOE2, APOE3 and APOE4 [23]. Apolipo-
protein E is a lipid transport protein regulating uptake
and excretion of lipids, and it is normally only consid-
ered in this capacity [23]. Interestingly, high concen-
trations of apolipoprotein E are found in the central
nervous system where apolipoprotein E is expressed
in astrocytes [24–26] were it may play an important
role in the distribution of cholesterol and phospholip-
ids [27]. Presence of the APOEe4 allele increases the
risk of developing Alzheimer’s disease by reducing the
average age of disease manifestation [28]. On the other
Joachim Mutter, Johannes Naumann, Catharina Sadaghiani, Rainer Schneider & Harald Walach
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Figure 1. Distribution pattern of Alzheimer’s disease-related neurobrillary tangles
Frontal sections of brain samples with typical Alzheimer’s disease-related neurobrillary tangles (NFT). The left
and middle part of the gure show the uncus of the hippocampal formation and the anterior part of the gyrus
parahippocampalis. The distribution pattern and the severity of the lesions permit distinction of six NFT stages. The
rst two stages (I and II) do not yet show clinical symptoms. Stage III is associated with initial cognitive decits which
establish the diagnosis. The severe stages V and VI are associated with the full-blown clinical picture of Alzheimer’s
disease. The arrows mark key neuropathologic features typical for the different stages. The right part of the gure shows
the progression of Alzheimer’s disease-related lesions in a right hemisphere (seen from medial)(acc. to Braak et al.
20
).
    





 
      
     
Figure 2. Frequency of stages (I through VI) according severity of neurobrillary tangles (NFT) in brain samples
depending on age (n=3261)
Frequency of stages of Alzheimer-related lesions in different age categories: the diagram represents a total of 3261
autopsy cases. White columns represent cases without neurobrillary tangles (NFT). Pale-grey sections correspond to
stages I and II, dark-grey sections to stages III and IV, black sections to stages V and VI (also see Figure 1) (acc. to
Braak et al.
20
)
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hand, presence of the APOEe2 allele appears to reduce
affection risk [28]. A meta-analysis with 6000 patients
and 8000 controls showed that APOEe4/e4 homozy-
gotes have a relative risk of developing Alzheimer’s
disease of 14.9 compared with APOEe3/e3 homozy-
gotes, whereas combinations with APOEe2 are protec-
tive (Table I) [29].
Apolipoprotein E consists of 299 amino acids. At po-
sition 112 and 158, different amino acids occur: Apoli-
poprotein E2 contains 2 cysteines, apolipoprotein E3
contains 1 cysteine and 1 arginine, and apolipoprotein
E4 contains 2 arginines [23]. In contrast to arginine,
cysteine contains one sulfhydryl group (SH), at which
metals may bind, especially chemically bivalent metals
(e.g. lead, mercury, copper, zinc). Therefore, some vari-
ants of apolipoprotein E, namely those showing cyste-
ine rests (i.e. apolipoprotein E2 and E3), could bind
and detoxify heavy metals in the nerve cell and liquor,
while others (apolipoprotein E4) cannot [30].
Recent observations may conrm this assumption.
529 individuals who had been in contact with lead 16
years ago, were tested neuropsychologically, and lead
content in bones, as well as APOE-type was exam-
ined. Persons having at least one APOEe4 allele had
poorer test results than those with the same lead con-
tent but without the APOEe4 allele [31]. In a group
displaying symptoms from dental amalgam, 400 par-
ticipants, as opposed to 426 healthy control, had signif-
icantly more frequently the APOEe4 allele and less of-
ten the “protective” APOE constellations (APOEe2/e2
and APOEe2/e3) [32].
It should be noted, however, that presence of the
APOEe4 allele is not a necessary condition for the de-
velopment of Alzheimer’s disease. In over 50% of the
patients with Alzheimer’s disease, no APOEe4 allele
can be found, and one study was able to demonstrate
that 85% of individuals older than 80 years with an
APOEe4/e4 status did not suffer from cognitive im-
pairments [33]. African populations show a frequency
of APOEe4 allele of up to 40% (Europe 15%) but are
nonetheless affected to a lower degree than popula-
tions of Western industrial countries [34]; whether
this is due to less efcient diagnostic facilities or a true
difference remains to be seen. Conversely, Afro-Ameri-
cans show a signicantly increased risk of Alzheimer’s
disease than Caucasians [35].
MERCURY AND ALZHEIMERS DISEASE
Major human sources of mercury include sh con-
sumption [36, 37], dental amalgams [38} and vaccines
[36]. Regular sh consumption and intake of Omega-3-
fatty acids reduces the risk of developing Alzheimer’s
disease [35,39–42]. Selenium, which is found in sh, is
essential for the function of glutathione peroxidase re-
generating glutathione, which is a important antiox-
idant and detoxication enzyme. Furthermore, sele-
nium disposes mercury directly by tightly binding it
to mercury selenite, which is non-toxic. This is shown
by autopsy studies that assess the ratio of selenium
and mercury in several organs [43]. Methyl mercury
in sh, being bound to cysteine, appears to be by far
less toxic than hitherto assumed and is about 20 times
less toxic than methyl mercury chloride usually used
in experiments [44]. For that reasons, methyl-mercury
found in sh seems not to be involved in the pathogen-
esis of Alzheimer’s disease. Inorganic mercury (found
in dental amalgam) or ethyl-mercury (found in vac-
cines) may play a major role.
Experimental mercury effects and
Alzheimer’s disease
Inhibition and deterioration of neurotubulin
It was shown that both organic [45] and inorganic
mercury [46] cause those biochemical changes in tu-
buli structures which can be found in brains of patients
with Alzheimer’s disease [46]. In healthy human brain
tissue cultures, only mercury, even in lower concentra-
tions, but not aluminum, lead, zinc or iron were able
to inhibit binding to guanosine-tri-phosphate (GTP),
which is necessary for tubulin synthesis and thus for
neuron function [46]. Mercury inhibits ADP-riboly-
zation of tubulin and actin [47]. This process leads to
an inhibition of polymerization of tubulin to microtu-
bulin. As a result, neurobrillary tangles and senile
plaques are formed. Living rats exposed to mercury
vapor (250+300µg/m
3
) four times a day exhibit the
same molecular changes in their brain tissue as those
caused in human brain cell cultures after 14 days [30].
These changes are similar to those found post mortem
in brains of patients with Alzheimer’s disease [46, 48,
49]. Tubulin is assumed to be the most vulnerable pro-
tein for mercury, because administration of very low
doses of inorganic mercury do not inhibit other GTP-
or ATP-binding proteins [48, 48]. Tubulin has at least
14 sulfhydryle groups which bind mercury with high
afnity resulting in functional losses of tubulin and
creation of neurobrillary tangles. Since human nerve
cells do not regenerate, any blocking of neurotubulin is
particularly grave.
Creation of neurobrillary tangles and amyloid
Administration of very low doses of inorganic mer-
cury (0.18µM) has been shown to promote hyperphos-
phorylation of tau-protein in neuronal cell cultures
within 24 hours [50]. Hyperphosphorylation of tau is
the rst biochemical change to be observed in the de-
velopment of Alzheimer’s disease and results in forma-
tion of neurobrillary tangles and failure of nerve cell
functions. Administration of mercury to nerve cells
provokes also production of b-amyloid 40 and 42 [50].
Glutathione consumption and increased
oxidative stress
Within 30 minutes, low doses of inorganic mer-
cury reduce glutathione concentration by increas-
ing oxidative stress in a cell culture model. Addition
of melatonin is able to protect the nerve cells from the
damaging impact of mercury [50]. Melatonin is an an-
tioxidant and in addition has the ability to bind and
eliminate metals [51]. Although cobalt also has been
Joachim Mutter, Johannes Naumann, Catharina Sadaghiani, Rainer Schneider & Harald Walach
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reported to decrease glutathione concentration in neu-
ronal cell cultures and to release secretion of b-amy-
loid [52], it is not able to hyperphosphorylize tau-pro-
tein and built up neurobrillary tangles [53]. Changes
brought about by Cobalt were only observable above
concentrations 1700 higher than those of mercury
(300µM Cobalt versus 180 nM mercury) [52,53].
Neurodegeneration through mercury
Leong et al. [54] demonstrated axon degenera-
tion and formation of neurobrillary tangles in ani-
mal neuronal cell cultures within minutes and with
lowest amounts of inorganic mercury (2 µl 100 nM in
2 ml neuronal cell culture nourishing solution). This
neurodegenerative effect was not demonstrable with
other metals like aluminum, lead, cadmium, or man-
ganese [54]. In neuronal stem cells, inorganic mer-
cury of 2 and 5 µg/ml impaired tubulin functions for 48
hours [55]. It caused apoptosis, the programmed cell
death of nerve cells, and induced expression of heat
shock proteins [55].
Comparison with mercury concentrations in
human brain tissues
Mercury load in the brain of patients with Alzheim-
er’s disease was specied at 20 and 178 ng/g [56–58].
This amounts to a molar mercury concentration of
0.1 to 0.89 µMol. In the above mentioned experimen-
tal studies on nerve cells, exclusive administration of
mercury of a nal concentration of 0.0001 µMol (2µl
0.1µMolar mercury in 2ml nourishing solution) re-
sulted in axon degeneration and creation of neuro-
brillary tangles [54]. Addition of 0.18 µMol mercury
lead to secretion of b-amyloid 40 and 42, to increased
oxidative stress and to hyperphosporylation of the tau
protein [50,52].
Increase of glutamate toxicity
It is assumed that toxicity of the excitatory neu-
rotransmitter glutamate plays a role in neuronal
death in neurodegenerative diseases [59]. Gluta-
mate is toxic when it accumulates and when protec-
tive mechanisms fail. One such protective mechanism
is the enzyme glutamine syntethase primarily found
in astrocytes [60]. Mercury inhibits re-uptake of glu-
tamate in the astrocytes and other cells of the ner-
vous system [61,62] resulting in extracellular accu-
mulation of glutamate. In addition, mercury and lead
inhibit the enzyme glutamine synthetase which con-
verts glutamate to nontoxic glutamine [63]. Inorganic
mercury (Hg
++
) appears to inhibit GS to a larger de-
gree than methyl mercury [64]. It has been shown that
glutamine synthetase is reduced in the brain of pa-
tients with Alzheimer’s disease [60,65], whereas the
concentration of glutamine synthetase in the liquor
is increased [66]. Glutamine synthetase concentration
in the liquor, stemming from enhanced degradation of
astrozytes having a high concentration of glutamine
synthetase, could thus have diagnostic relevance for
Alzheimer’s disease [66,67].
Enzyme inhibition
Creatininkinase (CS) is an enzyme crucial for en-
ergy production in all body cells. Its function is re-
duced in patients with Alzheimer’s disease [68]. Since
it possesses many sulfhydrid groups, similar to glu-
tamine synthetase and tubulin, mercury inhibits its
functions [18].
With respect to Alzheimer’s disease, protein kinase
plays an important role in the production of normal
amyloid. Whenever these are inhibited, the enzyme b-
secretase modulates the metabolisms of APP (Amyloid
Precursor Protein) in a way that b-amyloid is increas-
Table II. Overview of the effects of mercury found by in vitro studies and animal experiments
Effect References
Hyperphosphorylisation of the tau-protein [50]
Formation of neurobrillary tangles in nerve cells [54, 50]
Cessation of tubules function through impairment of nucleotides [30, 46, 47, 48, 49]
Increased production of amyloid ß-protein [50, 52]
Enhanced oxidative distress [50, 52]
Degeneration of nerve cells [54]
Reduction of the amount of glutathione (GSH) [50, 52]
Binding of Selenium and reduction of available selenium [44]
Table I. Alzheimer’s disease as a function of the APOE genotype
Relative Risk APOE Genotype Pct of US Population Diagnosis at Age Sulfhydryl-Groups (SH)
0.6 2/2 < 1 ? 4
0.6 2/3 11 > 90 3
1.0 3/3 60 80–90 2
2.6 2/4 5 80–90 2
3.2 3/ 4 21 70–80 1
14.9 4/4 2 < 70 0
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ingly produced [50]. Protein kinase C is inhibited by
mercury both in vitro and in the brain tissue [69,70].
Synergistic effects of other metals
The Alzheimer’s disease-typical neuronal changes
(hyperphosphorylization of tau-protein, occurrence of
neurobrillary tangles, b-amyloid, tubulin inhibition,
axon degeneration, increase of glutamine synthetase
in the liquor) found in nerve cells and animals may not
be caused by other metals (lead, cadmium, aluminum,
copper, zinc, iron, chrome, manganese), but other met-
als may potentize mercury effects by contributing to
oxidative stress [18, 46, 53, 54].
Experimental effects of estrogens
Estrogen is able to compensate the damaging effects
of mercury in a cell model, when it is concurrently ad-
ministered [52]. This could provide an explanation for
the ndings of some studies showing reduced risk of
developing Alzheimer’s disease with high dose estro-
gen replacement [52, 71–73], which, however, is not a
consistent nding [74].
Summary of experimental mercury effects
In lower doses, mercury has been shown to have
biochemical effects on nerve cells, both in in vitro and
in animal experiments, which are typical for Alzheim-
er’s disease (Table II):
Mercury in patients with Alzheimer’s
disease
Mercury in brains of patients with
Alzheimer’s disease
Ehmann et al. [56] examined 81 brain specimens
from 14 patients with Alzheimer’s disease and 147
specimens from 28 controls with the same age. Out of
17 target elements, the biggest differences were found
for mercury and brome levels in the cerebral brain tis-
sue of patients with Alzheimer’s disease (3.4 ± 3.7 ng/
g versus 17.5 ± 1.3ng/g, p < 0.05). In the gray mat-
ter, they found more mercury (patients with Alzheim-
er’s disease: 42.7ng/g versus 14.7ng/g, controls: 29.0
ng/g versus 20.5) [56]. In the nucleus basalis Meynert,
mercury concentration was four times higher in 14 pa-
tients with Alzheimer’s disease compared with 15 con-
trols [57]. Other elements were signicantly increased,
too (iron, sodium, and zinc) [57]. In tissue specimens
from temporal lobes of 10 patients with Alzheimer’s
disease and 12 controls, there were signicant in-
creases of mercury concentrations in the microsomes
of the brain cells and non-signicantly increased mer-
cury values in other brain fractions (temporal lobe, mi-
tochondria, and cell nuclei) [75]. The total mercury
content in the temporal lobes of the patients with Al-
zheimer’s disease was 176 ng/g, as compared to 69.6
ng/g of the controls [75].
In the pituitary, signicant differences were found
for mercury content between 43 patients with Al-
zheimer’s disease and 15 controls [76]. Other studies
found non-signicantly increased mercury values in
the olfactory region of the amygdale [77] and amygdala
and hippocampus, respectively [78], but non-signi-
cantly decreased mercury values in the cerebellum and
rhinencephalon [78]. Another study found no elevated
mercury levels in brains of patients with Alzheimer’s
disease compared to controls [79].
Saxe et al. [58] were unable to nd signicant mer-
cury increases in an autopsy study of specic brain re-
gions of 68 patients with Alzheimer’s disease (mer-
cury on average 20.3–61.1 ng/g depending on the area)
when compared to 33 controls with the same age (mer-
cury on average 30.1–88.9 ng/g). Also, there was nei-
ther a correlation between number and duration of
amalgam lling and mercury concentration in the Al-
zheimer’s disease group nor in the control group [58].
This is astonishing because other human autopsy
studies show such correlations [80–87]. Interestingly,
in patients unaffected by Alzheimer’s disease, mercury
concentration in the olfactory region was twice as high
as in controls (88.9 ng/g versus 41.7 g/ng) [58]. In sum,
autopsy studies examining mercury load in the brains
of patients with Alzheimer’s disease, although sugges-
tive, are not consistent. One potential confounding fac-
tor might be the loosely dened staging of patients
with Alzheimer’s disease when autopsied.
Mercury in living patients with
Alzheimer’s disease
Mercury blood concentration in 33 patients with Al-
zheimer’s disease was twice as high (2.64µg/l) as that of
45 depressed patients (1.20µg/l) and 65 patients with-
out psychiatric disorders (1.09µg/l) (p<0.0005) [88].
In the early form of Alzheimer’s disease (13 persons
younger than 65 years), difference was even higher
(3.32µg/l, p = 0.0002). Correlation with blood mer-
cury concentration and the amyloid-b-protein (Ab) in
the liquor cerebrospinalis was signicant (p = 0.0015).
These ndings were conrmed [89], yet disconrmed
[90]. The average mercury load in the urine of 9 pa-
tients with Alzheimer’s disease (2.96 ± 1.13 µg/l) as
compared to 9 controls (1.86 ± 0.9 µg/l) was not signif-
icantly different [90]. This obviously is a power prob-
lem, as the effect size of this difference (standardized
mean difference) is 1.1 and thus large.
Several studies measuring the nails and hair of pa-
tients with Alzheimer’s disease found less mercury in
the patients compared to controls [91,92]. This could
be attributable to the fact that nail and hair merely
reect a recent mercury exposure. Patients with Al-
zheimer’s disease would be less exposed to environ-
mental mercury than controls because they are accom-
modated in foster homes [92]. Mercury concentrations
in the blood may only be elevated when nerve cell dam-
age is greatest (presumably at intermediate stages),
suggesting a curvilinear association between Alzheim-
er’s disease and mercury excretion, a possibility that
researchers have eschewed so having normally sup-
posed and looked for a linear relationship.
Joachim Mutter, Johannes Naumann, Catharina Sadaghiani, Rainer Schneider & Harald Walach
336
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337
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
Dental condition and the risk of developing
Alzheimer’s disease
A recent analysis of 10,263 individuals from Can-
ada yielded a distinct association between dental con-
dition and the risk for Alzheimer’s disease. The fewer
the number of teeth the higher the risk [93]. The au-
thors took this as evidence for the fact that amalgam
llings are not causal for Alzheimer’s disease [93]. Al-
zheimer’s disease takes about 30–50 years to clinically
manifest itself [20]. Patients with fewer teeth previ-
ously had poorer dental conditions and had therefore
presumably been provided with mercury containing
amalgam over longer period. Thus, they are likely to
have been exposed to mercury-vapor in a vulnerable
phase and to a larger extent than persons still having
teeth in advanced years.
Metal chelation as potential therapy of
Alzheimer disease?
If mercury is involved in the genesis of Alzheimer’s
disease, preventive and possibly therapeutic strategies
may be developed provided neurodegeneration has not
progressed too much.
It has been suggested that aluminum and iron play
an important role in Alzheimer’s disease [94]. There-
fore, the chelator desferroxamine, which has the ca-
pacity to bind iron, aluminum and to a lesser degree
mercury was tested in clinical trials [95,96]. Recently,
clioquinole, formerly approved as an antibiotic in Ja-
pan, has been successfully applied in animal [97] and
clinical studies [98–100] to treat Alzheimer’s disease
due to its capacity as a chelating agent to bind copper
and zinc. Chelating agents, which bind copper and zinc
usually also have the capacity to bind mercury.
IMPLICATIONS
Converging ndings from experimental, epidemio-
logical, and clinical studies identify inorganic mercury
as one of the potential exogenous factors responsi-
ble for Alzheimer’s disease. The main source for in-
organic mercury in habitants of industrial developed
countries is dental amalgam [38, 101]. Other metals
and noxes might have synergistic effects with mercury.
Due to the complex relationships and restricted tech-
nical measurement equipment in some studies, indi-
vidual ndings appear contradictory and a lot remains
to be claried. This is a situation analogous to other
hotly debated areas, like the association of smoking
and cancer, or estrogen replacement and myocardial
infarction.
Obviously, denite knowledge about the causal role
of mercury in Alzheimer’s disease may only be derived
from large, long-term prospective epidemiological
studies examining occurrence of Alzheimer’s disease
in subjects exposed to the risk of mercury in amalgam
and other sources, compared with those at lower risk.
Since apolipoprotein E could constitute an important
protective or risk factor, it should be monitored in fu-
ture studies. Additionally, clinical studies with chelat-
ing agents measuring mercury excretion could give in-
direct evidence and would offer a therapeutic strategy
for Alzheimer’s disease at early stages. The ndings
reviewed here should have made plausible that the po-
tential association between mercury and Alzheimer’s
disease should be one of prime importance, since the
public health impact is enormous.
Acknowledgement
HW and RS are supported by the Samueli Institute.
JM received support from Foundation Landesbank
Baden-Württemberg, Natur und Umwelt, Stuttgart.
REFERENCES
1 Ernst RL, Hay JW. Economic research on Alzheimer disease: a
review of the Alzheimer. Dis Assoc Disord 1997; 11(Suppl 6):
135–45.
2 Helmuth L. Detangling Alzheimer’s disease. New insights into
the biological bases of the most common cause of dementia are
pointing to better diagnostics and possible therapeutics. Sci Ag-
ing Knowledge Environ 2003; 2003:oa2.
3 Brookmeyer R, Gray S. Methods for projecting the incidence and
prevalence of chronic diseases in aging populations: application
to Alzheimer’s. Stat Med 2000;19:1481–93.
4 Breteler MM, Claus JJ, van Duijn CM, Launer LJ, Hofman A. Epi-
demiology of Alzheimer’s. Epidemiol Rev 1992; 14:59–82.
5 Dickson DW. Neuropathology of Alzheimer’s disease and other
dementias. Clin Geriatr Med 2001; 17:209–28.
6 Wenk GL. Neuropathologic changes in Alzheimer’s disease. J Clin
Psychiatry 2003; 64:7–10.
7 Arendt Th. Neuronale Pathologie. In: Beyreuther K, Einhäupl KM,
Förstl H, Kurz A, eds. Demenzen. Stuttgart, Germany: Thieme
2002:106–17.
8 Braak H, Del Tredici K, Schultz C, Braak E. Vulnerability of select
neuronal types to Alzheimer’s disease. Ann N Y Acad Sci 2000;
924:53–61.
9 Sassin I, Schultz C, Thal DR, et al. Evolution of Alzheimer’s
disease-related cytoskeletal changes in the basal nucleus of
Meynert. Acta Neuropathol 2000; 100:259–69.
10 White AR, Huang X, Jobling MF, et al. Homocysteine potentiates
copper- and amyloid beta peptide-mediated toxicity in primary
neuronal cultures: possible risk factors in the Alzheimer’s-type
neurodegenerative pathways. J Neurochem 2001; 76:1509–20.
11 Buttereld DA. Amyloid beta-peptide (1-42)-induced oxidative
stress and neurotoxicity: implications for neurodegeneration in
Alzheimer’s disease brain. A review. Free Radic Res 2002; 36:
1307–13.
12 Jellinger KA. General aspects of neurodegeneration. J Neural
Transm Suppl 2003; 65:101–44.
13 Bush AI. The metallobiology of Alzheimer’s disease. Trends Neu-
rosci 2003; 26:207–14.
14 Bush AI. Copper, zinc, and the metallobiology of Alzheimer’s
disease. Alzheimer Dis Assoc Disord 2003; 17:147–50.
15 Hendrie HC, Osuntokun BO, Hall KS, et al. Prevalence of Alzheim-
er’s disease and dementia in two communities: Nigerian Africans
and African Americans. Am J Psychiatry 1995; 152:1485–92.
16 Grant WB. Dietary Links to Alzheimer’s Disease: 1999 Update. J
Alzheimer’s Dis 1999; 1:197–201.
17 Osuntokun BO, Hendrie HC, Ogunniyi AO, et al. Cross-cultural
studies in Alzheimer’s disease. Ethn Dis 1992; 2:352–7.
18 Haley B: The relationship of toxic effects of mercury to ex-
acerbation of the medical condition classied as Alzheimer’s
disease. 2002 [cited 2004, May 16]. Available from: URL: http:
//www.fda.gov/ohrms/dockets/dailys/02/Sep02/091602/
80027dd5.pdf.
19 Braak E, Grifng K, Arai K, Bohl J, Bratzke H, Braak H. Neuropa-
thology of Alzheimer’s disease: what is new since A. Alzheimer?
Alzheimer Disease: Mercury as pathogenetic factor and apolipoprotein E as a moderator
338
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
339
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
Eur Arch Psychiatry Clin Neurosci 1999; 249:14–22.
20 Braak H, Grifng K, Braak E. Neuroanatomy of Alzheimer’s dis-
ease. Alzheimer’s Res 1997; 3:235–47.
21 Dickson DW, Crystal HA, Mattiace LA, et al. Identication of
normal and pathological aging in prospectively studied nonde-
mented elderly humans. Neurobiol Aging 1992; 13:179–89.
22 Braak H, Braak E, Yilmazer D, Bohl J. Age-related changes of the
human cerebral cortex. In: Cruz-Sanchez FF, Ravid R, Cuzner ML,
eds. Neuropathological diagnostic criteria for brain banking.
Amsterdam, Biomedical Health Research IOS Press, 1995:14–9.
23 Mahley RW. Apolipoprotein E: cholesterol transport protein with
expanding role in cell biology. Science 1988; 240:622–30.
24 Harris FM, Tesseur I, Brecht WJ, et al. Astroglial regulation of
apolipoprotein E expression in neuronal cells. Implications for
Alzheimer’s disease. J Biol Chem 2004; 279:3862–8.
25 Neely MD, Montine TJ. CSF lipoproteins and Alzheimer’s disease.
J Nutr Health Aging 2002; 6:383–91.
26 Han X, Cheng H, Fryer JD, Fagan AM, Holtzman DM. Novel role for
apolipoprotein E in the central nervous system. Modulation of
sulfatide content. J Biol Chem 2003; 278:8043–51.
27 Pitas RE, Boyles JK, Lee SH, Hui D, Weisgraber KH. Lipoproteins
and their receptors in the central nervous system. Characteriza-
tion of the lipoproteins in cerebrospinal uid and identication
of apolipoprotein B,E(LDL) receptors in the brain. J Biol Chem
1987; 262:14352–60.
28 Strittmatter WJ, Roses Alzheimer’s disease. Apolipoprotein E and
Alzheimer’s disease. Annu Rev Neurosci 1996; 19:53–77.
29 Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and
ethnicity on the association between apolipoprotein E genotype
and Alzheimer disease. A meta-analysis. APOE and Alzheimer
Disease Meta Analysis Consortium. JAMA 1997; 278:1349–56.
30 Pendergrass JC, Haley BE, Vimy MJ, Wineld SA, Lorscheider FL.
Mercury vapor inhalation inhibits binding of GTP to tubulin in
rat brain: similarity to a molecular lesion in Alzheimer diseased
brain. Neurotoxicology 1997; 18:315–24.
31 Stewart WF, Schwartz BS, Simon D, Kelsey K, Todd AC. APOE
genotype, past adult lead exposure, and neurobehavioral func-
tion. Environ Health Perspect 2002; 110:501–5.
32 Godfrey ME, Wojcik DP, Krone CA. Apolipoprotein E genotyping as
a potential biomarker for mercury neurotoxicity. J Alzheimers Dis
2003; 5:189–95.
33 Hyman BT, Gomez-Isla T, Briggs M, et al. Apolipoprotein E and
cognitive change in an elderly population. Ann Neurol 1996; 40:
55–66.
34 Corbo RM, Scacchi R. Apolipoprotein E (APOE) allele distribution
in the world. Is APOE*4 a ‘thrifty’ allele? Ann Hum Genet 1999;
63(Pt 4):301–10.
35 Grant WB. Dietary Links to Alzheimer’s Disease. Alzheimer’s Dis-
ease Review 1997;2:42–55.
36 Clarkson TW, Magos L, Myers GJ. The toxicology of mercury cur-
rent exposures and clinical manifestations. N Engl J Med 2003;
349:1731–7.
37 Schober SE, Sinks TH, Jones RL, et al. Blood mercury levels in
US children and women of childbearing age, 1999–2000. JAMA
2003; 289:1667–74.
38 Mutter J, Naumann J, Sadaghiani C, Walach H, Drasch G. Amal-
gam studies: Disregarding basic principles of mercury toxicity.
Int J Hyg Environ Health, in print 2004.
39 Grant WB, Campbell A, Itzhaki RF, Savory J. The signicance of
environmental factors in the etiology of Alzheimer’s disease. J
Alzheimers Dis 2002; 4:179–89.
40 Clarke R, Smith Alzheimer’s disease, Jobst KA, Refsum H, Sutton
L, Ueland PM. Folate, vitamin B12, and serum total homocyste-
ine levels in conrmed Alzheimer disease. Arch Neurol 1998; 55:
1449–55.
41 Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler
MM: Dietary fat intake and the risk of incident dementia in the
Rotterdam Study. Ann Neurol 1997; 42:776–82.
42 Morris MC, Evans DA, Bienias JL, et al. Consumption of sh and n-
3 fatty acids and risk of incident Alzheimer disease. Arch Neurol
2003; 60:940–6.
43 Drasch G, Mail der S, Schlosser C, Roider G. Content of non-mer-
cury-associated selenium in human tissues. Biol Trace Elem Res
2000; 77:219–30.
44 Harris HH, Pickering IJ, George GN. The chemical form of mercury
in sh. Science 2003; 301:1203.
45 Falconer MM, Vaillant A, Reuhl KR, Laferriere N, Brown: The mo-
lecular basis of microtubule stability in neurons. Neurotoxicol-
ogy 1994; 15:109–22.
46 Duhr EF, Pendergrass JC, Slevin JT, Haley BE. HgEDTA complex
inhibits GTP interactions with the E-site of brain beta-tubulin.
Toxicol Appl Pharmacol 1993; 122:273–280.
47 Palkiewicz P, Zwiers H, Lorscheider FL. ADP-ribosylation of brain
neuronal proteins is altered by in vitro and in vivo exposure to
inorganic mercury. J Neurochem 1994; 62:2049–52.
48 Pendergrass JC, Haley BE Mercury-EDTA Complex Specically
Blocks Brain-Tubulin-GTP Interactions: Similarity to Observa-
tions in Alzheimer’s Disease. In: Friberg LT, Schrauzer GN, eds.
Status Quo and Perspective of Amalgam and Other Dental Materi-
als. International Symposium Proceedings. Thieme, Stuttgart-
New-York, 1995:98–105.
49 Pendergrass JC, Haley BE: Inhibition of Brain Tubulin-Guanosine
5’-Triphosphate Interactions by Mercury: Similarity to Observa-
tions in Alzheimer’s Diseased Brain. In: Sigel H, Sigel A, eds.
Metal Ions in Biological Systems. V34. Marcel Dekker, New York
1996:461–78.
50 Olivieri G, Brack C, Muller-Spahn F et al. Mercury induces cell
cytotoxicity and oxidative stress and increases beta-amyloid se-
cretion and tau phosphorylation in SHSY5Y neuroblastoma cells.
J Neurochem 2000; 74:231–6.
51 Limson J, Nyokong T, Daya S. The interaction of melatonin and
its precursors with aluminium, cadmium, copper, iron, lead, and
zinc: an adsorptive voltammetric study. J Pineal Res 1998; 24:
15–21.
52 Olivieri G, Novakovic M, Savaskan E, et al. The effects of beta-
estradiol on SHSY5Y neuroblastoma cells during heavy metal
induced oxidative stress, neurotoxicity and beta-amyloid secre-
tion. Neuroscience 2002; 113:849–55.
53 Olivieri G, Hess C, Savaskan E, et al. Melatonin protects SHSY5Y
neuroblastoma cells from cobalt-induced oxidative stress, neu-
rotoxicity and increased beta-amyloid secretion. J Pineal Res
2001; 31:320–5.
54 Leong CC, Syed NI, Lorscheider FL. Retrograde degeneration of
neurite membrane structural integrity of nerve growth cones
following in vitro exposure to mercury. Neuroreport 2001; 12:
733–737.
55 Cedrola S, Guzzi G, Ferrari D et al. Inorganic mercury changes the
fate of murine CNS stem cells. FASEB J 2003; 17:869–71.
56 Ehmann WD, Markesbery WR, Alauddin M, Hossain TI, Brubaker
EH. Brain trace elements in Alzheimer’s disease. Neurotoxicology
1986; 7:195–206.
57 Thompson CM, Markesbery WR, Ehmann WD, Mao YX, Vance DE.
Regional brain trace-element studies in Alzheimer’s disease.
Neurotoxicology 1988; 9:1–7.
58 Saxe SR, Wekstein MW, Kryscio RJ, et al. Alzheimer’s disease,
dental amalgam and mercury. J Am Dent Assoc 1999; 130:
191–9.
59 Bleich S, Romer K, Wiltfang J, Kornhuber J. Glutamate and the
glutamate receptor system: a target for drug action. Int J Geriatr
Psychiatry 2003; 18:S33–40.
60 Robinson SR. Changes in the cellular distribution of glutamine
synthetase in Alzheimer’s disease. J Neurosci Res 2001; 66:
972–80.
61 Aschner M, Yao CP, Allen JW, Tan KH. Methylmercury alters gluta-
mate transport in astrocytes. Neurochem Int 2000; 37:199–206.
62 Brookes N. In vitro evidence for the role of glutamate in the CNS
toxicity of mercury. Toxicology 1992; 76:245–56.
63 Sierra EM, Tiffany-Castiglioni E. Reduction of glutamine syn-
thetase activity in astroglia exposed in culture to low levels of
inorganic lead. Toxicology 1991; 65:295–304.
64 Allen JW, Mutkus LA, Aschner M. Mercuric chloride, but not meth-
ylmercury, inhibits glutamine synthetase activity in primary
cultures of cortical astrocytes. Brain Res 2001; 891:148–57.
65 Buttereld DA, Hensley K, Cole P, et al. Oxidatively induced
structural alteration of glutamine synthetase assessed by analy-
sis of spin label incorporation kinetics: relevance to Alzheimer’s
Joachim Mutter, Johannes Naumann, Catharina Sadaghiani, Rainer Schneider & Harald Walach
338
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
339
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X www.nel.edu
disease. J Neurochem 1997; 68:2451–57.
66 Gunnersen D, Haley B. Detection of glutamine synthetase in the
cerebrospinal uid of Alzheimer diseased patients: a potential
diagnostic biochemical marker. Proc Natl Acad Sci USA 1992; 89:
11949–53.
67 Tumani H, Shen G, Peter JB, Bruck W. Glutamine synthetase in
cerebrospinal uid, serum, and brain: a diagnostic marker for
Alzheimer disease? Arch Neurol 1999; 56:1241–6.
68 David S, Shoemaker M, Haley BE. Abnormal properties of cre-
atine kinase in Alzheimer’s disease brain: correlation of reduced
enzyme activity and active site photolabeling with aberrant cy-
tosol-membrane partitioning. Brain Res Mol Brain Res 1998; 54:
276–87.
69 Matsuoka M, Wispriyono B, Iryo Y, Igisu H. Mercury chloride ac-
tivates c-Jun N-terminal kinase and induces c-jun expression in
LLC-PK1 cells. Toxicol Sci 2000; 53:361–8.
70 Rajanna B, Chetty CS, Rajanna S, Hall E, Fail S, Yallapragada PR.
Modulation of protein kinase C by heavy metals. Toxicol Lett
1995; 81:197–203.
71 Henderson VW. Oestrogens and dementia. Novartis Found Symp
2000; 230:254–65.
72 Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buck-
walter JG. Estrogen replacement therapy in older women. Com-
parisons between Alzheimer’s disease cases and nondemented
control subjects. Arch Neurol 1994; 51:896–900.
73 Paganini-Hill A, Henderson VW. Estrogen deciency and risk
of Alzheimer’s disease in women. Am J Epidemiol 1994; 140:
256–61.
72 Rapp SR, Espeland MA, Shumaker SA, et al. Effect of estrogen
plus progestin on global cognitive function in postmenopausal
women: the Women’s Health Initiative Memory Study: a random-
ized controlled trial. JAMA 2003;289:2663–72.
75 Wenstrup D, Ehmann WD, Markesbery WR. Trace element imbal-
ances in isolated subcellular fractions of Alzheimer’s disease.
Brain Res 1990; 533:125–31.
76 Cornett CR, Ehmann WD, Wekstein DR, Markesbery WR. Trace ele-
ments in Alzheimer’s disease pituitary glands. Biol Trace Elem
Res 1998; 62:107–14.
77 Samudralwar DL, Diprete CC, Ni BF, Ehmann WD, Markesbery WR.
Elemental imbalances in the olfactory pathway in Alzheimer’s
disease. J Neurol Sci 1995; 130:139–45.
78 Cornett CR, Markesbery WR, Ehmann WD. Imbalances of trace el-
ements related to oxidative damage in Alzheimer’s disease brain.
Neurotoxicology 1998; 19:339–45.
79 Fung YK, Meade AG, Rack EP, Blotcky AJ. Brain mercury in
neurodegenerative disorders. J Toxicol Clin Toxicol 1997; 35:
49–54.
80 Drasch G, Schupp I, Ho H, Reinke R, Roider G. Mercury burden
of human fetal and infant tissues. Eur J Pediatr 1994; 153:
607–10.
81 Drasch G, Schupp I, Riedl G, Günther G. Einuß von Amalgam-
füllungen auf die Quecksilberkonzentration in menschlichen
Organen. Dtsch Zahnärztl Z 1992; 47:490–6.
82 Guzzi G, Grandi M, Cattaneo C. Should amalgam llings be re-
moved? Lancet 2002; 360:2081.
83 Nylander M. Mercury in pituitary glands of dentists. Lancet
1986;1:442.
84 Nylander M, Friberg L, Lind B. Mercury concentrations in the
human brain and kidneys in relation to exposure from dental
amalgam llings. Swed Dent J 1987; 11:179–187.
85 Nylander M, Weiner J. Mercury and selenium concentrations and
their interrelations in organs from dental staff and the general
population. Br J Ind Med 1991; 48:729–34.
86 Eggleston DW, Nylander M. Correlation of dental amalgam with
mercury in brain tissue. J Prosthet Dent 1987; 58:704–7.
87 Weiner JA, Nylander M. The relationship between mercury con-
centration in human organs and different predictor variables. Sci
Total Environ 1993; 138:101–15.
88 Hock C, Drasch G, Golombowski S, et al. Increased blood mercury
levels in patients with Alzheimer’s disease. J Neural Transm
1998; 105:59–68.
89 Basun H, Forssell LG, Wetterberg L, Winblad B. Metals and trace
elements in plasma and cerebrospinal uid in normal aging
and Alzheimer’s disease. J Neural Transm [P-D Sect] 1991; 3:
231–58.
90 Fung YK, Meade AG, Rack EP, et al. Determination of blood
mercury concentrations in Alzheimer’s patients. J Toxicol Clin
Toxicol 1995; 33:243–7.
91 Vance DE, Ehmann WD, Markesbery WR. Trace element imbal-
ances in hair and nails of Alzheimer’s disease patients. Neuro-
toxicology 1988; 9:197–208.
92 Vance DE, Ehmann WD, Markesbery WR. A search for longitudinal
variations in trace element levels in nails of Alzheimer’s disease
patients. Biol Trace Elem Res 1990; 26–27:461–70.
93 Lund JP, Mojon P, Pho M, Feine JS. Alzheimer’s disease and eden-
tulism. Age Ageing 2003; 32:228–9.
94 Kruck TP. Aluminium Alzheimer’s link? Nature 1993; 363:119.
95 McLachlan DR, Smith WL, Kruck TP. Desferrioxamine and
Alzheimer’s disease: video home behavior assessment of clinical
course and measures of brain aluminum. Ther Drug Monit 1993;
15:602–7.
96 Crapper McLachlan DR, Dalton AJ, Kruck TP, et al. Intramuscular
desferrioxamine in patients with Alzheimer’s disease. Lancet
1991; 337:1304–8.
97 Cherny RA, Atwood CS, Xilinas ME, et al. Treatment with a cop-
per-zinc chelator markedly and rapidly inhibits beta-amyloid
accumulation in Alzheimer’s disease transgenic mice. Neuron
2001; 30:665–76.
98 Bush AI. Metal complexing agents as therapies for Alzheimer’s
disease. Neurobiol Aging 2002; 23:1031–8.
99 Finefrock AE, Bush AI, Doraiswamy PM. Current status of metals
as therapeutic targets in Alzheimer’s disease. J Am Geriatr Soc
2003; 51:1143–8.
100
Helmuth L. New therapies. New Alzheimer’s treatments that may
ease the mind. Science 2002; 297:1260–2.
101
Lorscheider FL, Vimy MJ, Summers AO. Mercury exposure from
“silver“ tooth llings: emerging evidence questions a traditional
dental paradigm. FASEB J 1995;9:504–8.
To cite this article:
Neuroendocrinol Lett 2004; 25(5):331–339
Alzheimer Disease: Mercury as pathogenetic factor and apolipoprotein E as a moderator
... Other diseases include HunterÀRussell syndrome, acrodynia, etc. (Nolan et al., 2003;Taki et al., 2012) [44,45]. Higher concentration of mercury is found in the blood of living patient and the brain of deceased patient of Alzheimer's disease (Mutter et al., 2004) [46]. ...
... Other diseases include HunterÀRussell syndrome, acrodynia, etc. (Nolan et al., 2003;Taki et al., 2012) [44,45]. Higher concentration of mercury is found in the blood of living patient and the brain of deceased patient of Alzheimer's disease (Mutter et al., 2004) [46]. ...
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... In SH-SY5Y cells, mercury also disturbed the clearance of Aβ plaques by suppressing the activity of neprilysin (Miguel et al., 2015). Mercury showed neural toxicity since APOE4 owned a weak combination with mercury (Mutter et al., 2004). Olivieri et al. (2010) reported that mercury stimulated the expression of Aβ and phosphorylation of tau. ...
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