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Alzheimer Disease: Mercury as pathogenic factor and apolipoprotein E as a moderator



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.
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172–780X
Neuroendocrinology Letters No.5 October Vol.25, 2004
Copyright © 2004 Neuroendocrinology Letters ISSN 0172–780X
Alzheimer Disease: Mercury as pathogenetic factor and
apolipoprotein E as a moderator
Joachim Mutter*, Johannes Naumann*, Catharina Sadaghiani*,
Rainer Schneider*
& Harald Walach*
*Institute for Environmental Medicine and Hospital Epidemiology, University Hospital Freiburg,
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
Submitted: July 26, 2004 Accepted: August 4, 2004
Key words:
mercury; amalgam; Alzheimer’s disease; neurotoxicity;
neurodegeneration; neurobrillary tangles; Apolipoprotein E;
Neuroendocrinol Lett 2004; 25(5):331–339 NEL250504R01 Copyright © Neuroendocrinology Letters
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.
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
ApoE Apolipoprotein E
AD Alzheimer’s disease
Hg mercury
GS Glutamine Synthetase
CS Creatininkinase
Sulfhydryl group SH
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.
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.
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
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
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.
    
 
      
     
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.
Alzheimer Disease: Mercury as pathogenetic factor and apolipoprotein E as a moderator
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
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].
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
) 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
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
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
Alzheimer Disease: Mercury as pathogenetic factor and apolipoprotein E as a moderator
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
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
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
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Neuroendocrinology Letters No.5 October Vol.25, 2004 Copyright © Neuroendocrinology Letters ISSN 0172780X
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.
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
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.
HW and RS are supported by the Samueli Institute.
JM received support from Foundation Landesbank
Baden-Württemberg, Natur und Umwelt, Stuttgart.
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To cite this article:
Neuroendocrinol Lett 2004; 25(5):331–339
Alzheimer Disease: Mercury as pathogenetic factor and apolipoprotein E as a moderator
... 28,32−35 Why APOE-ε4 carriers are more susceptible to both mercury intoxication and AD remains unclear. A number of possible explanations have been proposed, 28,36,37 including the possibility that the ApoE protein might be involved in the clearance of Hg and/or of amyloid-β (Aβ) peptides, 21,27,38 whose aggregation plays a central role in AD pathology. 39,40 Apolipoprotein E (ApoE) is a 299-residue-long (34 kDa) glycoprotein ( Figure 1) involved in lipid metabolism: it transports lipid-soluble vitamins and lipids such as cholesterol in the central nervous system, into the lymph system, and then into the blood. ...
... 22,42 As the cysteine −SH groups are capable of binding metal ions including Hg ions, 35,45−47 it has been speculated that the ApoE residues Cys112 and Cys158 might bind Hg ions, which subsequently could be transported out from the tissue. 6,21,22,28,46,48 ApoE4 would then not be able to perform this task very well as it has Arg instead of Cys residues at positions 112 and 158 ( Figure 1). Mercury would then accumulate in the tissues of APOE-ε4 individuals, which would aggravate the toxic effects, which possibly could include Hginduced neurodegeneration and AD. 6 To the best of our knowledge, no one has so far tested this hypothesis experimentally. ...
... These conclusions clearly contradict the previously suggested hypothesis that different binding affinities to mercury ions could explain why the APOE-ε4 gene is a risk factor in Hg intoxication but not the APOE-ε2 and APOE-ε3 genes. 6,21,22,28,46,48 However, it cannot be ruled out that other forms of mercury, such as organic methyl-Hg or ethyl-Hg, could display different binding properties to the different ApoE variants. Future studies might investigate the details of ApoE binding to other forms of Hg than the inorganic ions studied here. ...
Full-text available
Mercury intoxication typically produces more severe outcomes in people with the APOE-ε4 gene, which codes for the ApoE4 variant of apolipoprotein E, compared to individuals with the APOE-ε2 and APOE-ε3 genes. Why the APOE-ε4 allele is a risk factor in mercury exposure remains unknown. One proposed possibility is that the ApoE protein could be involved in clearing of heavy metals, where the ApoE4 protein might perform this task worse than the ApoE2 and ApoE3 variants. Here, we used fluorescence and circular dichroism spectroscopies to characterize the in vitro interactions of the three different ApoE variants with Hg(I) and Hg(II) ions. Hg(I) ions displayed weak binding to all ApoE variants and induced virtually no structural changes. Thus, Hg(I) ions appear to have no biologically relevant interactions with the ApoE protein. Hg(II) ions displayed stronger and very similar binding affinities for all three ApoE isoforms, with K D values of 4.6 μM for ApoE2, 4.9 μM for ApoE3, and 4.3 μM for ApoE4. Binding of Hg(II) ions also induced changes in ApoE superhelicity, that is, altered coil-coil interactions, which might modify the protein function. As these structural changes were most pronounced in the ApoE4 protein, they could be related to the APOE-ε4 gene being a risk factor in mercury toxicity.
... Dopaminergic neurons in the Substantia nigra have lengthy axons with microtubules made up of tubulin molecules 56 . Very low concentrations of inorganic mercury block tubulin production but not other ATP-or GTP-binding proteins [57][58] . Tubulin has at least 14 groups made up of sulfhydryl (SH-), and mercury has a strong affinity for sulfhydryl. ...
... The immune system, brain, kidney, heart, and lung can be damaged by exposure to low levels of mercury for an extended time [231,232]. Mercury is a highly poisoning metal that may cause genotoxic, immunotoxic, and neurotoxic effects through human exposure or food-chain accumulation resulting in several severe diseases, including Hunter-Russell syndrome and Alzheimer's disease [233,234]. Many high-quality techniques have been established for the detection of mercury, but they are time-consuming, high cost, and require bulky equipment [235,236]. ...
... Mercury can be consumed through either vaccine, fish consumption, or air pollution in urban areas; mercury binds to cysteine and methionine of tubulin protein and inhibits the guanosine triphosphate (GTP) binding and ADP ribolyzation essential for cell integrity and prevention of cell death (Palkiewicz et al. 1994;Kepp 2012). The exposure of mercury to CNS results in initiating the cascade of events, such as tau hyperphosphorylation and formation of NFTs (Mutter et al. 2004;Kepp 2012 sources include rice, vegetables, seafood, tobacco smoke, and exposure to other environmental pollutants. Hyperhomocysteinemia, usually experienced by smokers, is also an AD risk factor (Okumura and Tsukamoto 2011). ...
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The development of early non-invasive diagnosis methods and identification of novel biomarkers are necessary for managing Alzheimer’s disease (AD) and facilitating effective prognosis and treatment. AD has multi-factorial nature and involves complex molecular mechanism, which causes neuronal degeneration. The primary challenges in early AD detection include patient heterogeneity and lack of precise diagnosis at the preclinical stage. Several cerebrospinal fluid (CSF) and blood biomarkers have been proposed to show excellent diagnosis ability by identifying tau pathology and cerebral amyloid beta (Aβ) for AD. Intense research endeavors are being made to develop ultrasensitive detection techniques and find potent biomarkers for early AD diagnosis. To mitigate AD worldwide, understanding various CSF biomarkers, blood biomarkers, and techniques that can be used for early diagnosis is imperative. This review attempts to provide information regarding AD pathophysiology, genetic and non-genetic factors associated with AD, several potential blood and CSF biomarkers, like neurofilament light, neurogranin, Aβ, and tau, along with biomarkers under development for AD detection. Besides, numerous techniques, such as neuroimaging, spectroscopic techniques, biosensors, and neuroproteomics, which are being explored to aid early AD detection, have been discussed. The insights thus gained would help in finding potential biomarkers and suitable techniques for the accurate diagnosis of early AD before cognitive dysfunction. Graphical Abstract
... Fig. 2. represents the pathogenic mechanisms of AD caused by heavy metals, while the signaling pathways are shown in Fig. 3. The main pathogenic mechanisms of AD followed by exposure to heavy metals, include (i) oxidative DNA damage, which led to increase of β-amyloid levels and damage to the neural system [67,68], (ii) aggregation of amyloid beta peptides (AβPs) [69], and (iii) inhibition of the proper function of tubulin, which may be attributed to neuronal damage and consequently Alzheimer's disease [70]. ...
Beta-amyloid (Aβ) peptide is one of the main characteristic biomarkers of Alzheimer's disease (AD). Previous clinical investigations have proposed that unusual concentrations of this biomarker in cerebrospinal fluid, blood, and brain tissue are closely associated with the AD progression. Therefore, the critical point of early diagnosis, prevention, and treatment of AD is to monitor the levels of Aβ. In view of the potential of metal-organic frameworks (MOFs) for diagnosing and treating the AD, much attention has been focused in recent years. This review discusses the latest advances in the applications of MOFs for the early diagnosis of AD via fluorescence and electrochemiluminescence (ECL) detection of AD biomarkers, fluorescence detection of the main metal ions in the brain (Zn2+, Cu2+, Mn2+, Fe3+, and Al3+) in addition to magnetic resonance imaging (MRI) of the Aβ plaques. The current challenges and future strategies for translating the in vitro applications of MOFs into in vivo diagnosis of the AD are discussed.
... Both selenium and mercury have been linked to the development and pathogenesis of AD, however, the clinical relevance and connections have been conflicting [76,[86][87][88][89][90][91]. The many similarities between mercury toxicity and AD pathology have recently been emphasized by Siblerud et al. [92] and Bjørklund et al. [86]. ...
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Methylmercury (MeHg) is a well-known environmental contaminant, particularly harmful to the developing brain. The main human dietary exposure to MeHg occurs through seafood consumption. However, seafood also contains several nutrients, including selenium, which has been shown to interact with MeHg and potentially ameliorate its toxicity. The aim of this study was to investigate the combined effects of selenium (as selenomethionine; SeMet) and MeHg on mercury accumulation in tissues and the effects concomitant dietary exposure of these compounds exert on the hippocampal proteome and transcriptome in mice. Adolescent male BALB/c mice were exposed to SeMet and two different doses of MeHg through their diet for 11 weeks. Organs, including the brain, were sampled for mercury analyses. Hippocampi were collected and analyzed using proteomics and transcriptomics followed by multi-omics bioinformatics data analysis. The dietary presence of SeMet reduced the amount of mercury in several organs, including the brain. Proteomic and RNA-seq analyses showed that both protein and RNA expression patterns were inversely regulated in mice receiving SeMet together with MeHg compared to MeHg alone. Several pathways, proteins and RNA transcripts involved in conditions such as immune responses and inflammation, oxidative stress, cell plasticity and Alzheimer’s disease were affected inversely by SeMet and MeHg, indicating that SeMet can ameliorate several toxic effects of MeHg in mice.
... A genomewide association study in the UK Biobank has identified additional genes and has estimated the heritability of brain iron in deep grey matter structures to range between 0.08 and 0.58 [18]. Some studies indicate an interaction with the APOE gene, whose ε4 allele is the major risk factor for AD [19][20][21][22][23][24]. BMI, diabetes, AGING hypertension and smoking have been identified as lifestyle factors associated with brain iron [10,[25][26][27][28][29][30]. ...
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Background: While iron is essential for normal brain functioning, elevated concentrations are commonly found in neurodegenerative diseases and are associated with impaired cognition and neurological deficits. Currently, only little is known about genetic and environmental factors that influence brain iron concentrations. Methods: Heritability and bivariate heritability of regional brain iron concentrations, assessed by R2* relaxometry at 3 Tesla MRI, were estimated with variance components models in 130 middle-aged to elderly participants of the Austrian Stroke Prevention Family Study. Results: Heritability of R2* iron ranged from 0.46 to 0.82 in basal ganglia and from 0.65 to 0.76 in cortical lobes. Age and BMI explained up to 12% and 9% of the variance of R2* iron, while APOE ε4 carrier status, hypertension, diabetes, hypercholesterolemia, sex and smoking explained 5% or less. The genetic correlation of R2* iron among basal ganglionic nuclei and among cortical lobes ranged from 0.78 to 0.87 and from 0.65 to 0.97, respectively. R2* rates in basal ganglia and cortex were not genetically correlated. Conclusions: Regional brain iron concentrations are mainly driven by genetic factors while environmental factors contribute to a certain extent. Brain iron levels in the basal ganglia and cortex are controlled by distinct sets of genes.
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Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions, including Alzheimer's disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is the deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aβ aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aβ production, and these metals bind to Aβ peptides and modulate their aggregation. The possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aβ peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aβ peptides with affinities in the micromolar range, induce structural changes in Aβ monomers and oligomers, and inhibit Aβ fibrillization. This suggests a possible link between AD and U exposure, which could be further explored by cell, animal, and epidemiological studies. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation.
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Alzheimer's disease (AD) is a common type of dementia or decline in intellectual function first described by A. Alzheimer [1907]. Some of the characteristics include intraneuronal fibril-lary tangles, diffuse, neuritic and burned-out plaques and neu-ronal loss [Harman, 1995; Lippa et al., 1996]. Epidemiological studies have not identified causal factors for Alzheimer's disease as seen in a number of reviews [Heyman et al., van Duijn, 1996]. However, recently sev-eral orally ingested substances have been found to delay the onset or progression of AD: estrogen [Tang et al., 1996b]; non-steroidal antiinflammatory drugs (NSAIDs) [Stewart et al., 1997]; and vitamin E [Sano et al., 1997].
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From a morphological perspective, Alzheimer's disease (AD) is primarily a degenerative disorder of the neuronal cytoskeleton involving lipofuscin-laden cortical projection neurons with long, thin, and sparsely myelinated axons. The neocortical primary fields, relatively small in extent but functionally sophisticated, exhibit an early and brief myelination cycle, whereas the much more expansive but relatively simply organized association areas undergo a late and prolonged myelination process. The greater the degree of myelination and the less intense the pigmentation, the more resistant a given projection neuron may be to oxidative stress as well as to the development of AD-related neurofibrillary changes and vice versa. The neurofibrillary pathology commences from those cortical areas that are less completely myelinated and gradually progresses to the most functionally developed cortical fields that display the highest degree of myelination, thereby reflecting a hierarchy in the susceptibility of diverse cortical areas to the evolution of the AD-associated cytoskeletal pathology.
Alzheimer's disease involves multiple neuronal systems and results from changes in the neuronal cytoskeleton which develop in only a few susceptible types of nerve cell. Essential for neuropathological diagnosis is assessment of the presence of neurofibrillary tangles and neuropil threads. These alterations result from the gradual formation of abnormal tau protein and its aggregation to an argyrophilic fibrillary material. The destructive process focusses upon particular cortical areas and subcortical nuclei. It begins in predisposed cortical induction sites, then invades other portions of the cerebral cortex and specific sets of subcortical nuclei in a predictable sequence, with very little variation. In the course of the disease process, accompanying changes gradually appear, including the extracellular deposition of β-amyloid protein and the formation of neuritic plaques. The appearance of the first traces of abnormal neurofibrillary material intracellularly, at whatever age it occurs, signals the beginning of the degenerative process that continues inexorably until death. An extended period of time elapses between the beginning of histologically verifiable lesions and the appearance of initial clinical symptoms. But once initiated, the destructive process progresses immutably, and neither remission nor recovery is observed.
The authors explored the possibility that estrogen loss associated with menopause may contribute to the development of Alzheimer's disease by using a case-control study nested within a prospective cohort study. The Leisure World Cohort includes 8,877 female residents of Leisure World Laguna Hills, a retirement community in southern California, who were first mailed a health survey in 1981. From the 2,529 female cohort members who died between 1981 and 1992, the authors identified 138 with Alzheimer's disease or other dementia diagnoses likely to represent Alzheimer's disease (senile dementia, dementia, or senility) mentioned on the death certificate. Four controls were individually matched by birth date (+/- 1 year) and death date (+1 year) to each case. The risk of Alzheimer's disease and related dementia was less in estrogen users relative to nonusers (odds ratio = 0.69, 95 percent confidence interval 0.46-1.03). The risk decreased significantly with increasing estrogen dose and with increasing duration of estrogen use. Risk was also associated with variables related to endogenous estrogen levels; it increased with increasing age at menarche and (although not statistically significant) decreased with increasing weight. This study suggests that the increased incidence of Alzheimer's disease in older women may be due to estrogen deficiency and that estrogen replacement therapy may be useful for preventing or delaying the onset of this dementia.
The release of both Aβ 1-40 and Aβ 1-42 into the culture medium was increased by exposure of SHSY5Y cells to mercury. Melatonin preincubation resulted in a significant decrease in Aβ release. The mercury-induced increase in Aβ release may be caused through mercury’s deleterious action on essential kinase enzymes involved in the α-secretase pathway of APP metabolism. The result could be that cells are pushed toward the β-secretase pathway of APP metabolism, resulting in an increase in Aβ release. Mercury has previously been shown to be a potent inhibitor of enzymes, especially those containing sulfhydryl groups (Edstrom and Mattsson, 1976). Protein kinase C activity in vitro and in brain tissue is markedly reduced in a concentration-dependent manner by mercury (Rajanna et al., 1995). Phorbol ester binding to protein kinase C is also inhibited by micromolar concentrations of mercury (Rajanna et al., 1995). It is thus possible that increased levels of mercury reduce protein kinase C-mediated α-secretase activity with the consequence of increased Aβ formation because protein kinase C mediates activation of the α-secretase pathway. Mercury induces both Aβ production and oxidative stress; thus, the chelation of mercury by melatonin could shift the APP metabolism back toward the α-secretase pathway, reducing Aβ production and the concomitant oxidative stress-inducing effects of mercury and Aβ. Aβ-Fibrillogenesis is also inhibited by melatonin, thereby potentially reducing the toxic buildup of Aβ 1-40 and Aβ 1-42 fibrils (Pappolla et al., 1998). Furthermore, melatonin has been shown to reduce the release of soluble APP from cells in culture and to reduce the levels of APP mRNA and other housekeeping protein mRNAs (Song and Lahiri, 1997). These data suggest that melatonin may be involved in metabolic mechanisms regulating APP and other essential cellular protein production, over and above its antioxidant capacity.