Alzheimer Disease:

Mercury as pathogenetic factor and
apolipoprotein E as a moderator.Joachim Mutter*,Johannes Naumann*,Catharina Sadaghiani*,Copyright © Rainer Schneider*1 &Harald Walach*

Institute for Environmental Medicine and Hospital Epidemiology,University Hospital Freiburg,
GER MA NY.
1 Samueli Institute,European Office,Freiburg,GER MA NY.
Correspondence to:Joachim Mutter,MD
Institute for Environmental Medicine and Hospital Epidemiology
University Hospital Freiburg,
Hugstetter Str.55
79106 Freiburg,GER MA NY
PHONE:+49 761-270-5489
FA X:+49 761-270-5440
EMA I L :jmutter@iuk3.ukl.uni-freiburg.de
Submitted:July 26,2004 Accepted:August 4,2004
Key words:mercury;amalgam;Alzheimer's disease;neurotoxicity;
neurodegeneration;neurofibrillary 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 findings from epidemiological and demographical studies,the
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

INTRODUCT ION
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
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-
According to estimations,a total of 16
million individuals will be affected by the year 2050
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
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 inflammatory processes,which in turn
produce oxidative stress that accelerates neuron dam-
The neuro-degeneration starts with a hyperpho-
sporilization of the tau-protein due to as yet unknown
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-
The vital processes of the neuron are dis-
turbed and finally neuron death ensues.
The deposits cannot be adequately removed and
form neurofibrillary tangles which in turn acceler-
ate the inflammatory cascade and the positive feed-
back circle that leads to the progression of the dis-
Nerve cell degeneration produces damages in
the cholinergic projective systems of the basal prefron-
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
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-
Fiber mass consists of insoluble b -Amyloid-Pro-
Therefore,it cannot be removed by antibod-
Accretion of A b causes induction of inflammatory
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.
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 neurofibril-
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-
fibrillary 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,neurofibrillary 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 neurofibril-
lary tangles in their brains.In this cohort,35%have
highest numbers of histological detectable neurofibril-
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
neurofibrillary 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 difficult findings.
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 ].