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Aluminum and Alzheimer's Disease: After a Century of Controversy, Is there a Plausible Link?

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The brain is a highly compartmentalized organ exceptionally susceptible to accumulation of metabolic errors. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of the elderly and is characterized by regional specificity of neural aberrations associated with higher cognitive functions. Aluminum (Al) is the most abundant neurotoxic metal on earth, widely bioavailable to humans and repeatedly shown to accumulate in AD-susceptible neuronal foci. In spite of this, the role of Al in AD has been heavily disputed based on the following claims: 1) bioavailable Al cannot enter the brain in sufficient amounts to cause damage, 2) excess Al is efficiently excreted from the body, and 3) Al accumulation in neurons is a consequence rather than a cause of neuronal loss. Research, however, reveals that: 1) very small amounts of Al are needed to produce neurotoxicity and this criterion is satisfied through dietary Al intake, 2) Al sequesters different transport mechanisms to actively traverse brain barriers, 3) incremental acquisition of small amounts of Al over a lifetime favors its selective accumulation in brain tissues, and 4) since 1911, experimental evidence has repeatedly demonstrated that chronic Al intoxication reproduces neuropathological hallmarks of AD. Misconceptions about Al bioavailability may have misled scientists regarding the significance of Al in the pathogenesis of AD. The hypothesis that Al significantly contributes to AD is built upon very solid experimental evidence and should not be dismissed. Immediate steps should be taken to lessen human exposure to Al, which may be the single most aggravating and avoidable factor related to AD.
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Journal of Alzheimer’s Disease 23 (2011) 567–598
DOI 10.3233/JAD-2010-101494
IOS Press
567
Review
Aluminum and Alzheimer’s Disease:
After a Century of Controversy,
Is there a Plausible Link?
Lucija Tomljenovic
Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences,
University of British Columbia, Vancouver, BC, Canada
Handling Associate Editor: Christopher Exley
Accepted 12 November 2010
Abstract. The brain is a highly compartmentalized organ exceptionally susceptible to accumulation of metabolic errors.
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease of the elderly and is characterized by regional
specificity of neural aberrations associated with higher cognitive functions. Aluminum (Al) is the most abundant neurotoxic
metal on earth, widely bioavailable to humans and repeatedly shown to accumulate in AD-susceptible neuronal foci. In spite of
this, the role of Al in AD has been heavily disputed based on the following claims: 1) bioavailable Al cannot enter the brain in
sufficient amounts to cause damage, 2) excess Al is efficiently excreted from the body, and 3) Al accumulation in neurons is a
consequence rather than a cause of neuronal loss. Research, however, reveals that: 1) very small amounts of Al are needed to
produce neurotoxicity and this criterion is satisfied through dietary Al intake, 2) Al sequesters different transport mechanisms
to actively traverse brain barriers, 3) incremental acquisition of small amounts of Al over a lifetime favors its selective accu-
mulation in brain tissues, and 4) since 1911, experimental evidence has repeatedly demonstrated that chronic Al intoxication
reproduces neuropathological hallmarks of AD. Misconceptions about Al bioavailability may have misled scientists regarding
the significance of Al in the pathogenesis of AD. The hypothesis that Al significantly contributes to AD is built upon very solid
experimental evidence and should not be dismissed. Immediate steps should be taken to lessen human exposure to Al, which
may be the single most aggravating and avoidable factor related to AD.
Keywords: Aging, aluminum, Alzheimer’s disease, amyloidosis, bioavailability, brain compartmentalization, cholinergic dys-
function, G-proteins, neurofibrillary tangles, neurotoxicity
INTRODUCTION
Alzheimer’s disease (AD) is a progressive form of
dementia of the elderly and the most prevalent neurode-
generative disease in the world [1]. It is characterized
by regional specificity of neural aberrations associated
with higher cognitive functions in the hippocampus
Correspondence to: Lucija Tomljenovic, PhD, University of
British Columbia 828 W, 10th Ave, Vancouver, BC V5Z
1L8, Canada. Tel.: +1 604 875 4111 (68373); E-mail:
lucijat77@gmail.com.
and neocortex [2–9]. Notably, such compartmentalized
distribution of neural abnormalities is a main feature by
which AD is distinguished from other forms of demen-
tia, such as Huntington’s, Parkinson’s, and Wilson’s
diseases, which primarily involve neurological deficits
affecting brainstem nuclei function [10]. Since its ini-
tial report in 1906, AD has reached global proportions
and currently, it is one of the most burdensome and dis-
abling health problems, affecting 24.3 million people
[11]. More than 4.5 million new cases are diagnosed
each year and it is predicted that by 2040 there will be
ISSN 1387-2877/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved
568 L. Tomljenovic / Aluminum and Alzheimer’s Disease
81.1 million people with AD [11]. A very small per-
centage of AD cases is inherited (familial AD, early
onset of symptoms, <65 years), whilst >95% are idio-
pathic (late onset, >65 years) [1, 12, 13], and although
several causative agents have been proposed, none is
unambiguously proved nor ruled out [1, 3, 12, 14–20].
Depositions of amyloid -protein precursor
(APP)-derived amyloid-(A) fibrils, which form
extracellular senile plaques (Fig. 1), and aggregates of
hyperphosphorylated microtubule-associated protein
(MAP) tau, which combines to form paired helical
filaments (PHFs) within neurons (Fig. 2 [1, 12, 14]),
are principal histopathological markers of AD [1,
12, 14]. However, it is not clear what triggers senile
plaques and neurofibrillary tangles (NFT) formation
in the absence of predisposing genetic susceptibilities.
Furthermore, none of the alternative hypotheses that
have been suggested thus far, including: 1) oxidative
stress [17, 21], 2) dysregulation of calcium [12, 22,
23] and iron homeostasis [24–27], 3) deficits in micro-
tubules (MTs [20]), 4) deficits in neurotransmission
and G-protein-coupled receptor (GPCR) signaling
[3–5, 8, 28], and 5) upregulation of neuroinflammatory
signaling [16, 29], are able to explain the regional
A
B
Fig. 1. Domain structure and processing of the APP. Panel A depicts the overall structure and cleaving sites for -, - and -secretases. APP
is a type 1 trans-membrane protein that undergoes differential processing by two mutually exclusive pathways. Cleavage by -secretase yields
a neuroprotective soluble s-APP and precludes the formation of the amyloidogenic neurotoxic A1-40/1-42 species which are produced by
the sequential cleavage of - and -secretase. There are several APP isoforms: APP751 and APP770 are glial-specific, while APP695 is the
predominant neuronal isoform [12]. Panel B shows two distinct mechanisms by which PLC regulates APP processing: PKC-dependent and
Ca2+ dependent/PKC-independent (adapted from Buxbaum et al. [22]). Both pathways favor the formation of the neuroprotective s-APP at
the expense of the amyloidogenic Aspecies. Al promotes amyloidosis as it antagonizes the neuroprotective s-APP pathway, by inhibiting
agonist-stimulated PIP2hydrolysis by PLC and the formation of second messengers DAG and IP3(for further details see Fig. 2).
L. Tomljenovic / Aluminum and Alzheimer’s Disease 569
Fig. 2. Schematic illustration of 1) phospholipase C (PLC)/inositol 1,4,5-trisphosphate (IP3) and 2) adenylate cyclase (AC)/cyclic AMP (cAMP)
pathways. 1) Agonist (ACh) stimulation of cholinergic muscarinic receptors (MR) promotes GDP to GTP exchange and activation of receptor-
coupled Gq-proteins which activate PLC. Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by activated PLC yields two important
signaling molecules: IP3and diacylglycerol (DAG). IP3stimulates release of Ca2+ from the ER and the mitochondria, and DAG, in concert
with Ca2+, activates protein kinase C (PKC). Ca2+ and PKC work by two separate mechanisms to stimulate the non-amyloidogenic pathway
of APP processing by -secretase, which results in production of the neuroprotective soluble APP (s-APP). PKC promotes the budding
of APP-containing secretory vesicles from the trans-Golgi network (TGN) and potentially targets -secretase at the plasma membrane. Ca2+
activates calmodulin (CaM) which regulates the activityof the Ca2+ /Mg2+-ATPases responsible for extrusionof cytosolic Ca2+ . 2) AC is activated
by adrenergic receptor stimulation (AR) and consequent activation of AR-coupled Gs-protein via GDP to GTP exchange. Activated AC catalyzes
ATP to form the second messenger cAMP which then activates protein kinase A (PKA). PKA phosphorylates microtubule-associated protein
(MAP) tau on PKA-dependent serine residues. Hyperphosphorylated tau dissociates from the MTs and assembles into paired helical filament
(PHF)-structures, main constituents of neurofibrillary tangles (NFT). Note that MAP tau has multiple phosphorylation sites but PKA-dependent
serine phosphorylation is associated with increased formation of NFT in AD [225]. Al interferes with the PLC/IP3and AC/cAMP pathways in
a biphasic manner, by negative and positive modulations (indicated and respectively), and at multiple levels. By impairing MRstimulated
PIP2hydrolysis Al may promote both amyloidosis and cholinergic dysfunction. Note that acetylcholine (ACh) is a central neurotransmitter
critical for higher cognitive functions and a classical activator of MRreceptors. Deficits in cholinergic signaling are a hallmark of AD and are
reciprocated by Al. Conversely, by increasing cAMP, Al may induce the formation of NFTs.
specificity of neuronal degeneration, nor account for
the subtle and persistent changes which over time
result in progressive neural deterioration. Nor can
these factors encompass the diversity of histological
and molecular abnormalities observed in AD. While
it is irrefutable that all of the aforementioned may be
contributing events in AD, they cannot be instigated in
the absence of either genetic predispositions or envi-
ronmental triggers. Moreover, identical twin studies
show that in 60% of cases, AD affects only one twin
(the rate is similar for both monozygotic and dizygotic
twins [30]), thus further underscoring the importance
of environmental factors in the etiology of AD. Out
of all bioavailable factors considered, aluminum (Al)
is the only one that has been experimentally shown to
trigger all major histopathological events associated
with AD, at multiple levels (Table 1). It is also the
most controversial proposed instigator [15, 31–36].
570 L. Tomljenovic / Aluminum and Alzheimer’s Disease
Table 1
Al’s neurotoxic effects related to AD
Effects on memory, cognition and psychomotor control
Significantly decreases cognitive and psychomotor performance in humans and animals [10, 38, 39, 46, 48, 61, 63, 70, 87, 98, 165, 169,
170, 246, 248–253]
Impairs visuo-motor coordination, long-term memory, and increases sensitivity to flicker in humans and rats [169, 170]
Impairs memory and hippocampal long-term potentiation (LTP) in rats and rabbits in vivo (electrophysiological model of synaptic
plasticity and learning [150, 254])
Effects on neurotransmission and synaptic activity
Depresses the levels and activity of key neurotransmitters known to decline in AD in vivo: acetylcholine, serotonin, norepinephrine,
dopamine and glutamate [178, 255]
Reproduces hallmark cholinergic deficits observed in AD patients [3, 159, 160] by impairing the activity of cholinergic synthetic and
transport enzymes:
impairs acetylcholinesterase activity [256–258]
reduces neural choline acetyltransferase [158–160, 255]
inhibits choline transport in rat brain [159, 259] and in synaptosomes from cortex and hippocampus [219]
attenuates acetylcholine levels in rabbit hippocampus and concomitantly induces a learning deficit [63]
may cause acetylcholine deficit by acting upon muscarinic receptors and potentiating the negative feedback controlling acetylcholine
release into the synaptic cleft [6]
Inhibits neuronal glutamate-nitric oxide (NO)-cyclic GMP (cGMP) pathway necessary for LTP [260]
Damages dendrites and synapses [2, 70, 165, 261]
Impairs the activity of key synaptosomal enzymes dependent on Na-K, Mg2+ and Ca2+ [262]
Inhibits glutamate, GABA and serotonin uptake into synaptosomes [64, 263]
Impairs neurotransmission by disrupting post-receptor signal transduction mediated by the two principal G-protein regulated pathways:
PLC and AC (see Effects on G-proteins and Ca2+ homeostasis)
Inhibits dihydropteridine reductase, essential for the maintenance of tetrahydrobiopterin (BH4), a cofactor important in the synthesis and
regulation of neurotransmitters [264]
Impairs ATP-mediated regulation of ionotropic and metabotropic receptors-cholinergic, glutamatergic and GABAergic [6]
Interferes with receptor desensitization by increasing the stability of the metal-ATP receptor complex and causes prolonged receptor
activity (by replacing Mg2+ from the metal site) [6]
Effects on G-proteins and Ca2+ homeostasis
Alters IP and cAMP signaling cascades by interfering with G-proteins (as AlF), second messengers and second messenger/Ca2+ targets
[6, 77–79, 147, 167, 219, 265, 266]:
potentiates agonist-stimulated cAMP production following chronic oral exposure in rats, by inhibiting the GTPase activity of the
stimulatory G protein (Gs), leading to prolonged activation of Gsafter receptor stimulation and increased cyclic AMP production
by AC [167]
increases cAMP levels by 30–70% in brains of adult and weanling rats [167]
inhibits muscarinic, adrenergic and metabotropic receptor-stimulated IP3accumulation by inhibiting Gq-dependent hydrolysis of PIP2
by PLC [147, 219, 265, 266]
decreases IP3in the hippocampus in rats following chronic oral administration [167]
inhibits PKC [147, 265, 267]
blocks the fast phase of voltage-dependent Ca2+ influx into synaptosomes [268]
binds to CaM and interferes with numerous CaM-dependent phosphorylation/dephosphorylation reactions [146, 151, 269]
impairs Ca2+/CaM dependent LTP [150, 260]
May cause a prolonged elevation in intracellular Ca2+ levels by:
interfering with desensitization of the N-methyl D-aspartate (NMDA) receptor channel [6]
delaying the closure of voltage-dependent Ca2+ channels [6] and
blocking CaM-dependent Ca2+/Mg2+ -ATPase responsible for extrusion of excess intracellular Ca2+ [6, 148, 150]
Elicits a Ca2+-dependent excitotoxic cascade by frequent stimulation of the NMDA receptor which may result in:
persistent further activation of NMDA receptor by endogenous glutamate and exacerbation of glutamate excitotoxicity [50, 137, 270]
mitochondrial and ER Ca2+ store overload [6]
compromised neuronal energy levels [271]
erosion of synaptic plasticity [6]
increased susceptibility to apoptosis and accelerated neuronal loss [6, 50, 271]
Perturbs neuronal Ca2+ homeostasis and inhibits mitochondrial respiration in a complex with amyloidogenic Apeptide in a triple
transgenic mouse model of AD [271]
Metabolic and inflammatory effects
Inhibits utilization of glucose in the brain [146, 219]
Inhibits hexokinase and G6PD [19, 146, 154]
Reduces glucose uptake by cortical synaptosomes [272]
Alters Fe2+/Fe3+ homeostasis [19, 152, 205] and potentiates oxidative damage via Fenton chemistry [19, 137, 209, 211, 212]
L. Tomljenovic / Aluminum and Alzheimer’s Disease 571
Table 1
(Continued)
Alters membrane properties by:
decreasing the content of acidic phospholipid classes: phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidic acid (PA)
in rat brain myelin by 70% [216]
inducing the clustering of negatively charged phospholipids, thereby promoting phase separation, membrane rigidification and
facilitating brain-specific LPO [212]
Increases the permeability of the BBB by:
increasing the rate of trans-membrane diffusion [163] and
selectively changing saturable transport systems [27, 68, 163, 175]
Facilitates glutamate transport across the BBB and potentiates glutamate excitotoxicity [50, 133–135, 137]
Decreases antioxidant activity of SOD and catalase in the brain [164]
Increases cerebellar levels of nitric oxide synthase (NOS) [232]
Augments specific neuro-inflammatory and pro-apoptotic cascades by inducing transcription from a subset of HIF-1 and NF-B–
dependent promoters (APP, IL-1precursor, cPLA2, COX-2 and DAXX [70, 209, 237])
Activates microglia, exacerbates inflammation and promotes degeneration of motor neurons [87, 273]
Nuclear effects
Binds to phosphonucleotides and increases the stability of DNA [236]
Binds to linker histones, increases chromatin compaction, depresses transcription [65, 157, 174, 182–185]
Inhibits RNA polymerase activity [155–157]
Reduces the expression of the key cytoskeletal proteins -tubulin and -actin [155, 274]
Downregulates the expression of the light chain of the neuron-specific neurofilament (NFL) gene in 86% of surviving neurons in the
superior temporal gyrus of AD patients [184]
Up-regulates well known AD-related genes: amyloid precursor-like protein (APLP)-1 and APLP-2, tau and APP, in human
neuroblastoma cells when complexed with A, to a larger extent than other A-metal complexes (A-Zn, A-Cu and A-Fe) [14]
Up-regulates HIF-1 and NF-B – dependent gene expression (see Metabolic and inflammatory effects)
Effects on MTs, cytoskeleton and NFT formation
Induces neurofibrillary degeneration in basal forebrain cholinergic neurons [43], cortical and hippocampal neurons [43, 49, 59, 220, 253,
255] and accumulates in NFT-bearing neurons [42, 46, 47, 275]
Causes neurite damage and synapse loss in hippocampal and cortical pyramidal neurons by disabling their capacity for MT assembly [2, 70]
Directly alters MT assembly by interfering with magnesium and GTP-dependent MT-polymerization mechanisms. Actively displaces
magnesium from magnesium-binding sites on tubulin and promotes tubulin polymerization [147, 149, 276]
Decreases the sensitivity of MTs to calcium-induced depolymerisation and effectively disables the regulatory circuits that are set to
maintain the sensitive dynamics between polymerization and depolymerisation cycles of tubulin, and ultimately, impairs MT assembly
[20, 149]
Inhibits axonal and dendritic transport mechanisms by depleting MTs [10]
Induces cAMP-dependent protein kinase phosphorylation of MAPs and NFs in rats following chronic oral exposure [167] and enhances the
formation of insoluble NF aggregates [250, 274, 277]. Al-induced hyperphosphorylated NFs are resistant to dephosphorylation and
degradation by calcium-dependent proteases (calpain) [277]
Promotes highly specific non-enzymatic phosphorylation of tau in vitro by catalysing a covalent transfer of the entire triphosphate group
from ATP to tau via O-linkage (cAMP-dependent protein kinase phosphorylation sites [225]), at concentrations similar to those reported
in AD brains [162, 227]
Induces tau phosphorylation and motor neuron degeneration in vivo (as a vaccine adjuvant [87])
Facilitates cross-linking of hyperphosphorylated tau in PHFs, stabilizes PHFs and increases their resistance to proteolysis [45, 278, 279]
Inhibits dephosphorylation of tau in synaptosomal cytosol fractions [280]
Decreases levels of specific MAP isoforms [168]
Effects on amyloidosis
Elevates APP expression and induces senile plaque deposition in 30% of patients subjected to chronic dialysis treatment [44]
Elevates APP expression, promotes Adeposition and amyloidosis in hippocampal and cortical pyramidal neurons in rats and mice
following chronic oral exposure [70, 82, 83, 231]
Binds the amyloidogenic Apeptide and perturbs its structure from a soluble -helical form to the insoluble random turn -sheet
conformation at physiologically relevant concentrations [281, 282]. The neurotoxic A-sheet conformation may be reversed by the
addition of a natural Al binder-silicic acid, a promising therapeutic agent for AD [37, 283]
Promotes the formation of amyloid fibrils in complex with ATP [284] and induces their aggregation [285]
Induces conformational changes in Aand enhances its aggregation in vitro in cultured mouse cortical neurons, following chronic (50M,
>3 weeks) but not acute exposure (10–100M, 1 week [285])
Appears to be the most efficient cation in promoting A1-42 aggregation and potentiating A1-42 cellular toxicity in human neuroblastoma
cells:
induces a specific oligomeric state of A1-42 and by stabilizing this assembly markedly reduces cell viability and alters membrane
structure, an effect not seen with other metal complexes (A1-42-Zn, A1-42-Cu and A1-42 -Fe) or A1-42 alone [14, 286]
strongly enhances the spontaneous increase of A1-42 surface hydrophobicity (compared to A1-42 alone, A1-42-Zn, A1-42 -Cu and
A1-42-Fe), converting the peptide into partially folded conformations [14, 286]
572 L. Tomljenovic / Aluminum and Alzheimer’s Disease
Table 1
(Continued)
May promote amyloidosis by interfering with the muscarinic acetylcholine receptor-stimulated IP3/PLC-regulated production of the
neuroprotective nonamyloidogenic s-APP (Fig. 2 [4, 8, 22, 241, 287, 288]):
as fluoroaluminate, blocks DAG/PKC-dependent budding of secretory vesicles containing APP from the trans-Golgi network
(TGN), thus inhibiting APP redistribution towards the plasma membrane where it would undergo processing by -secretase
to produce s-APP [289]
may inhibit IP3/Ca2+ – dependent production of s-APP [22, 288]
may inhibit PKC-dependent APP cleavage by -secretase [289, 290]
Inhibits proteolytic degradation of Aby cathepsin D [291]
There are many unresolved questions about Al
bioavailability. This perhaps leads to erroneous con-
clusions regarding the significance of Al in the
pathogenesis of AD. This review elucidates how: 1) the
brain’s inherent structural and functional heterogene-
ity provides a basis for differential susceptibility
of specific cellular systems to Al neurotoxicity and
2) how Al’s active sequestration of specific systemic
transport mechanisms results in its compartmentalized
distribution within the brain in a pattern that strongly
implicates its role in AD. Special emphasis is given to
Al’s chemical and physical properties and their rele-
vance to the etiology of AD.
ALUMINUM AND AD: WHY IS THERE
A DEBATE?
Al, the third most abundant element on earth (after
oxygen and silicon [37–40]), has been demonstrated
in the literature to be a neurotoxin (Table 1). It
is widely bioavailable to humans (Tables 3–5) and
known to accumulate at higher concentrations in brain
regions that are selectively affected in AD, including
the entorhinal cortex (an area that shows the earliest
pathological changes in AD), hippocampus, and the
amygdala [2, 41–48]. Pyramidal cells in the hippocam-
pus and cortex, basal forebrain cholinergic neurons,
and upper brainstem catecholaminergic neurons asso-
ciated with higher cognitive functions are the most
affected neuronal populations in AD and also, the most
susceptible to Al-induced neurofibrillary degeneration
[10, 43, 47, 49, 50]. A strong association of Al with
NFTs in AD was first observed by Perl and Brody
[42], who used a combination of scanning electron
microscopy and X-ray spectrometry, which enabled
them to assess the localization of Al in brain biop-
sies at cellular and subcellular levels. Al foci were
explicitly found within the nuclear regions of NFT-
bearing neurons in the hippocampi from AD patients
as well as non-demented elderly controls, while they
were absent from adjacent healthy neurons from both
groups of patients. Perl and Brody’s observations were
later confirmed by Andrasi et al. [51] using more
sophisticated method (which eliminated the interfering
reaction of phosphorous) and were also experimen-
tally reproduced by Uemura [52] in an animal model
of Al-induced neurofibrillary degeneration. Contrary
to previous experiments, Uemura [52] was one of the
first to examine the effects of chronic administration
of Al in animals (administered subcutaneously over a
period of either 40 or 90 days, rather than as a single
intracerebral sub-lethal dose). Using a similar X-ray
microprobe approach as Perl and Brody, Uemura [52]
found elevated levels of Al within the nucleus of a
high percentage of NFT-bearing neurons in the spinal
cord and hippocampus. Also in concordance with Perl
and Brody’s results, Al was not detected in NFT-free
neurons.
In spite of these observations, the causative role
of Al in AD has been disputed, as some researchers
failed to detect elevated levels of Al in AD brains
despite using highly sophisticated and sensitive detec-
tion methods [53, 54]. These discrepancies fuelled
further criticism about the Al-AD hypothesis and were
further bolstered by the fact that Al has no biolog-
ical essentiality, appears to be both poorly absorbed
and efficiently excreted from the body [38–40, 55–57]
and presumably, cannot accumulate in brain tissue
in sufficient amounts to cause damage under physi-
ologically relevant conditions [38, 40]. The presence
of Al in the brain was subsequently attributed to
experimental artifacts [54] or to passive uptake by
dysfunctional neurons [58]. Furthermore, although
Al-induced dialysis encephalopathy in chronic renal
failure patients and intracerebral injection of a lethal
threshold doses of Al in experimental animals results
in development of neurofibrillary-like tangles, these
lesions are less common and/or show distinct cellular
topology and morphology from those in AD (although
they are immunochemically similar to classical NFTs;
Table 2). Similarly, the frequent occurrence of seizures,
rapid progression, and severity of neuropathological
abnormalities associated with Al-induced neurofibril-
lary degeneration in dialysis patients and experimental
L. Tomljenovic / Aluminum and Alzheimer’s Disease 573
Table 2
Comparisons between AD, dialysis dementia and animal models of neurofibrillary degeneration and amyloidosis
AD Dialysis dementia Early animal models Recent animal models of AD
of neurofibrillary degeneration and AD-like amyloidosis
Duration and
outcome
Fatal within 18 months–27 years
(average 10 years) [10]
Fatal within 3–7 months following onset of
symptoms unless treated (DFO and reverse
osmosis to remove Al salts from the water
used to prepare the dialysis fluid) [57, 180,
248, 252]
Fatal unless treated with
anti-epileptic medications,
treated animals survive but with
persistent neurophysiological
deficits [246]
Aged rats and mice are normally sacrificed
following exacerbation of symptoms [70]
Symptoms Gradual and steady decline in mental
abilities appearing first in memory
and later in speech and
psychomotor control, behavioral
changes including paranoia,
depression, delusions and
hallucinations [1, 10]
Symptoms appear suddenly and worsen
either during or immediately after a
dialysis session [248, 252, 292–294].
The first symptom to appear is a speech
abnormality, then tremors, impaired
psychomotor control, memory losses,
impaired concentration, behavioral
changes, epileptic seizures, coma and
death [57, 248, 252, 292–294]
Decline in memory, impaired
learning responses,
deterioration in psychomotor
control, epileptic seizures and
death [220, 250, 253, 295–298]
Memory deficits and impaired performance
in learning tasks, impaired concentration,
behavioral changes including confusion
and repetitive behavior [48, 61, 70, 165,
169]
Age of onset Idiopathic AD (95–99% prevalence)
>65 years [1, 13]
Familial AD (1–5% prevalence) <65
years [1, 13]
Depending on duration of dialysis treatment,
generally in patients who have been
undergoing dialysis for 2–7 years [248,
252, 294]. Flendrig et al. [252] reported
6 cases of dialysis dementia, the youngest
patient was 15 years and the rest were
between 39–61 years of age when they
died
7–10 days after injection [220,
296]
At human equivalent, in Al-treated rats
generally by 27 months [2, 48, 61, 70, 82,
83] in AlF-treated rats by 15 months [82,
83]. In transgenic mice by 12 months
[231]. Adult rats are generally maintained
on an low Al-supplemented diet
throughout life [2, 48, 61, 70, 82, 83]
and mice for 12 months [231]
Amyloid/senile
plaques
Common [1, 12–14, 16, 18] Detected in 30–50% of patients [44, 45] Uncommon Uncommon [2, 70, 82, 83, 231] typical
extracellular senile plaques are
species-specific and do not normally
develop in rodents [70] but APP
accumulation is observed in affected
dendrites and axons [70, 299] and Ain
cerebral vessels [82]
Common in APP transgenic mice [231]
NFTs Common, composed of paired helical
filaments (PHFs) [1, 7, 14, 20, 47,
225, 275, 279]
Uncommon [44], but when present,
composed of PHFs [45]
Common but morphologically
and topologically distinct from
those in AD (due to
species-specific differences),
composed of straight filaments
[298, 300, 301]. Nonetheless,
both share the
immunoreactivity for
phosphorylated tau and NF
proteins [302–304]
Uncommon in rats but their main
component, hyperphosphorylated tau,
is common [305]
574 L. Tomljenovic / Aluminum and Alzheimer’s Disease
Table 2
(Continued)
AD Dialysis dementia Early animal models Recent animal models of AD
of neurofibrillary degeneration and AD-like amyloidosis
Al source Dietary, environmental, lifestyle
(vaccines, cosmetics,
pharmaceuticals, processed foods
antiperspirant etc.; see Tables 3–6)
Primary source: intravenously-administered
dialysis fluid (derived from Al-treated tap
water [57, 251, 252]). There were no
incidences of dialysis dementia prior to
introduction of Al salts in water supplies
[251, 252]
Secondary source: Al containing oral
medications [294]
Intracerebral injection of a
sub-lethal Al dose [220, 253,
295, 297]
Dietary, either in food or water [2, 48, 61,
70, 82, 83, 165, 178, 231]
Al brain burden Non-demented controls: 0–2 g/g
dry weight [275, 306]
AD: 3–4 ×the control level
(3–7 g/g dry weight) [41, 49, 275]
10–15 ×the control levels (23g/g dry
weight) [59, 247, 248, 306]
Similar to AD: 4–6 g/g dry
weight [49, 246, 253, 275]
2×the control level >2.5g/g dry weight
[82]
Al localization –
cellular and
subcellular
NFTs, amyloid plaques, neuronal
nuclei, throughout cells, perinuclei
and granulovacuolar degeneration
[42, 47, 59, 174, 247, 307]
Generally, uniform [59] NFTs, neuronal nuclei [59] Neuronal nucleoli, nuclei, throughout cells,
granulovacuolar degeneration [70, 82, 83,
231, 305]
Al localization –
tissue
Largely restricted to specific
compartments of the brain-
hippocampus, cortex [41, 46, 47,
49, 247, 296]
In the brain: focal accumulations are
sometimes observed in the hippocampus
and cortex [44, 173]. In other tissues:
primarily bone and red blood cells, giving
rise to bone disease-osteomalacia (or renal
osteodystrophy) and microcytic anemia
[56, 57, 179, 180, 308]. Parathyroid gland,
joints, lung, heart, liver, spleen, muscle,
skin and hair may also be affected [56,
179, 180, 252]
May depend on the site of
injection [301]
Largely restricted to specific compartments
of the brain-hippocampus, cortex, red
blood cells, kidney tubules [2, 48, 70, 82,
83, 165, 231]
Reversal by
DFO
Partially effective, slows down
progression but does not reverse
AD [60]. Recent experiments show
that a combination of two Al
chelators, ascorbate and Feralex-G,
is effective in removing Al from
the nuclei and hence a potentially
useful pharmacotherapeutic
approach to AD [278, 309]
Effective [180, 310, 311] NFTs reversed by DFO in rabbit
brains [302]
L. Tomljenovic / Aluminum and Alzheimer’s Disease 575
animals, contrasts with the insidious and latent devel-
opment of neurological deficits in AD (Table 2).
Moreover, brain biopsy samples show that in spite of
high overall Al brain burden, intranuclear Al is not sig-
nificantly elevated in dialysis dementia patients [59].
Finally, while chelating Al by desferrioxamine (DFO),
successfully reverses dialysis dementia, it is less effec-
tive in improving the clinical outcome of AD (Table 2)
[60]. Taken together, these discrepancies have been his-
torically used to dismiss the significance of Al toxicity
in AD.
Nonetheless, such dismissals may not be warranted
as it is well known that the severity and clinical out-
come of metal intoxication primarily depends on the
dose, route, and duration of exposure as well as species
differences. Al is no exception [6, 61–64]. In addition,
intranuclear Al is particularly resistant to removal by
chelating agents [65], and this most likely accounts
for decreased responsiveness to DFO treatment in
AD patients. Furthermore, a possible explanation for
the absence of widespread neurofibrillary tangle-like
pathology in dialysis patients which is so typical of
AD, as well as animal models of Al-induced neurofib-
rillary degeneration (Table 2), may be the presence
of oxygenated metabolites capable of binding Al and
modifying its toxic action. Such metabolites would be
expected to accumulate in abnormal amounts due to
chronic renal failure [15]. Noteworthy, the significance
of Landsberg et al. [54, 66] work is questionable due
to a number of inconsistencies for which no adequate
explanation is provided. For example, Landsberg et al.
produced a subsequent paper in 1993 in which they
were able to detect Al in plaques of AD brains [66],
contrary to their widely cited precedent study [54].
This is despite the fact that their detection method
in the former experiment was stated as being three
times more sensitive. Nonetheless, they suggest that
Al presence in stained plaques was due to a con-
tamination of a staining solution [66]. In addition,
Landsberg et al. provided no data in regards to the
elemental content on NFTs [54, 66] where Al is
known to accumulate in high amounts and concluded
that Al does not have a role in AD. Resolving this
dilemma, Walton et al. [67] used 26Al isotope and
ultra sensitive accelerator mass spectrometry (AMS)
which enabled them to study Al toxicokinetics at
physiologically relevant levels of Al exposure in rats
(26Al can be quantified by AMS with extreme sen-
sitivity, 1×106atoms as the 26Al : 27Al ratio [33,
68, 69]. Their results showed that trace amounts of Al
from the equivalent of a single glass of water readily
entered the brains of rats [67], thereby providing the
most compelling evidence to date against the hypoth-
esis that the accumulation of Al in neurons is an
artifact.
Finally, it should be fairly obvious that AD does
not result from a direct intracerebral injection of a
sub-lethal dose of Al routinely used in animal models
of neurofibrillary degeneration, nor sub-acute intra-
venous exposure commonly associated with dialysis
dementia (Table 2). Accordingly, the prolonged clini-
cal course of AD is suggestive of a chronic life-long
exposure to low doses of a neurotoxicant such as Al
[6, 48]. Consistent with this and more relevant to
human exposure, recent studies by Walton [2, 48, 70]
show that chronic ingestion of Al in rats, in amounts
equivalent to those humans routinely ingest, results
in neuropathological outcomes characteristic of AD,
including cognitive deterioration, hippocampal, and
cortical increases in APP expression and deposition
and higher Al content in the perikarya of pyramidal
cells. Walton’s work [2, 48, 70] demonstrates how
small doses of a known neurotoxicant can accumulate
over lifetime in sufficient amounts to trigger a neurode-
generative disease in otherwise healthy animals with
no obvious genetic predispositions.
BIOAVAILABLE ALUMINUM
As noted by Exley et al. [37] “In the absence of
recent human interference in the biogeochemical cycle
of aluminium the reaction of silicic acid with alu-
minium has acted as a geochemical control of the
biological availability of aluminium.” Unlike man-
ufactured Al compounds (such as food additives),
naturally occurring compounds such as aluminosili-
cates (essential components of rock and soil minerals)
are poorly absorbed and insoluble at neutral pH
[38–40]. Al easily transits from solid to liquid phase at
low pH values, and is quickly mobilized by acid rain
which results in its accumulation in plants and natural
water systems [38, 39, 57, 71, 72]. Surface waters have
naturally a much higher Al content than ground waters
[57, 73]. Notably, human exposure to Al was rather lim-
ited up until late 1880s, when Al production increased
for industrial and commercial purposes [74]. There-
after, Al salts were introduced in rapid water filtration
systems for water purification purposes, to reduce
organic matter, turbidity, and microorganisms [71]. Al
sulfate is the most commonly used flocculant [39, 71],
thought to reduce particulate forms of Al (and this
presumably decreases the total Al water content). How-
ever, flocculation by Al sulfate frequently increases
the levels of the more toxic soluble monomeric inor-
576 L. Tomljenovic / Aluminum and Alzheimer’s Disease
Fig. 3. Al fractions in water. Note that AlF increasingly forms in fluoridated potable supplies. Adapted from Srinivasan et al. [317].
ganic forms in the finished water (Fig. 3) [39, 75, 76].
Interestingly, during a survey of 186 randomly selected
community water supplies in the USA, Miller et al. [73]
noted that there was a 40 to 50% chance that the total
Al content in the finished water (0.014–2.67 mg Al/L)
would be above the original content of un-treated
natural water (0.014–0.29 mg Al/L ground water
and 0.016–1.17 mg Al/L surface water). Notewor-
thy, in certain cases Al-treated water had more
than double the Al content of the naturally more
contaminated surface water (2.67 vs 1.17 mg Al/L)
[73]. Of significant concern is the presence of poten-
tially extremely toxic fluoroaluminates (AlFx), which
form in aqueous solutions containing fluoride anions
and trace amounts of Al [39, 77]. These complexes
act as structural analogues of PO3
4in cellular signal-
ing cascades and have the potential to cause numerous
adverse systemic effects in humans [77–81]. Further-
more, fluoroaluminates are easily transported across
the blood brain barrier (BBB), and in rats, chronic
dietary exposure to AlFxcomplexes causes severe
damage to cerebrovascular endothelia and neurons,
in a region-specific manner reminiscent of AD [82,
83]. The enhanced toxicity in the fluoroaluminate
group (compared to that treated with sodium fluoride),
resulted from the ingestion of an additional 0.1 mg
Al/kg bw/day [82]. From these observations it is evi-
dent that in the presence of fluoride, only trace amounts
of Al are needed to produce substantial neuronal injury.
Both fluoride and Al when complexed in AlFxappear
to be more easily absorbed from the gastrointestinal
(GI) tract compared to their ionic forms [39, 82, 83].
In spite of these observations, water fluoridation per-
sists in USA, Canada, Australia, and New Zealand
while most of Europe has abandoned this practice [77,
84]. Of note, contrary to World Health Organization
(WHO) predictions, the incidence of dental caries has
decreased significantly after the suspension of water
fluoridation in Japan and many European countries
[84]. In fluoride-treated water, fluoroaluminates are
the prevalent species [39]. The enhanced transport of
fluoroaluminates across the GI tract and the BBB,
in context to their highly neurotoxic potential, raises
significant concerns about the prevalence of these com-
pounds in drinking water of various countries [82, 83].
The first case of AD was reported in Frankfurt 20
years following the expansion in use of Al products
The case presented even in the clinic such a differ-
ent picture, that it could not be categorised under
known disease headings, and also anatomically it
provided a result which departed from all previously
known disease pathology” (Dr Alois Alzheimer) [85].
Alzheimer’s astute observations were later supported
by a report in Lancet, which affirmed AD as a rare con-
dition (by 1926, a total of 33 cases of AD have been
confirmed) [86]. Al is now widespread, AD affects
24.3 million of the world’s population (a new case is
diagnosed every 7 seconds) [11], and most people are
unaware of their chronic routine exposure to Al com-
pounds (Tables 3–6). Al is present in natural as well
as processed foods, beverages, pharmaceuticals, vac-
cines, cosmetics, and many modern life-style utilities
(Tables 3–5) [38, 39, 72, 87–98].
Since 1989 a considerable number of studies have
related elevated Al levels in water to an increased risk
of cognitive impairment and Alzheimer-type dementia
[99–105], especially in conditions of low silica con-
tent [102, 104, 106]. Recently Campbell et al. [107]
L. Tomljenovic / Aluminum and Alzheimer’s Disease 577
Table 3
Estimates of daily and weekly intakes of Al in humans
Major sources of Al Daily Al intake Weekly Al ÷PTWI(1 mg/kg/bw; Amount delivered daily into
exposure in humans (mg/day) intake (mg/day) for an average 70kg systemic circulation (at 0.25%
human PTWI = 70 mg) absorption rate)
Natural Food 1–10 [38, 195] 7–70 0.1–1 2.5–25 g
Food with Al 1–20 (individual 7–140 (700) 0.1–2 (10) 2.5–50 g (250 g)
additives intake can exceed
100) [89, 109]
Water 0.08–0.224 [38, 195] 0.56–1.56 0.008–0.02 0.2–0.56 g
Pharmaceuticals
(antacids, buffered
analgesics,
anti-ulceratives,
anti-diarrheal
drugs)
126–5000 [38, 88, 195] 882–35,000 12.6–500 315–12,500 g
Vaccines (HepB, Hib,
Td, DTP)
0.51–4.56 [312] NA NA 510–4560 g
Cosmetics, skin-care 70 [88, 312] 490 NA 8.4 g (at 0.012% absorption
products and rate [118, 313])
antiperspirants §
Cooking utensils and
food packaging
0–2 [38] 0–14 0–0.2 0–5 g
PTWI (Provisional Tolerable Weekly Intake) is based on orally ingested Al, generally only 0.1–0.4% of Al is absorbed from the GI tract,
however, Al may form complexes with citrate, fluoride, carbohydrates, phosphates and dietary acids (malic, oxalic, tartaric, succinic, aspartic
and glutamic), which may increase its GI absorption (0.5–5% [38, 39]). Co-exposure with acidic beverages (lemon juice, tomato juice, coffee)
also increases Al absorption as well as conditions of Ca2+,Mg
2+,Cu
2+ and Zn2+ deficiency [38, 57, 178, 195].
A single dose of vaccine delivers the equivalent of 204–1284 mg orally ingested Al (0.51–4.56 mg), all of which is absorbed into systemic
circulation [117, 118]. Al hydroxide, a common vaccine adjuvant has been linked to a host of neurodegenerative diseases, it also induces
hyperphosporylation of MAP tau in vivo [87, 129, 314].
§The risk of antiperspirants is both from dermal exposure and inhalation of aerosols. Inhaled Al is absorbed from the nasal epithelia into
olfactory nerves and distributed directly into the brain [118, 313].
have validated concerns over Al in drinking water by
demonstrating that exposure to low levels of Al lac-
tate (0.01, 0.1, and 1 mM) in drinking water for 10
weeks increased inflammatory processes selectively
in the brains of mice (as no parallel changes were
observed in the serum or liver of treated animals).
The authors noted that the lowest of these levels are
in the range found to increase the prevalence of AD
in regions where the concentrations of the metal are
elevated in municipal drinking water [108]. Nonethe-
less, as pointed out by Rogers and Simon [91] (authors
of the sole study that assessed the role of dietary Al
in relation to AD), they have all ignored one of the
most important sources of Al for an average citizen:
food (representing 95% of the daily oral intake) [88].
Although average estimates of total daily intakes vary
between 2 and 25 mg Al/day (14–175 mg/week) [38,
89, 94, 109], individual intake in urban societies can
easily exceed 100 mg/day (700mg/week; Table 3) due
to a widespread increase in consumption of processed
convenience foods which are typically high in Al-
containing additives (Table 4). In 2006, the Food and
Agriculture (FAO) WHO Expert Committee amended
their provisional tolerable weekly intake (PTWI) for Al
from 7 mg/kg/bw (490 mg/week, for an average 70kg
human) to 1 mg/kg/bw (70 mg/week) [110]. The Com-
mittee concluded that “aluminum compounds have the
potential to affect the reproductive system and devel-
oping nervous system at doses lower than those used in
establishing the previous PTWI and therefore revised
the PTWI” [110]. The take home message is that a
large proportion of people are unwittingly consuming
significantly more Al than what is considered safe by
the expert food authorities (Tables 3 and 5).
Of particular concern is exposure to Al in children
through diet and vaccination programs. Infants are at
particular risk, as are all those under 5 years of age,
since the BBB in young children is immature and
more permeable to toxic substances [38, 110, 111].
Unfortunately, these are also the groups that obtain
most Al from both of the aforementioned sources
(Tables 5 and 6). According to the latest vaccination
schedule, every child in the USA will receive a total of
5–6 mg of Al by the age of 2 years, or up to 1.475 mg
of Al during a single visit to the pediatrician (Table 6).
This is contrary to the upper limit of 5 g Al/kg/day
set by the Food and Drug Administration (FDA) for
premature neonates and individuals with impaired
578 L. Tomljenovic / Aluminum and Alzheimer’s Disease
Table 4
Foods and pharmaceuticals with highest and lowest Al content
mg Al/serving mg Al/kg mg Al/L (beverages)
Pharmaceuticals (1 tablet or 5 mL liquid)
Antacids 35–208 [38]
Buffered aspirin 9–52 [38]
Anti-ulceratives 35–1450 [38]
Anti-diarrheal drugs 207 [38]
Beverages
Tea (natural) 0.1–0.73 (250 mL) 0.424–2.931 [38]
Soft drinks 0.02–0.52 (250 mL) 0.103–2.084 [38]
Foods
Natural unprocessed foods 0.15–0.7 (30–150 g) <5 [38,39]
Ready to eat pancake, waffle mixes 52–182 (120–140g) 430–1280 [89]
Cheese, processed 11.5–40 (28 g) 411–1440 [88,89]
Cornbread 18 (1 piece, 45 g) 400 [130]
Tortillas 3.9 (1 medium, 30 g) 129 [130]
Muffins 5.1 (1 muffin, 40 g) 128 [130]
Miscellaneous
Baking powder (containing SALP) 20–30 (1g) 20,000–28,000 [89]
Non-dairy creamer 0.1–1.5 (2–3 g) 50–600 [89]
Table salt (with Al-anticaking agents) 0.1–0.2 (1 g) 125–195 [89]
Herbs and spices (natural) <0.05 (1g) 3.74–56.50 [38]
Infant formulas
Soy-based 0.5 (200 mL) up to 2.5 [38,315]
Milk-based 0.012–0.03 (200 mL) 0.06–0.15 [38]
Mother’s milk 0.002 (200 mL) <0.05 [38]
Most natural foods have <5mg Al/kg with some exceptions such as herbs, spices and tea, however, Al in tea may be
bound to polyphenolic compounds and poorly absorbed [88, 177].
SALP-acidic sodium Al phosphate.
kidney function [112]. Healthy neonates may be able
to handle more Al, however, there are no such studies
available upon which we could safely estimate accept-
able upper levels of Al from parenteral or injectable
sources in healthy children. In that respect, it is worth
noting that the FDA document states that Al accumu-
lation at levels associated with central nervous system
and bone toxicity may occur at even lower rates of
exposure [112]. Thus, a baby weighing 3 kg (6.6
pounds) at birth, receives a potentially toxic dose of
Al that is 17–30 times greater than the best currently
available estimate of 5g Al/kg/day, and that from a
single HepB vaccine (Table 6). At their 3rd regularly
scheduled vaccination appointment, babies weighing
5.5 kg at two months (12 pounds), receive 45 to
50 times more Al than what is considered safe by
the FDA (Table 6). The long-term consequences of
such an aggressive vaccination policy have not been
adequately investigated, although it is interesting to
note that since the dramatic increase in the number
of vaccinations deemed to be required prior to school
entry (from 10 in the late 70s to 32 in 2010, 18 of
which contain Al adjuvants; Table 6), the prevalence
of neurological disorders in children in developed
countries has increased by 2000–3000% (from less
than 5 per 10,000 [113] to 110–157 per 10,000 [114,
115]). What those who are pro-vaccination assert is
that vaccines contain similar amounts of Al to those
found in infant formulas [116]. What they fail to stress
is that unlike dietary Al of which only 0.25% is
absorbed into systemic circulation (Table 3), Al from
vaccines is absorbed at nearly 100% efficiency [117,
118]. Moreover, the sizes of most antigen-Al com-
plexes (24–69kDa [119, 120]), are higher than the
molecular weight cut-off of the glomerulus of the kid-
ney (18 kDa [121]), which would preclude efficient
excretion of Al adjuvants. Thus, vaccine-derived Al
would have a much greater potential to induce neu-
rological damage than that obtained through diet. It
is true that vaccines are not administered on a daily
basis; however, they are administered frequently dur-
ing the most critical period of brain development
(Table 6) [38, 111, 122]. Further concern about neuro-
toxicity risks from Al vaccine adjuvants is warranted
by the fact that even adults may be susceptible to
adverse effects from these compounds [123–128]. In
addition, injection of Al hydroxide in amounts rel-
evant to human vaccine exposure, leads to motor
neuron death, increase in brain inflammatory mark-
ers, impairments in motor function, and decrements
in spatial memory in young outbred CD-1 male mice
[87, 129].
L. Tomljenovic / Aluminum and Alzheimer’s Disease 579
Table 5
Dietary Al intake in children. Data compiled from ATSDR [38]
Age Daily Al Daily Al Weekly Al ÷PTWI Major Al food sources
intake (mg/day) intake/kg bw intake/kg bw (1 mg/kg/bw)
(mg/kg/day) (mg/kg/day)
0–3 months 1.50.05 3.53.5Soy-based formula (2.5 mg Al/l)
(3 ×200 mL/day)
0–3 months 0.09 0.03 0.21 0.21 Milk-based formula (0.15 mg Al/l)
(3 ×200 mL/day)
0–3 months 0.006 0.002 0.014 0.014 Mother’s milk (0.01mg Al/l)
(3 ×200 mL/day)
6–11 months 0.70.10 0.70.7 Soy-based formula, American processed
cheese, yellow cake with icing, green
beans, strained, pancakes
2 years 4.60.35 2.45 2.45Cornbread, American processed cheese,
yellow cake with icing, fish sticks,
pancakes, tortillas, muffins, taco, tea
6 years 6.50.30 2.12.1American processed cheese, yellow cake
with icing, pancakes, fish sticks,
cornbread, tortillas, taco, muffins,
hamburger
10 years 6.80.11 0.77 0.77 American processed cheese, cornbread,
pancakes, tortillas, yellow cake with
icing, fish sticks, taco, muffins,
chocolate cake
14–16 years
(females)
7.70.15 1.05 1.05 American processed cheese, yellow cake
with icing, cornbread, taco, pancakes,
tortillas, muffins, cheeseburger, tea, fish
sticks
14–16 years
(males)
11.50.18 1.26 1.26Cornbread, American processed cheese,
pancakes, yellow cake with icing, taco,
tortillas, cheeseburger, tea, hamburger,
fish sticks
bw – body weight.
Age groups consuming over the PTWI limit for Al.
Table 6
Al administered to children under the current USA vaccination program [316]. Children from 2–18 months of age who regularly receive
multiple vaccinations may exceed current FDA safety limits for Al exposure from parenteral sources (5 gAl/kg/day [112]) by a factor of 50.
Note that these FDA guidelines would be applicable to vaccination since all Al injected from a vaccine would eventually be absorbed into
systemic circulation [118]. By 2 and 6 years of age, children receive a total of 5.2–5.9mg Al and 5.8–6.5 mgAl respectively. HepB-Hepatitis B,
RV-Rotavirus, DTP-Diphteria, Tetanus, Pertussis, Hib-Haemophilus influenza type b, PCV-Pneumococcal, IPV-Inactivated Poliovirus, MMR-
Measles, Mumps, Rubella, Var-Varicella, HepA-Hepatitis A. Table source: Centers for Disease Control and Prevention (CDC) [316]. Al content
in vaccines according to Offit and Jew [116]
Al/dose (mg)Birth 1 2 4 6 12 15 18 19–23 2–3 4–6
month months months months months months months months years years
0.25–0.5 HepB HepB HepB
– RVRVRV
0.625 DTP DTP DTP DTP DTP
0.225 Hib Hib Hib Hib
0.125 PCV PCV PCV PCV
IPV IPV IPV IPV
MMR MMR
Var Var
0.25 HepA HepA
–IfIfIf
Al /visit (mg) 0.25–0.50 1.225–1.475 0.975 1.225–1.475 1.125 0.25 0.625
Regarding other sources of Al exposure in children,
according to ATSDR [38], 50% of them over the age
of 6 months consume more than their PTWI limit for
Al, while the remaining 50% are within the upper range
(Table 5). Two-year olds consume almost three times
their PTWI limit (Table 5), while infants (0–3 months)
580 L. Tomljenovic / Aluminum and Alzheimer’s Disease
fed exclusively with certain soy-based formulas may
ingest as much as 1.5 mg Al/day, which is 250 times
the amount they would get from mother’s milk and
almost three and a half times over their PTWI (Table 5).
Out of all infant formulas, highest levels of Al are
found in highly processed soy formulas (up to 2.5 mg
Al/L), and lowest in products that require no or mini-
mal processing and have few additives, such as human
milk (unless the mother consumes a high level of Al
additives) and bottled glucose water (<0.05mg Al/L;
Table 4). Al additives are also widely used as preserva-
tives, emulsifiers, leavening, anticaking, and coloring
agents [38, 72, 88–91, 93, 94, 97, 98, 130]. Among
the most common are: 1) basic sodium Al phosphates
(SALPs), emulsifying agents in cheese, and 2) acidic
SALPs (which react with sodium bicarbonate to cause
a leavening action), used in commercial baking pow-
ders, biscuit, pancake, waffle, cake, doughnut, muffin,
and self-rising flour mixes [88, 89, 97, 98, 130]. A sin-
gle serving of a ready-to-eat pancake may yield 4 times
the Al PTWI (180 mg; Table 4), while a typical serving
of processed cheese (28 g) may provide 11.5–40 mg
of dietary Al (1/7 – >1/2 the PTWI; Table 4). It
is worth noting that the same processed food items
(including soy infant formulas), which contain Al,
often also contain potentially excitotoxic amounts of
monosodium glutamate (MSG) [131, 132]. Glutamate
significantly enhances Al transport across the BBB and
accumulation in AD-susceptible regions (Fig. 4) [133–
135]. It may also increase Al absorption from the GI
tract [39, 136]). Conversely, Al potentiates glutamate
excitotoxic effects in vivo [135] in cultured hippocam-
pal pyramidal neurons [50] and in primary neuronal
cultures (Table 1) [137]. Notably, neuronal lesions
resulting from synchronistic application of Al and glu-
tamate show mitochondrial abnormalities which are
characteristic for early excitotoxic events (swelling and
disruption of the mitochondria and microvacuolization
of the perikaryal cytoplasm) [50].
As early as 1911, William Gies expressed concerns
about the use of Al in baking powders [98]. Based on
seven years of research on the effects of Al salts in
animals and humans, Gies concluded that Al should
be excluded from food in the interest of conserva-
tion of the most valuable natural resource: human
health [98]. More recently, Rogers and Simon [91]
who conducted the sole preliminary study to deter-
mine whether dietary Al intake differs in individuals
with and without AD (and found that AD subjects
consumed significantly more of the highest SALP-
containing food category, p= 0.025), noted: “Current
dietary patterns in the USA are akin to a grand-scale
experiment whereby some individuals are consuming
large quantities of aluminum while others are not, the
long term effects of which have not been investigated.
It is important to determine whether William Gies was
correct in his admonitions”. Interestingly, the 357 page
ATSDR report [38] states that “Oral exposure to alu-
Fig. 4. Major routes of Al transport in and out of the brain: from the blood, Al enters the brain ECF primarily through the BBB via transferrin-
mediated uptake. Al influx from the brain ECF to the cellular compartments is mediated by transferrin-dependent and independent mechanisms.
Neurons and glia compete for Al uptake from the brain ECF, however, long-lived terminally differentiated neurons tend to accumulate more Al
over time. Some Al in the brain is rapidly effluxed as Al-citrate by the MCT-transporter. A significant portion of Al is retained in the cellular
compartments (nucleus, ER, bound to ATP or membrane phospholipids). BBB-blood brain barrier, CP-choroid plexus, CSF-cerebrospinal fluid,
ECF-extracellular fluid, MCT-monocarboxylate transporter, Glut-glutamate transporter. The dashed line represents the absence of a membrane
barrier between the CSF and brain ECF (adapted from Yokel et al. [68]).
L. Tomljenovic / Aluminum and Alzheimer’s Disease 581
minum is usually not harmful”, although it recognizes
that the neurological effects of such exposure have not
been “adequately investigated in healthy humans”. The
report further notes that “There is a rather extensive
database on the oral toxicity of aluminum in animals.
These studies clearly identify the nervous system as the
most sensitive target of aluminum toxicity” [38].
The data presented by the ATSDR in relation to
Al toxicity following dermal and inhalation expo-
sures in humans is equally scant. The report states
that “Limited information is available regarding the
distribution of aluminum following inhalation expo-
sure in humans or animals...No studies were located
regarding respiratory, cardiovascular, gastrointesti-
nal, hematological, hepatic, renal, endocrine, ocular,
body weight, or metabolic effects in humans or
animals after dermal exposure to various forms
of aluminum....No studies were located regard-
ing immunological/lymphoreticular effects in humans
after intermediate or chronic-duration dermal expo-
sure to various forms of aluminum....No studies were
located regarding neurological effects in humans after
acute- or intermediate-duration dermal exposure to
various forms of aluminum” [38]. The ATSDR then
makes a claim that “Aluminum compounds are widely
used in antiperspirants without harmful effects to the
skin or other organs” [38]. The study which the
ATSDR uses to back their conclusion on the safety
of antiperspirant use dates back to 1974 [138], even
though there are several more recent reports which
implicate antiperspirant use with the increased risk
of Al-related diseases, including AD [92, 139–141].
Similarly, in response to concerns raised by citizens in
regards to the safety of Al-based antiperspirants, the
FDA asserts that it “has no data showing that products
containing up to 35 percent aluminum chlorhydrates
or aluminum zirconium chlorhydrates increase alu-
minum absorption and is not revising the monograph
to provide for powder roll-on dosage forms contain-
ing up to 35 percent antiperspirant active ingredient,
without additional safety data being provided” and
that “the majority of researchers investigating the
[cause or origin] of Alzheimer’s disease would con-
sider current evidence insufficient to link aluminum
to Alzheimer’s disease...current scientific information
does not support the need to reclassify the safety of
aluminum-containing antiperspirants” [142]. A sim-
ilar view is held by the Alzheimer’s Society Canada:
Most researchers no longer regard aluminum as a risk
factor for Alzheimer’s disease...At this point, there is
no convincing evidence that aluminum increases a per-
son’s risk of developing Alzheimer’s disease” [143].
In contrast to such statements, there is solid evidence
implicating even less common routes of Al exposure,
such as inhalation, in preclinical cognitive and behav-
ioral disorders which might prelude AD [144, 145].
MECHANISMS OF ALUMINUM TOXICITY
Physical and chemical properties: aluminum’s
toxic mimicry
Much like mercury, and unlike iron, copper, zinc,
and manganese, Al has no biological role and is un-
questionably a neurotoxin [32, 38, 39, 146]. A small
ionic radius and high charge are main properties
by which Al exerts its neurotoxic activity. The Al
ion (0.054 nm) is roughly the same size as the
ferric ion (0.065 nm) and much smaller than mag-
nesium (0.072 nm) and calcium ions (0.100 nm). In
biological systems, Al can effectively replace these
essential biometals in many enzymatic reactions [39,
147–151]. For example, Al binds the extracellular-
iron carrier transferrin [19, 146, 152] which in
turn, may facilitate its transport across the brain
barriers (Fig. 4). Furthermore, due to its greater affin-
ity for anionic groups, Al potently interferes with
reactions that depend on reversible dissociation. Pro-
cesses involving rapid Ca2+ exchange are inhibited
by Al substitution [6, 39, 150, 151]. Similarly, at
nanomolar concentrations, Al inhibits many Mg2+ and
ATP-dependent enzymes, including: tubulin GTPase
[149], Na+K+ATPase [153], hexokinase [146, 154],
RNA polymerase [155–157], choline acetyltrans-
ferase [158–160], ferroxidase (ceruloplasmin [161]),
calmodulin-dependent ATPase [6, 148, 150], as it binds
ATP in a complex that is several orders of magnitude
more stable than that with magnesium (the association
constant for Al3+ is 107times that of Mg2+ [149]).
Al also binds other nucleotides (GTP and CTP)
[162] as well as phosphate headgroups of lipid moieties
in membrane systems. Apart from altering mem-
brane properties [163], it has the potential to interfere
with any reaction that requires phosphoryl transfer
and ATP/GTP hydrolysis [6, 39, 147]. As mentioned
previously, Al in solution readily associates with fluo-
ride to form highly toxic fluoroaluminate complexes,
which are well known to interfere with the activity
of G-proteins and calcium homeostasis [39, 77–81].
Given the ubiquity of enzymatic systems and signaling
cascades that depend on GPCR signaling, phospho-
rylation, ATP, GTP, calcium, magnesium, and iron,
the spectrum of physiological processes that can be
582 L. Tomljenovic / Aluminum and Alzheimer’s Disease
adversely affected by Al is extremely vast. In spite of
this, in the absence of chronic renal failure, the toxic
effects of Al (especially at low doses) appear to be pri-
marily manifested in the brain (Table 1) [2, 6, 18, 19,
38, 47, 48, 50, 63, 70, 87, 107, 133, 146, 163–170],
although in vulnerable populations such as infants,
prolonged exposure at both high and low doses of Al
may also lead to metabolic bone disease [171, 172].
Notably, Al neurotoxicity appears to be compartmen-
talized as highly sensitive imaging techniques, as well
as methods for quantifying focal accumulations of Al,
repeatedly show that Al associates with specific brain
regions and cellular compartments [2, 41–44, 46–48,
59, 165, 173, 174]. That Al is a neurotoxin is beyond
debate, what appears to be or may be debatable is
whether it contributes to AD.
Regulation of body aluminum burden:
neurotoxicity increases with aging
In the human body Al burden is partitioned at four
levels: GI tract, blood-kidneys, brain barriers, and brain
extracellular fluid (ECF) [6, 27, 39, 68, 175, 176].
While the efficiency of absorption from the GI tract
and removal by the kidneys determines the amount of
Al in the blood, regulation at the brain barrier/brain
ECF levels determines where in the brain Al is dis-
tributed [6]. Systemic regulation of Al is far more
complex than initially thought as there are numerous
factors that affect Al partitioning at all four levels
(Table 3 – see footnote; Fig. 4) [6, 38, 39, 88, 93,
109, 135, 136, 177, 178]. The regulation of the Al
burden by the brain is geared towards maintaining opti-
mal neuronal function [6]. There are specific transport
mechanisms which ensure active and dynamic distri-
bution of the Al burden in the brain and this partially
mitigates its neurotoxic effects [6, 63, 68, 175]. These
observations indicate that the earlier animal models
of neurofibrillary degeneration (based on intracerebral
injection of Al), may not be adequate in assessing
the significance of bioavailable Al in the etiology of
AD. Likewise, dialysis dementia is not representative
of a truly chronic exposure to dietary ingested Al-
the chief risk for the majority of people, as the GI
barrier is bypassed by intravenous dialysate delivery.
Furthermore, patients with disabled urinary clearance
undergoing chronic treatment with Al-contaminated
dialysate, accumulate Al in tissues other than brain
(primarily bone and red blood cells; Table 2) [56, 179,
180]. In contrast, in healthy people only a minor frac-
tion of Al is absorbed from the GI tract (<1%) [33, 39,
88, 93], which is then in large proportion removed by
the kidneys. Hence, symptoms of Al intoxication only
become apparent when kidney function is impaired,
which occurs normally during aging as humans lose
up to 50% of their glomeruli between 40 and 85 years
of age [181]. Kidneys are a major route by which met-
als are excreted from the blood, and their essential
role in eliminating excess Al is emphasized by in vivo
observations which show that concurrent with neu-
rodegeneration, Al intoxication is often accompanied
by elevated Al kidney burden, glomerular distortions,
and renal failure [82].
Thus, when urinary clearance is impaired, the risk of
Al neurotoxicity significantly increases as it increases
the Al brain burden. This implies that a strong predis-
position for gradual accumulation of metabolic errors
consequent to Al toxicity, is somewhat inherent to the
aging process and explains how a life-long exposure
to low doses of Al could lead to Al accumulation
in neural cells and instigate a progressive cascade
of subtle neuropathological events that culminate in
AD. This contention is supported by the late age
of onset of clinical symptoms (>65 years) and rel-
atively slow progression of idiopathic AD (average
duration of illness is 10 years; Table 2), as well as
experimental evidence: 1) older persons have typi-
cally higher brain Al content than younger ones [41],
and subjects with AD have an even higher content
than non-demented age-matched controls (Table 2),
2) lower levels of serum Al than those routinely
reported in dialysis patients are known to produce
cognitive impairments associated with AD [169]. Per-
formance in behavioral tests correlates with serum
Al levels in elderly subjects and elevated Al is asso-
ciated with impaired visuo-motor coordination, poor
long-term memory and increased sensitivity to flicker.
Remarkably, the same effects are seen in rats chron-
ically fed with Al [169]. 3) Analysis of brain tissue
from AD patients shows a stage-specific accumulation
of Al in hippocampal neurons [47], 4) the studies of
Walton [2, 48, 70], elegantly demonstrate that in rats,
even at low doses, chronically administered dietary
Al preferentially accumulates in AD-susceptible brain
compartments, at levels sufficient to up-regulate APP
mRNA and protein expression.
The implication of these observations is that incre-
mental acquisition of small amounts of Al (as through
dietary intake), favors its selective accumulation in
brain tissues. The association between distribution of
brain Al and AD pathology likely implicates spe-
cific transport mechanisms, both circulatory and at the
level of brain barriers/brain ECF. Less likely, however,
remains the possibility that such compartmentalized
L. Tomljenovic / Aluminum and Alzheimer’s Disease 583
distribution reflects the impact of transport by non-Al
specific processes.
Aluminum toxicokinetics across the brain
barriers: more than just diffusion
Normal brain function is critically reliant on the
efficacy of brain barriers to maintain the delicate neuro-
chemical balance between neurons and their synaptic
connections [111]. Both, the BBB and the choroid
plexus (CP), play major roles in maintaining this bal-
ance by regulating the exchange of substances between
the blood ECF (plasma) and brain ECF (Fig. 4), and
thus any agent that can alter membrane properties has
a potential to initiate neurotoxic events. Alteration in
brain barrier permeability is not a prerequisite for Al
entry into the brain, as Al sequesters a myriad different
transport mechanisms to actively traverse membrane
systems, including receptor mediated endocytosis and
carrier-mediated transports (Fig. 4). The surface area
of the BBB capillaries in humans is 12 m2, which is
10,000-fold that of the choroid plexus (10 cm2) and
experimental evidence strongly implies that plasma Al
gains entrance to the brain ECF via the BBB route,
rather than through the CP (Fig. 4) [68]. Furthermore,
the kinetics of brain Al transport unequivocally points
to a carrier-mediated process and not passive diffu-
sion [27, 63, 68, 175]. Once in the brain ECF, Al will
either bind to polar headgroups of membrane phos-
pholipids, or enter intracellular pools, most probably
via transferrin uptake, monocarboxylate transporter
(MCT) – and/or organic anion transporter-mediated
mechanisms [6, 27, 68, 152, 175]. Endoplasmic retic-
ulum (ER), nuclear chromatin, hyperphosphorylated
tau, and ATP are believed to be the major binding tar-
gets of intracellular Al [6, 174, 182–184]. Repeated
chelation therapy with DFO in 26Al-treated rats shows
that some Al persists in the brain for a long time
(half-life of brain 26Al was estimated to be 150 and
55 days in the control and DFO-treated group respec-
tively) [68]. These data indicate that Al is tightly bound
to intracellular pools and are consistent with frequent
observations of perinuclear and nuclear foci of Al in
AD brains [10, 42, 47, 59, 182, 185].
Pyramidal neurons are a population of brain cells
that are particularly susceptible to Al accumulation and
toxicity [2, 43, 47, 50, 70]. These are also the largest
cells in the brain and one of the most vulnerable cell
populations in AD [1, 10, 43, 186, 187]. Cognitive
abilities as well as psychomotor control are intimately
associated with function of pyramidal cells [188, 189].
It is well known that brain tissue has a limited prolif-
erative capacity and as such, an intrinsic tendency for
accumulating metals [19, 146, 152, 190]. Toxins are
diluted in undifferentiated cells undergoing mitosis.
However, because pyramidal neurons are terminally
differentiated, the Al transported into these cells will
tend to accumulate over time. When accumulation of
metabolic errors at susceptible foci exceeds a certain
threshold, as a result of persistent latent Al toxicity,
clinical symptoms will become apparent. Consistent
with this hypothesis, abnormally high levels of Al are
routinely found in AD brains, up to fourfold the level
of healthy controls (Table 2) and sensitive quantify-
ing techniques demonstrate that perikarya of pyramidal
cells of the hippocampus and entorhinal cortex are
foci where Al accumulation is most pronounced, while
interneurons are spared [2, 43, 47, 50].
It is quite clear that Al partitioning within the brain
is highly complex and dynamic (Fig. 4). There are
three principal sources of bioavailable brain Al: extra-
cellular, membrane-bound, and intracellular. There is
also a further sub-partitioning among these sources.
Unlike the former two, the intracellular Al pool does
not appear to be readily mobilized as the kinetic control
at the level of terminally differentiated neurons favors
its accumulation (Fig. 4). This provides the basis for
a region-specific accumulation of Al, in a manner that
highly implicates its involvement in AD.
Fate of dietary aluminum: implications for
dysregulation of iron homeostasis and oxidative
damage
Al absorbed from the GI tract either becomes rapidly
bound to various high-molecular-weight carrier pro-
teins (including the iron-specific carriers transferrin
and ferritin as well as 2-macroglobulin, immunoglob-
ulin, hepatoglobin, and albumin) [19, 27, 68, 191–193]
or by low-molecular ligands such as citrate (Fig. 4)
[27, 175]. Experimental evidence has suggested that
at equilibrium, 80–90% of total Al in the plasma is
carried by transferrin [39, 68, 192], the chief iron trans-
port protein in vertebrates [19, 25, 152]. Although the
relative proportions of different Al complexes may
be different in non-equilibrium [194], it is the high
molecular weight-bound fraction of plasma Al (such
as transferrin-Al) that is perhaps more biologically
relevant, since it is refractory to excretion by the kid-
neys [38, 93]. Transferrin has a similarly high affinity
for Al3+ ions as for Fe3+ ions [152] and typically,
even under conditions of iron overload, only 30%
of transferrin is occupied by iron [19]. This leaves
a potentially high fraction of free transferrin avail-
584 L. Tomljenovic / Aluminum and Alzheimer’s Disease
able to Al and other metal ions which have been
shown to bind transferrin (zinc, gallium, manganese)
[152]. The cellular intake of transferrin-bound iron
occurs via transferin receptor (TfR)-mediated endocy-
tosis of the TfR-transferrin (iron) complexes [27, 68,
152, 195–197]. Several reports indicate that density
and binding to TfRs is decreased in AD. Morris et al.
[196] report a reduction in binding to TfRs in pyra-
midal cell layers of the hippocampus in AD brains,
which led them to conclude that TfR-mediated Al
uptake is not a major contributor to AD. However,
such localized loss of TfR-mediated endocytosis would
not significantly affect hippocampal Al uptake since
it is estimated that only 4% of Al within the brain
ECF pool is bound to transferrin and 90% is bound
to citrate, a vehicle for the MCT transporter (Fig. 4)
[68]. Furthermore, Al is known to use TfR-independent
mechanisms to gain access to brain compartments
from the brain ECF and the most likely candidate
for this process is citrate, the major Al carrier in the
brain ECF (Fig. 4) [27, 68, 175]. Most notably, recent
research evidence shows that Al-transferrin complexes
are not bound by the TfR [198–200] because of an
incomplete open/closed form which precludes them
from forming specific ionic inter-residual interactions,
such as those formed by iron-transferrin and the TfR
[198]. This implies that Al-transferrin transfer from
the blood stream to cytoplasm may not follow the
classical iron-TfR acquisition pathway. Nonetheless,
cellular uptake of Al-transferrin complexes has been
observed in different cell lines [201–204] indicating
that such complexes may be utilizing a yet unknown
mechanism by which they circumvent the incompati-
bility with the TfR to gain access to the intracellular
milieu. Apart from transferrin, Al may also bind to
the chief iron storage protein ferritin, and according to
a study by Fleming and Joshi [205], ferritin-bound Al
isolated from AD brains is 6-fold higher than that from
age-matched controls. Nonetheless, some investigators
have reported relatively little Al in ferritin deposits
[206, 207], suggesting that less Al is sequestered and
more is freely available to cause damage in cells [206].
Free iron is thought to be a principal mediator of
oxidation in cellular systems due to its ability to gener-
ate highly reactive oxidative species (ROS) via Fenton
chemistry [19, 26, 137, 208–210]. Unlike iron, Al is
redox inert and its ability to induce oxidative damage
is related to a synergistic action that involves iron [209,
211, 212]. Experimental evidence suggests that senile
amyloid plaques can act as sinks for free metals, both
redox active (iron and copper) and redox inactive (zinc
and Al) [213]. In addition, it has been shown that A42
can influence the Fenton chemistry through aggrega-
tion state-specific binding of both ferrous iron, Fe(II)
and ferric iron, Fe(III). According to Khan et al. [213],
the net result of these interactions was a delayed precip-
itation of redox-inactive iron (III) hydroxide, Fe(OH)3,
such that Fe(II)/Fe(III) were cycled in redox-active
forms over a substantially longer time period than if
peptide had been absent from preparations. Further
aggregation state-specific binding of both Fe(II) and
Fe(III) determined critical equilibria involved in the
formation of hydrogen peroxide via the superoxide
radical anion in favor of maintaining Fe(II) in solu-
tion [213]. The additional presence of Al, copper and
zinc influenced both the aggregation state of A42, and
therefore its binding of Fe(II) and Fe(III), as well as
the redox chemistry, most specifically through direct
interactions with the superoxide radical anion which
is heavily implicated in ROS mediated neurotoxicity
[213]. Finally, it was demonstrated that the addition
of pathophysiologically significant concentration of Al
exacerbated superoxide radical anion -induced toxicity
in the presence of A42 while both copper and zinc,
mitigated against oxidative damage but only providing
that Al was absent [213].
In conclusion, it is evident that by hijacking several
cellular transport mechanisms, Al gains direct access
to brain tissue, and that not all areas of the brain are
equally capable of removing the burgeoning Al bur-
den. Thus, long-term, the overt manifestations of Al
neurotoxicity may not be determined by the rate of
Al influx as much as Al efflux. Taken together, these
observations nullify the arguments that Al cannot enter
the brain actively and/or in sufficient amounts to cause
damage, and that cellular transport routes are not effec-
tively exploited by Al to the extent in which it could
have an impact on AD. Because of its high neurotoxic
potential, the factor that is of particular relevance in
regards to the risk for AD, is that small amounts of Al
can access the brain continually, to a point at which
neurotoxicity occurs. As documented (Tables 3–5),
this criterion is satisfied through dietary Al intake.
BRAIN COMPARTMENTALIZATION:
BASIS FOR ALUMINUM’S SELECTIVE
NEUROTOXICITY IN AD
Interference with glucose metabolism and
damaging effects on the myelin sheath
What makes the brain in general and certain brain
areas specifically more susceptible to Al toxicity? In
answering these questions, it should be emphasized
L. Tomljenovic / Aluminum and Alzheimer’s Disease 585
that brain is a highly compartmentalized organ, both
at systemic, tissue, as well as cellular levels. On a
systemic level, the brain has intrinsically high glu-
cose and oxygen requirements [19, 214, 215], high
surface area of biological membranes (especially vas-
cular endothelium) [68], high tubulin content [20],
high phospholipid content, and a low concentration
of antioxidants, compared with other organs [212,
215, 216]. For example, although an adult human
brain only weighs 1.5 kg, it consumes 20% of total
body oxygen and 120 g of glucose/day, compared
to 190 g for the whole body [19]. Furthermore, the
utilization of glucose varies in response to differ-
ent stimuli and among brain compartments [217].
More than 80% of brain glucose is used in the
glycolytic pathway that requires ATP/magnesium-
dependent activity of hexokinase, while the rest is
metabolized by the glucose-6-phosphate dehydroge-
nase (G6PD)-dependent shunt pathway [19].
Experimental evidence has shown that Al inter-
feres with glucose metabolism by inhibiting both hexo-
kinase and G6PD [19, 146, 154]. The latter is of
special significance since the shunt pathway is primar-
ily utilized by myelinated neurons and its activity is
dependent on the degree of myelination [218]. Fur-
thermore, as shown by Verstraeten et al. [212], Al (due
to its lipophilic nature), binds avidly to membrane
phospholipids and by inducing changes in phospho-
lipid rheology (Table 1), promotes lipid peroxidation
(LPO). Consequently, myelin (due to its high lipid
to protein ratio, 70 : 30 and relatively low ubiquinol
content, as opposed to synaptic membranes, 30 : 70),
is the preferred target of Al-mediated oxidative dam-
age both in vitro and in vivo [212]. Moreover, chronic
oral exposure to Al in rats markedly reduces the con-
tent of specific classes of membrane phospholipids
in the brain myelin sheath [216]. Specifically, Al-fed
rats show a 70% decrease in acidic phosphatidylinos-
itol (PI), phosphatidylserine (PS), and phosphatidic
acid (PA), an effect which is expected to alter charge
distribution and insulation properties of the myelin
membrane [216]. Alterations of the myelin sheath may
lead to dysfunctions in memory and cognition while a
marked reduction of the brain PI content is likely to
cause deficiencies in inositol phosphate (IP) signaling
(Fig. 2). Both of these effects have been observed in
Al-treated animals [63, 150, 167, 219, 220] and are
also common to AD [3–5, 8, 22, 23].
It is interesting to note that the highest myelin con-
tent is associated with pyramidal cells. Studies suggest
that axon collaterals of pyramidal neurons contribute
most to the total myelin brain content, and that non-
pyramidal neurons and afferent fibers play a minor role
[221]. Moreover, it has been demonstrated that a pro-
gressive loss of myelin in the human nervous system
occurs after the age of 30 years and that people suffer-
ing from presenile and senile dementia have a reduced
myelin content compared to healthy people [222]. It
is noteworthy that, with advancing age, there is a
concomitant loss of myelin content along with the dete-
rioration of kidney function [181]. This observation
reinforces the notion that a predisposing susceptibil-
ity to Al neurotoxicity is inherently and incrementally
acquired during aging, thus exacerbating the risk for
idiopathic AD.
As shown by Walton, cognitively impaired Al-
fed rats develop substantial hippocampal and cortical
lesions (related to NFTs), consisting of Al-loaded
pyramidal neurons [2, 48, 70]. These cells also show
significant morphological abnormalities, displaying
swollen neurites with varicosities along their length,
and myelin matter which is strongly immunoreactive
for APP [2, 70]. Finally, the progressive structural
changes reported to occur during aging in cortical
pyramidal neurons remarkably resemble those induced
by chronic dietary Al intake and include a reduction
in neurite number, length, and branching and ulti-
mately, the appearance of varicose deformities [222].
It is tempting to speculate that these age-related neu-
ronal aberrations may be partly due to cumulative
age-dependent effects of Al toxicity.
Compartmentalization by the cytoskeleton: how
aluminum triggers NFTs
The neuron is a highly cross-linked compartment
with extensive transport and communication net-
works which are imparted by the cytoskeleton.
MTs, neurofilaments (NFs), and MAPs, are essential
cytoskeletal components that sustain neuronal function
[20, 223]. Since breached integrity of the cytoskele-
ton is detrimental to neuronal function, any significant
interference with its structural components can result
in neuronal de-differentiation or possibly death. The
brain’s cytoskeletal system is somewhat unique as it
achieves compartmentalization at tissue, cellular and
subcellular levels. The brain has a far higher tubulin
content than other tissues [20], which may be related
to its intrinsically high metabolic activity and greater
distance requirements for cellular transport. There are
several tubulin isoforms and their distribution varies
between different brain and cellular compartments
[20]. NFs localize to axons and dendrites and primar-
ily function in stabilizing the axonal cytoskeleton and
586 L. Tomljenovic / Aluminum and Alzheimer’s Disease
promoting neurite outgrowth [223, 224]. Adding to the
complexity of the cytoskeletal lattice are the MAPs,
which promote the assembly of tubulin into MT poly-
mers [20, 223]. Furthermore, like tubulins and NFs,
MAPs also tend to be compartmentalized within neu-
rons [20]. Notably, both tau and NFs contain multiple
phosphorylation sites and are subjected to regulation
by various kinases and phosphatases [1, 225–227]. It
is proposed that the functional compartmentalization
that characterizes brain cells is enabled by a distinctive
localization of cytoskeletal components.
There are numerous components of the MT sys-
tem which are susceptible to Al (Table 1). One major
mechanism by which Al preferentially impairs pyra-
midal neurons is by disabling their capacity for MT
assembly [2, 10, 70]. This would cause disruption of
axoplasmic and dendritic transports, neurite damage,
and eventually, cell death [186]. Consistent with this,
Al accumulation in pyramidal cells from AD brains
is associated with depletion of MTs and abundance of
NFTs that contain Al [2]. Accordingly, rats chronically
exposed to low dietary Al show cognitive impair-
ment concomitant with pyramidal cell Al accumulation
and microtubule depletion, shriveling neurites and
synapse loss [2, 70]. Likewise, Al-induced neurofibril-
lary degeneration in rabbits selectively affects cortical
pyramidal neurons while sparing interneurons [43].
Oxidative stress and lipid peroxidation
Oxidative damage is thought to be an early event in
AD [17, 21, 228, 229] and Al is a known pro-oxidant
in vivo (Table 1) [164, 166, 230–232]. Al potentiates
oxidative damage by multiple mechanisms: it inhibits
the key free-radical scavenging enzymes superoxide
dismutase (SOD) and catalase [164], increases LPO
[212, 231], and modulates the induction of neuronal
nitric oxide synthase [232]. High metabolic activity
and low free radical buffering capacity, coupled with
400 miles of brain capillaries (and associated mem-
brane phospholipids) within the BBB [68], make the
human brain a prime target for Al-induced oxidative
damage. Accordingly, oxidative stress in the brain
is primarily manifested as LPO, due to its excep-
tionally high content of polyunsaturated fatty acids
(PUFAs, constituents of membrane phospholipids),
that are particularly vulnerable to oxidation [21, 229].
Isoprostanes (iPs) are chemically stable isomers of
prostaglandins (formed by peroxidation of PUFAs)
and specific and sensitive markers of in vivo LPO
[233–235]. Studies show that levels of a major iP
marker 8,12-iso-iPF2-VI are increased postmortem
in AD-susceptible brain compartments [235] as well
as in the urine, plasma, and cerebrospinal fluid (CSF)
of patients with a clinical diagnosis of AD [234]
where 8,12-iso-iPF2-VI levels correlated with dis-
ease severity. Remarkably, these observations were
experimentally reproduced in a mouse model of AD-
like amyloidosis (Tg2576), in which mice overexpress
a double mutant human APP transgene. In Tg2576
mice, chronically administered dietary Al increased
8,12-iso-iPF2-VI levels in the hippocampus and neo-
cortex and concomitantly, also increased Alevels and
stimulated plaque deposition [231]. Notably, none of
these pathogenic changes were observed in Tg2675
mice fed a regular chow diet. Moreover, Al-induced
increases in 8,12-iso-iPF2-VI levels and amyloid
plaque burden in the hippocampus and neocortex were
directly correlated and almost completely reversed by
supplementation with antioxidant vitamin E. Further-
more, early in the course of treatment, plasma and urine
8,12-iso-iPF2-VI levels also increased in Al-fed mice,
but they were reduced in mice supplemented with vita-
min E [231]. These results provide compelling in vivo
evidence that dietary Al can drive and accelerate the
amyloid cascade by potentiating LPO and oxidative
stress. They are also in concordance with emerging
data from prior experiments in Tg2576 [21], as well as
studies of AD patients, which indicate that increased
levels of 8,12-iso-iPF2-VI in blood or urine appear
to precede the onset of AD, and that LPO is central
to AD [234]. Similar effects of Al on oxidative stress
were observed in rats (both adult and pups), where
chronically administered Al (by daily oral gavage) sig-
nificantly increased LPO and decreased the activity
of two key antioxidant enzymes, SOD and catalase in
specific brain regions [164].
Effects on chromatin structure and transcription
The nucleus is another prime target for Al toxic-
ity due to its high anionic microenvironment (Table 1)
[155, 236]. Consistently, focal accumulation of Al in
neuronal nuclei has been widely documented and rec-
ognized as a distinguishing feature in AD [42, 47,
59, 156, 174, 185]. Al binds to phosphonucleotides
and alters DNA interaction with nucleoproteins, tran-
scription factors and RNA polymerase. The effects
of nuclear Al have been extensively studied and are
accordingly best summarized by Lukiw et al. “The
presence of aluminum is an impediment to normal
brain gene function” [155]. At nanomolar concen-
trations, Al inhibits brain-specific gene transcription
from selected AT-rich promoters of human neocortical
L. Tomljenovic / Aluminum and Alzheimer’s Disease 587
genes [155]. Al repressive action on gene transcrip-
tion is linked to its ability to: 1) decrease the access of
transcriptional machinery to initiation sites on DNA
template by enhancing chromatin condensation [174,
182–185], 2) interfere with ATP-hydrolysis-powered
separation of DNA strands either indirectly (by binding
to phosphonucleotides and increasing the stability and
melting temperature of DNA) [155, 236] or directly
(by inhibiting the ATPase-dependent action of RNA
polymerase) [155]. These effects were experimentally
demonstrated at physiologically-relevant Al concen-
trations (10–100 nm [155, 157]) and at levels that have
been reported in AD chromatin fractions [185]. Of
particular relevance, highly condensed cortical chro-
matin fractions and increased linker histone content on
dinucleosomes are typical features of both idiopathic
and familial AD [185]. Al is well known to promote
chromatin compaction by increasing the association
of DNA with linker histones H10and H1 [174, 182,
184, 185]. Accordingly, compared to aged matched
controls, AD subjects show a nine-fold increase in
Al content in the dinucleosome fraction containing
repressed neuronal genes. Moreover, a highly signifi-
cant correlation was found between the Al DNA ratio
and the degree of chromatin compaction [65, 185].
It is particularly interesting to note that in spite
of its overall repressive action, Al can also promote
transcription. Based on experimental evidence, it has
been suggested that by promoting LPO and oxidative
stress, Al activates the ROS-sensitive transcription fac-
tors, hypoxia inducible factor-1 (HIF-1) and nuclear
factor (NF)-B and augments specific neuroinflamma-
tory and pro-apoptotic signaling cascades by driving
the expression from a subset of HIF-1 and NF-B–
inducible promoters [209, 237]. Out of eight induced
genes up-regulated in cultured human neurons by
100 nm Al sulfate (the same compound that is used as a
flocculant in water [38, 39]), seven showed expression
patterns similar to those observed in AD, includ-
ing HIF-1/NF-B-responsive APP, interleukin-1
(IL-1) precursor, NF-B subunits, cytosolic phos-
pholipase A2(cPLA2), cyclooxygenase (COX)-2, and
DAXX, a regulatory protein known to induce apop-
tosis and repress transcription [237]. Both HIF-1 and
NF-B are up-regulated in AD where they fuel the pro-
inflammatory cycle which leads to further exacerbation
of oxidative stress and inflammation, culminating in
neuronal death [16, 155, 209]. The ability to induce
HIF-1/NF-B-dependent up-regulation of APP may
well be the underpinning mechanism by which Al trig-
gers oxidative stress-mediated amyloidosis in Tg2576
mice [231].
Interference with neurotransmission, G-proteins,
and calcium homeostasis
Dysregulation of G-protein mediated signal trans-
duction and calcium homeostasis is central to the
etiology of AD and it is thought to precede the amy-
loid cascade and NFT changes [4, 5, 8, 12, 238].
G-proteins and calcium modulate vital neuronal pro-
cesses such as neurotransmission, synaptic plasticity,
and apoptosis [3, 12, 23, 28]. Al interferes with
several components of the two principal G-protein
signaling pathways: GPCR-regulated 1) phospholi-
pase C (PLC)/inositol 1,4,5-trisphosphate (IP3) and
2) adenylate cyclase (AC)/cyclic AMP (cAMP) path-
way (Table 1, Fig. 2). Alterations in both of these
pathways have been demonstrated in AD brains
at numerous levels [3–5, 8, 28, 239]. Explicitly,
impaired response to Gq-cholinergic muscarinic recep-
tor agonist-induced PI hydrolysis by PLC, decreased
levels and activity of PKC and the loss of IP3recep-
tors in the entorhinal cortex and hippocampus correlate
with AD-NFT pathology [3–5, 8, 239]. Disruptions
in the AC pathway in AD include impairments at the
levelofG
s-protein stimulation of AC [5], increased
cAMP in cerebral microvessels [239] and loss of cal-
cium/calmodulin (CaM) sensitive AC isoforms [5].
Overall, G-protein levels are largely preserved in AD,
indicating a functional deficit [4, 5, 8].
Al action on G-proteins has been shown to be highly
specific. While Al inhibits Gq-mediated PI hydrolysis
by PLC, it stimulates Gs-mediated cAMP production
by AC (Table 1, Fig. 2). Most notably, these effects
were observed in vivo after chronic oral exposure to
Al-treated drinking water in weanling and adult rats
[167]. In summary, impaired response to agonists at
Gq/Gslevels, elevated cAMP, PLC inhibition and IP3
decrease and impairment of calcium/CaM-dependent
enzymes are specific signatures of Al neurotoxicity
(Table 1, Fig. 2). These changes perfectly reproduce
the hallmark changes observed in AD [3–5, 8, 28, 239].
Similarly, the neurotoxic effects of Al mimic choliner-
gic dysfunction, another hallmark of AD, in a manner
that highly implicates its central role in the pathogen-
esis of this disease (Table 1). Acetylcholine (ACh)
release from cholinergic neurons alters the excitability
of hippocampal pyramidal neurons [150]. By interfer-
ing with G-proteins and altering calcium homeostasis,
Al toxicity causes reductions in neuronal excitabil-
ity, impairs neurotransmission and progressively leads
to memory and learning deficits. Furthermore, by
inhibiting agonist-mediated stimulation of cholinergic
muscarinic receptors and disabling the IP3/PLC signal
588 L. Tomljenovic / Aluminum and Alzheimer’s Disease
transduction pathway, Al may shift APP processing
towards an increase in production of the neurotoxic
A-peptide, at the expense of the neuroprotective
-secretase-derived soluble APP (s–APP;
Table 1, Figs 1 and 2). This would explain gross abnor-
malities in neurite morphology, losses of synapses and
neurons that are seen to occur concomitantly with
APP upregulation in Al-fed rats [2, 70, 82, 83]. This
is also consistent with the type of damage observed in
AD brains [2, 70, 82, 83], given that s-APP function
is required for proper neurite outgrowth and branching
[240, 241] and to counteract pro-apoptotic signaling
and synaptogenesis [241, 242]. It is worth emphasiz-
ing that Al may induce amyloidosis by up-regulating
APP expression, altering APP processing and traf-
ficking to increase the production of toxic Aspecies,
and promoting their aggregation into fibrillar structural
constituents of senile plaques (Table 1, Figs 1 and 2).
Thus, it appears that all pathological parameters
required for amyloidogenesis are efficiently targeted
by Al.
In summary, it is evident that the brain’s structural
and functional heterogeneity provides a basis for differ-
ential susceptibility of specific neuronal populations to
Al toxicity. The above observations re-emphasize the
hypothesis that Al aggravates the risk of developing
age-related dementia of the Alzheimer type, by driv-
ing subtle though persistent incremental deterioration
of neural functions at a susceptible foci.
CONCLUSIONS
Al is the third most abundant element on earth,
widely bioavailable to humans and a definite neuro-
toxin and AD is the most prevalent neurodegenerative
disease at the present age. The hypothesis that Al
significantly contributes to AD, more so than any
other single factor investigated, is built upon very
solid experimental evidence. Al has a direct and
active access to the brain where it accumulates in
a region-specific manner that highly implicates its
involvement in AD. Experimental data clearly shows
that all neurophysiological parameters required for
AD are efficiently targeted for impairment by Al. The
sum of latent neurophysiological alterations which
are known to precede overt clinical manifestations of
AD and are consistent with Al’s neurotoxic proper-
ties are: 1) enhanced amyloidosis, 2) neurofibrillary
abnormalities, disruption of axonal transport mech-
anisms, neurite degeneration, and loss of synapses,
3) deficits in neurotransmission (particularly choliner-
gic) and impairment of G-protein signal transduction
cascades, 4) disruption of neuronal energy metabolism
and brain metal homeostasis (particularly calcium iron
and magnesium), 5) potentiation of oxidative stress and
peroxidation of brain membrane lipids, 6) disruption
of brain barriers, 7) alterations in chromatin structure
and impairment of transcription, and 8) upregulation
of stress-related pro-inflammatory and pro-apoptotic
pathways. The latter may be of special significance
since elevated levels of intrinsic inflammation are asso-
ciated with neural aging and further exacerbated in
several neurodegenerative diseases. In stark contradic-
tion with the abundance of research evidence (Table 1),
there appear to be “several hostile intellectual atti-
tudes” [14] that reject the possibility that Al toxicity
contributes to the growing incidence of AD [243, 244].
Such widely circulated opinions hamper implementa-
tion of preventative plans to lessen exposure to Al,
which, according to some leading scientists’ advice,
would be the most sound and cost-effective approach
to reduce the growing incidence of Alzheimer’s type
dementia [32, 33, 91, 98, 100, 245, 246]. Given the
great socio-economical impact of AD, immediate steps
should be taken to minimize human exposure to Al, the
single most avoidable factor that poses a serious risk
for developing AD. The failure of government health
policy makers to take into account the most recent ani-
mal studies [2, 48, 61, 70, 82, 83, 107, 165, 167, 178,
231], as well as epidemiological data [99–105, 108]
which clearly relate long-term Al ingestion at levels
relevant to human exposure to an increased risk of cog-
nitive impairment and dementia of the Alzheimer-type,
leads to human AD cases as a major means for demon-
strating the neurotoxic potential of Al. This practice is
unacceptable but unfortunately prevalent at the present
time: “Current dietary patterns in the USA are akin
to a grand-scale experiment whereby some individu-
als are consuming large quantities of aluminum while
others are not, the long term effects of which have not
been investigated” [91]. It would appear that the prac-
tical considerations of warnings given by William Gies
are now 100 years overdue “These studies have con-
vinced me that the use in food of aluminum or any
other aluminum compound is a dangerous practice.
That the aluminum ion is very toxic is well known.
That aluminized food yields soluble aluminum com-
pounds to gastric juice (and stomach contents) has
been demonstrated. That such soluble aluminum is in
part absorbed and carried to all parts of the body by
the blood can no longer be doubted. That the organism
can “tolerate” such treatment without suffering harm-
ful consequences has not been shown. It is believed that
L. Tomljenovic / Aluminum and Alzheimer’s Disease 589
the facts in this paper will give emphasis to my convic-
tion that aluminum should be excluded from food” [98].
The same rationale would apply for Al in skin-care
products, antiperspirants, pharmaceuticals, and per-
haps significantly in vaccines, at least until independent
research is available to demonstrate that these products
can be used safely. In particular, Al in adjuvant form
carries a risk for long-term brain inflammation, cyto-
toxicity, and associated neurological complications,
and may thus have profound and widespread adverse
health consequences. We are long overdue for a com-
prehensive evaluation of the overall impact of Al on
human health. With regards to AD, such an evalua-
tion should include studies designed to elucidate the
molecular mechanisms involved in the neurotoxicity
caused by chronic Al intake and its association with
the metabolism of other compounds such as iron. Spe-
cial emphasis should be given to Al species which are
most relevant to human exposure (e.g., fluoroalumi-
nates, Al hydroxide, Al sulfate). As for the reasons for
the current complacency about Al toxicity to humans
from bioavailable sources, some on the other side of
the issue have noted that: “Some have argued that I
should have been more vocal about the fact that paid
consultants for the aluminum industry served as con-
sistent and vocal critics of our findings. I always felt,
perhaps naively, that our data were properly collected,
honestly and completely reported and were essentially
correct. Accordingly, I have felt that the truth would
eventually be known and ultimately accepted” [247].
Food for thought?
ACKNOWLEDGMENTS
The author would like to thank C. Exley, C.A. Shaw,
J.R Walton, and M.J. Ridd for critical discussions about
different parts of this manuscript. The author has no
actual or potential conflict of interest in this manuscript
or in the work that is the subject of this manuscript. No
commercial entity paid or directed, or agreed to pay
or direct, any benefits to the author or to any research
fund, foundation, educational institution, or other char-
itable or non-profit organization with which the author
is affiliated or associated.
The author’s disclosure is available online (http://
www.j-alz.com/disclosures/view.php?id=676).
REFERENCES
[1] Thomas P, Fenech M (2007) A review of genome mutation
and Alzheimer’s disease. Mutagenesis 22, 15-33.
[2] Walton JR (2009) Brain lesions comprised of aluminum-
rich cells that lack microtubules may be associated with the
cognitive deficit of Alzheimer’s disease. Neurotoxicology
30, 1059-1069.
[3] Thathiah A, De Strooper B (2009) G protein-coupled
receptors, cholinergic dysfunction, and Abeta toxicity in
Alzheimer’s disease. Sci Signal 2, re8.
[4] Garcia-Jimenez A, Cowburn RF, Ohm TG, Lasn H, Winblad
B, Bogdanovic N, Fastbom J (2002) Loss of stimulatory
effect of guanosine triphosphate on [(35)S]GTPgammaS
binding correlates with Alzheimer’s disease neurofibrillary
pathology in entorhinal cortex and CA1 hippocampal sub-
field. J Neurosci Res 67, 388-398.
[5] Cowburn RF, O’Neill C, Bonkale WL, Ohm TG, Fastbom
J (2001) Receptor-G-protein signalling in Alzheimer’s dis-
ease. Biochem Soc Symp 67, 163-175.
[6] Exley C (1999) A molecular mechanism of aluminium-
induced Alzheimer’s disease? J InorgBiochem 76, 133-140.
[7] Davis DG, Schmitt FA, Wekstein DR, Markesbery WR
(1999) Alzheimer neuropathologic alterations in aged cog-
nitively normal subjects. J Neuropathol Exp Neurol 58,
376-388.
[8] Greenwood AF, Powers RE, Jope RS (1995) Phosphoinosi-
tide hydrolysis, G alpha q, phospholipase C, and protein
kinase C in post mortem human brain: effects of post mortem
interval, subject age, and Alzheimer’sdisease. Neuroscience
69, 125-138.
[9] Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL
(1984) Alzheimer’s disease: cell-specific pathology isolates
the hippocampal formation. Science 225, 1168-1170.
[10] Bertholf RL (1987) Aluminum and Alzheimer’s disease:
perspectives for a cytoskeletal mechanism. Crit Rev Clin
Lab Sci 25, 195-210.
[11] Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L,
Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm
A, Mathers C, Menezes PR, Rimmer E, Scazufca M (2005)
Global prevalence of dementia: a Delphi consensus study.
Lancet 366, 2112-2117.
[12] LaFerla FM (2002) Calcium dyshomeostasis and intracel-
lular signalling in Alzheimer’s disease. Nat Rev Neurosci 3,
862-872.
[13] Annaert W, Cupers P, Saftig P, De Strooper B (2000) Pre-
senilin function in APP processing. Ann N Y Acad Sci 920,
158-164.
[14] Drago D, Bolognin S, Zatta P (2008) Role of metal ions in the
abeta oligomerization in Alzheimer’s disease and in other
neurological disorders. Curr Alzheimer Res 5, 500-507.
[15] Miu AC, Benga O (2006) Aluminum and Alzheimer’s dis-
ease: a new look. J Alzheimers Dis 10, 179-201.
[16] Lukiw WJ, Bazan NG (2000) Neuroinflammatory signal-
ing upregulation in Alzheimer’s disease. Neurochem Res
25, 1173-1184.
[17] Pratico D, Delanty N (2000) Oxidative injury in diseases of
the central nervous system: focus on Alzheimer’s disease.
Am J Med 109, 577-585.
[18] Walton JR (1996) Amyloid, aluminium and the aetiology of
Alzheimer’s disease. Med J Aust 164, 382-383.
[19] Joshi JG, Dhar M, Clauberg M, Chauthaiwale V (1994)
Iron and aluminum homeostasis in neural disorders.
Environ Health Perspect 102(Suppl 3), 207-213.
[20] Matsuyama SS, Jarvik LF (1989) Hypothesis: microtubules,
a key to Alzheimer disease. Proc Natl Acad Sci U S A 86,
8152-8156.
[21] Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM
(2001) Increased lipid peroxidation precedes amyloid
590 L. Tomljenovic / Aluminum and Alzheimer’s Disease
plaque formation in an animal model of Alzheimer amy-
loidosis. J Neurosci 21, 4183-4187.
[22] Buxbaum JD, Ruefli AA, Parker CA, Cypess AM,
Greengard P (1994) Calcium regulates processing of the
Alzheimer amyloid protein precursor in a protein kinase
C-independent manner. Proc Natl Acad SciUSA91, 4489-
4493.
[23] Kurumatani T, Fastbom J, Bonkale WL, Bogdanovic N,
Winblad B, Ohm TG, Cowburn RF (1998) Loss of inositol
1,4,5-trisphosphate receptor sites and decreased PKC levels
correlate with staging of Alzheimer’s disease neurofibrillary
pathology. Brain Res 796, 209-221.
[24] Thompson K, Menzies S, Muckenthaler M, Torti FM, Wood
T, Torti SV, Hentze MW, Beard J, Connor J (2003) Mouse
brains deficient in H-ferritin have normal iron concentra-
tion but a protein profile of iron deficiency and increased
evidence of oxidative stress. J Neurosci Res 71, 46-63.
[25] Connor JR, Menzies SL, St Martin SM, Mufson EJ (1992)
A histochemical study of iron, transferrin, and ferritin in
Alzheimer’s diseased brains. J Neurosci Res 31, 75-83.
[26] Kell DB (2009) Iron behaving badly: inappropriate iron
chelation as a major contributor to the aetiology of vas-
cular and other progressive inflammatory and degenerative
diseases. BMC Med Genomics 2,2.
[27] Yokel RA (2006) Blood-brain barrier flux of aluminum,
manganese, iron and other metals suspected to contribute
to metal-induced neurodegeneration. J Alzheimers Dis 10,
223-253.
[28] Lumbreras M, Baamonde C, Martinez-Cue C, Lubec G,
Cairns N, Salles J, Dierssen M, Florez J (2006) Brain G
protein-dependent signaling pathways in Down syndrome
and Alzheimer’s disease. Amino Acids 31, 449-456.
[29] Pratico D, Trojanowski JQ (2000) Inflammatory hypothe-
ses: novel mechanisms of Alzheimer’s neurodegeneration
and new therapeutic targets? Neurobiol Aging 21, 441-445;
discussion 451-443.
[30] Nee LE, Eldridge R, Sunderland T, Thomas CB, Katz D,
Thompson KE, Weingartner H, Weiss H, Julian C, Cohen R
(1987) Dementia of the Alzheimer type: clinical and family
study of 22 twin pairs. Neurology 37, 359-363.
[31] Gupta VB, Anitha S, Hegde ML, Zecca L, Garruto RM,
Ravid R, Shankar SK, Stein R, Shanmugavelu P, Jagannatha
Rao KS (2005) Aluminium in Alzheimer’s disease: are we
still at a crossroad? Cell Mol Life Sci 62, 143-158.
[32] Exley C (2001) Aluminium and Alzheimer’s Disease:
The Science that Describes the Link, Elsevier Science,
Amsterdam, p. 452.
[33] Moore PB, Day JP, Taylor GA, Ferrier IN, Fifield LK,
Edwardson JA (2000) Absorption of aluminium-26 in
Alzheimer’s disease, measured using accelerator mass spec-
trometry. Dement Geriatr Cogn Disord 11, 66-69.
[34] Savory J, Exley C, Forbes WF, Huang Y, Joshi JG, Kruck
T, McLachlan DR, Wakayama I (1996) Can the controversy
of the role of aluminum in Alzheimer’s disease be resolved?
What are the suggested approaches to this controversy and
methodological issues to be considered? J Toxicol Environ
Health 48, 615-635.
[35] Forbes WF, Hill GB (1998) Is exposure to aluminum a risk
factor for the development of Alzheimer disease? – Yes.
Arch Neurol 55, 740-741.
[36] Munoz DG (1998) Is exposure to aluminum a risk factor for
the development of Alzheimer disease? – No. Arch Neurol
55, 737-739.
[37] Exley C, Korchazhkina O, Job D, Strekopytov S, Polwart
A, Crome P (2006) Non-invasive therapy to reduce the body
burden of aluminium in Alzheimer’s disease. J Alzheimers
Dis 10, 17-24; discussion 29-31.
[38] ATSDR (2008) Toxicological profile for aluminum. Agency
for toxic substances and disease registry, Atlanta, GA,
p. 357, http://www.atsdr.cdc.gov/toxprofiles/tp22.html, Last
Updated August 7, Accessed on July 4 2010.
[39] Carson (2000) Aluminum Compounds. Review of Tox-
icological Literature, Abridged Final Report, Integrated
Laboratory Systems, Research Triangle Park, NC, p.
84, http://ntp.niehs.nih.gov/ntp/htdocs/Chem Background/
ExSumpdf/Aluminum.pdf, Accessed on July 2010.
[40] Priest ND (1993) Satellite symposium on Alzheimer’s dis-
ease and dietary aluminium. Proc Nutr Soc 52, 231-240.
[41] McDermott JR, Smith AI, Iqbal K, Wisniewski HM (1979)
Brain aluminum in aging and Alzheimer disease. Neurology
29, 809-814.
[42] Perl DP, Brody AR (1980) Alzheimer’s disease: X-ray
spectrometric evidence of aluminum accumulation in neu-
rofibrillary tangle-bearing neurons. Science 208, 297-299.
[43] Kowall NW, Pendlebury WW, Kessler JB, Perl DP, Beal
MF (1989) Aluminum-induced neurofibrillary degenera-
tion affects a subset of neurons in rabbit cerebral cortex,
basal forebrain and upper brainstem. Neuroscience 29,
329-337.
[44] Edwardson JA, Candy JM, Ince PG, McArthur FK, Morris
CM, Oakley AE, Taylor GA, Bjertness E (1992) Aluminium
accumulation, beta-amyloid deposition and neurofibrillary
changes in the central nervous system. Ciba Found Symp
169, 165-179; discussion 179-185.
[45] Harrington CR, Wischik CM, McArthur FK, Taylor GA,
Edwardson JA, Candy JM (1994) Alzheimer’s-disease-like
changes in tau protein processing: association with alu-
minium accumulation in brains of renal dialysis patients.
Lancet 343, 993-997.
[46] Perl DP, Moalem S (2006) Aluminum and Alzheimer’s dis-
ease, a personal perspective after 25 years. J Alzheimers Dis
9, 291-300.
[47] Walton JR (2006) Aluminum in hippocampal neurons from
humans with Alzheimer’s disease. Neurotoxicology 27, 385-
394.
[48] Walton JR (2009) Functional impairment in aged rats
chronically exposed to human range dietary aluminum
equivalents. Neurotoxicology 30, 182-193.
[49] McLachlan DRC, Krishnan SS, Dalton AJ (1973) Brain alu-
minum distribution in Alzheimer’sdisease and experimental
neurofibrillary degeneration. Science 180, 511-513.
[50] Matyja E (2000) Aluminum enhances glutamate-mediated
neurotoxicity in organotypic cultures of rat hippocampus.
Folia Neuropathol 38, 47-53.
[51] Andrasi E, Pali N, Molnar Z, Kosel S (2005) Brain alu-
minum, magnesium and phosphorus contents of control and
Alzheimer-diseased patients. J Alzheimers Dis 7, 273-284.
[52] Uemura E (1984) Intranuclear aluminum accumulation in
chronic animals with experimental neurofibrillary changes.
Exp Neurol 85, 10-18.
[53] Chafi AH, Hauw JJ, Rancurel G, Berry JP, Galle C (1991)
Absence of aluminium in Alzheimer’s disease brain tissue:
electron microprobe and ion microprobe studies. Neurosci
Lett 123, 61-64.
[54] Landsberg JP, McDonald B, Watt F (1992) Absence of alu-
minium in neuritic plaque cores in Alzheimer’s disease.
Nature 360, 65-68.
[55] Priest ND, Talbot RJ, Newton D, Day JP, King SJ, Fifield
LK (1998) Uptake by man of aluminium in a public water
supply. Hum Exp Toxicol 17, 296-301.
L. Tomljenovic / Aluminum and Alzheimer’s Disease 591
[56] Gupta DM (2003) Renal osteodystrophy and aluminium
bone disease in patients with chronic renal failure. JK Prac-
titioner 10, 107-111.
[57] Wills MR, SavoryJ (1985) Water content of aluminum, dial-
ysis dementia, and osteomalacia. Environ Health Perspect
63, 141-147.
[58] Shore D, Wyatt RJ (1983) Aluminum and Alzheimer’s dis-
ease. J Nerv Ment Dis 171, 553-558.
[59] McLachlan DRC, Quittkat S, Krishnan SS, Dalton AJ,
De Boni U (1980) Intranuclear aluminum content in
Alzheimer’s disease, dialysis encephalopathy, and exper-
imental aluminum encephalopathy. Acta Neuropathol 50,
19-24.
[60] McLachlan DRC, Dalton AJ, Kruck TP, Bell MY, Smith
WL, Kalow W, Andrews DF (1991) Intramuscular desfer-
rioxamine in patients with Alzheimer’s disease. Lancet 337,
1304-1308.
[61] Walton JR (2007) A longitudinal study of rats chronically
exposed to aluminum at human dietary levels. Neurosci Lett
412, 29-33.
[62] Klaasen CD (1996) Heavy metals and heavy metal antago-
nists. In Goodman & Gilson’s The Pharmacological Basis of
Therapeutics, Hardman JG, Limbird LE, eds, McGraw-Hill,
New York, pp. 1649-1672.
[63] Yokel RA, Allen DD, Meyer JJ (1994) Studies of aluminum
neurobehavioral toxicity in the intact mammal. Cell Mol
Neurobiol 14, 791-808.
[64] Lai JC, Lim L, Davison AN (1982) Effects of Cd2+,Mn
2+,
and Al3+on rat brain synaptosomal uptake of noradrenaline
and serotonin. J Inorg Biochem 17, 215-225.
[65] Lukiw WJ, Kruck TP, McLachlan DR (1987) Alterations
in human linker histone-DNA binding in the presence of
aluminum salts in vitro and in Alzheimer’s disease. Neuro-
toxicology 8, 291-301.
[66] Landsberg J, McDonald B, Grime G, Watt F (1993)
Microanalysis of senile plaques using nuclear microscopy.
J Geriatr Psychiatry Neurol 6, 97-104.
[67] Walton J, Tuniz C, Fink D, Jacobsen G, Wilcox D (1995)
Uptake of trace amounts of aluminum into the brain from
drinking water. Neurotoxicology 16, 187-190.
[68] Yokel RA (2002) Brain uptake, retention, and efflux of
aluminum and manganese. Environ Health Perspect 110
(Suppl. 5), 699-704.
[69] King SJ, Oldham C, Popplewell JF, Carling RS, Day JP,
Fifield LK, Cresswell RG, Liu K, di Tada ML (1997)
Determination of aluminium-26 in biological materials by
accelerator mass spectrometry. Analyst 122, 1049-1055.
[70] Walton JR, Wang MX (2009) APP expression, distribution
and accumulation are altered by aluminum in a rodent model
for Alzheimer’s disease. J Inorg Biochem 103, 1548-1554.
[71] WHO (1998) Aluminium in Drinking-water. Background
document for development of WHO Guidelines for
drinking-water quality. In Guidelines for Drinking-Water
Quality, 2nd ed., Addendum to Vol. 2. Health Health
Criteria and Other Supporting Information, Geneva, p. 14,
http://www.who.int/water sanitation health/dwq/chemicals/
en/aluminium.pdf, Accessed on July 4 2010.
[72] Barabasz W, Albi´
nska D, Ja´
skowska M, Lipiec J (2002)
Ecotoxicology of Aluminium. Pol J Env Stud 11, 199-203.
[73] Miller RG, Kopfler FC, Kelty KC, Stober JA, Ulmer NS
(1984) The occurrence of aluminum in drinking water.
J Am Water Works Assoc 76, 84-91.
[74] Plunkert PA (1998) Aluminum. Annual average pri-
mary aluminum price. USMB, 1-4, http://minerals.usgs.gov/
minerals/pubs/commodity/aluminum/050798.pdf
[75] Zhang P, McCormick M, Hughes J (1994) Behaviour of alu-
minium during water treatment. In Research report No. 85,
Melbourne: Urban WaterResearch Association of Australia,
Melbourne, p. 135.
[76] Shovlin MG, Yoo RS, Crapper-McLachlan DR, Cummings
E, Donohue JM, Hallman WK, Khachaturian Z,
OrmeZavaleta J, Teefy S (1993) Aluminium in drinking
water and Alzheimer’s disease; a resource guide. In AWWA
Research Foundation and the American Water Works
Association, Denver, CO, pp. 7-8.
[77] Strunecka A, Strunecky O, Patocka J (2002) Fluoride plus
aluminum: useful tools in laboratory investigations, but
messengers of false information. Physiol Res 51, 557-564.
[78] Strunecka A, Patocka J, Blaylock RL, Chinoy NJ (2007) Flu-
oride interactions: from molecules to diseases. Curr Signal
Transduct Ther 2, 190-213.
[79] Strunecka A, Patocka J (2002) Aluminofluoride complexes:
A Useful Tool in Laboratory Investigations, but a Hidden
Danger for Living Organisms? ACS Symposium Series, 822,
American Chemical Society, pp. 271-282.
[80] Chen Y, Penington NJ (2000) Competition between internal
AlF4-Stimulation of dorsal raphe neuron G-proteins cou-
pled to calcium current inhibition. J Neurophysiology 83,
1273-1282.
[81] Bigay J, Deterre P, Pfister C, Chabre M (1987) Fluoride
complexes of aluminium or beryllium act on G-proteins
as reversibly bound analogues of the gamma phosphate of
GTP. EMBO J 6, 2907-2913.
[82] Varner JA, Jensen KF, Horvath W, Isaacson RL (1998)
Chronic administration of aluminum-fluoride or sodium-
fluoride to rats in drinking water: alterations in neuronal
and cerebrovascular integrity. Brain Res 784, 284-298.
[83] Varner JA, Horvath WJ, Huie CW, Naslund HR, Isaacson
RL (1994) Chronic aluminum fluoride administration. I.
Behavioral observations. Behav Neural Biol 61, 233-241.
[84] Ziegelbecker F (1998) Fluoridation in Europe. Fluoride 31,
171-174.
[85] Alzheimer A (1907) Ueber einen eigenartige Erkrankung
der Hirnrinde. Zentralblatt fur Nervenheilkunde und Psy-
chiatrie 30, 177-179.
[86] James GWB (1926) The treatment of senile insanity. Lancet
2, 820-821.
[87] Shaw CA, Petrik MS (2009) Aluminum hydroxide injec-
tions lead to motor deficits and motor neuron degeneration.
J Inorg Biochem 103, 1555-1562.
[88] Yokel RA, Hicks CL, Florence RL (2008) Aluminum
bioavailability from basic sodium aluminum phosphate, an
approved food additive emulsifying agent, incorporated in
cheese. Food Chem Toxicol 46, 2261-2266.
[89] Saiyed SM, Yokel RA (2005) Aluminium content of some
foods and food products in the USA, with aluminium food
additives. Food Addit Contam 22, 234-244.
[90] Lopez FE, Cabrera C, Lorenzo ML, Lopez MC (2002) Alu-
minum levels in convenience and fast foods: in vitro study
of the absorbable fraction. Sci Total Environ 300, 69-79.
[91] Rogers MA, Simon DG (1999) A preliminary study of
dietary aluminium intake and risk of Alzheimer’s disease.
Age Ageing 28, 205-209.
[92] Exley C (1998) Does antiperspirant use increase the risk of
aluminium-related disease, including Alzheimer’s disease?
Mol Med Today 4, 107-109.
[93] Greger JL, Sutherland JE (1997) Aluminum exposure and
metabolism. Crit Rev Clin Lab Sci 34, 439-474.
[94] Pennington JA, Schoen SA (1995) Estimates of dietary
exposure to aluminium. Food Addit Contam 12, 119-128.
592 L. Tomljenovic / Aluminum and Alzheimer’s Disease
[95] Dabeka RW, McKenzie AD (1990) Aluminium levels in
Canadian infant formulate and estimation of aluminium
intakes from formulae by infants 0–3 months old. Food Addit
Contam 7, 275-282.
[96] Gitelman HJ (1989) Aluminum and Health: a Critical
Review, Dekker, New York.
[97] Pennington JA (1988) Aluminium content of foods and
diets. Food Addit Contam 5, 161-232.
[98] Gies WJ (1911) Some objections to the use of alum baking-
powder. JAMA 57, 816-821.
[99] Flaten TP (1990) Geographical associations between alu-
minum in drinking water and death rates with dementia
(including Alzheimer’s disease), Parkinson’s disease and
amyotrophic lateral sclerosis in Norway. Environ Geochem
Health 12, 152-167.
[100] McLachlan DRC, Bergeron C, Smith JE, Boomer D,
Rifat SL (1996) Risk for neuropathologically confirmed
Alzheimer’s disease and residual aluminum in municipal
drinking water employing weighted residential histories.
Neurology 46, 401-405.
[101] Rondeau V, Commenges D, Jacqmin-Gadda H, Dartigues
JF (2000) Relation between aluminum concentrations in
drinking water and Alzheimer’s disease: an 8-year follow-
up study. Am J Epidemiol 152, 59-66.
[102] Rondeau V, Jacqmin-Gadda H, Commenges D, Helmer C,
Dartigues JF (2009) Aluminum and silica in drinking water
and the risk of Alzheimer’s disease or cognitive decline:
findings from 15-year follow-up of the PAQUID cohort. Am
J Epidemiol 169, 489-496.
[103] Martyn CN, Barker DJ, Osmond C, Harris EC, Edwardson
JA, Lacey RF (1989) Geographical relation between
Alzheimer’s disease and aluminum in drinking water.
Lancet 1, 59-62.
[104] Jacqmin-Gadda H, Commenges D, Letenneur L, Dartigues
JF (1996) Silica and aluminum in drinking water and cog-
nitive impairment in the elderly. Epidemiology 7, 281-285.
[105] 500Neri LC, Hewitt D (1991) Aluminium, Alzheimer’s dis-
ease, and drinking water. Lancet 338, 390.
[106] Gillette-Guyonnet S, Andrieu S, Nourhashemi F, de La
Gueronniere V, Grandjean H, Vellas B (2005) Cognitive
impairment and composition of drinking water in women:
findings of the EPIDOS Study. Am J Clin Nutr 81, 897-902.
[107] Campbell A, Becaria A, Lahiri DK, Sharman K, Bondy SC
(2004) Chronic exposure to aluminum in drinking water
increases inflammatory parameters selectively in the brain.
J Neurosci Res 75, 565-572.
[108] Flaten TP (2001) Aluminium as a risk factor in Alzheimer’s
disease, with emphasis on drinking water. Brain Res Bull
55, 187-196.
[109] Greger JL (1993) Aluminum metabolism. Annu Rev Nutr
13, 43-63.
[110] FAO/WHO (2006) Summary and conclusions of the
sixty-seventh meeting of the Joint FAO/WHO Expert
Committee on Food Additives (JECFA), Sixty-seventh
meeting in Rome, 20–29 June 2006, p. 11, http://www.
who.int/ipcs/food/jecfa/jecfa67 call%20final.pdf, Issued
July 7 2006, Accessed on July 2010.
[111] Zheng W (2001) Neurotoxicology of the brain barrier sys-
tem: new implications. J Toxicol Clin Toxicol 39, 711-719.
[112] Poole RL, Hintz SR, Mackenzie NI, Kerner JA Jr (2008)
Aluminum exposure from pediatric parenteral nutrition:
meeting the new FDA regulation. J Parenter Enteral Nutr
32, 242-246.
[113] Newschaffer CJ, Croen LA, Daniels J, Giarelli E, Grether
JK, Levy SE, Mandell DS, Miller LA, Pinto-Martin J,
Reaven J, Reynolds AM, Rice CE, Schendel D, Windham
GC (2007) The epidemiology of autism spectrum disorders.
Annu Rev Public Health 28, 235-258.
[114] Kogan MD, Blumberg SJ, Schieve LA, Boyle CA, Perrin
JM, Ghandour RM, Singh GK, Strickland BB, Trevathan E,
van Dyck PC (2009) Prevalenceof parent-reported diagnosis
of autism spectrum disorder among children in the US, 2007.
Pediatrics 124, 1395-1403.
[115] Baron-Cohen S, Scott FJ, Allison C, Williams J, Bolton
P, Matthews FE, Brayne C (2009) Prevalence of autism-
spectrum conditions: UK school-based population study. Br
J Psychiatry 194, 500-509.
[116] Offit PA, Jew RK (2003) Addressing parents’ concerns: do
vaccines contain harmful preservatives,adjuvants, additives,
or residuals? Pediatrics 112, 1394-1397.
[117] Flarend RE, Hem SL, White JL, Elmore D, Suckow MA,
Rudy AC, Dandashli EA (1997) In vivo absorption of
aluminium-containing vaccine adjuvants using 26Al. Vac-
cine 15, 1314-1318.
[118] Yokel RA, McNamara PJ (2001) Aluminium toxicokinetics:
an updated minireview. Pharmacol Toxicol 88, 159-167.
[119] GlaxoSmithKline (2009) Boostrix product monograph,
Combined diphtheria, tetanus, acellular pertussis (adsorbed)
vaccine for booster vaccination, Date of Approval:
October 21, 2009, http://www.gsk.ca/english/docs-pdf/
Boostrix PM 20091021 EN.pdf, Accessed on August 4
2010.
[120] Makidon PE, Bielinska AU, Nigavekar SS, Janczak KW,
Knowlton J, Scott AJ, Mank N, Cao Z, Rathinavelu S,
Beer MR, Wilkinson JE, Blanco LP, Landers JJ, Baker JR
Jr (2008) Pre-clinical evaluation of a novel nanoemulsion-
based hepatitis B mucosal vaccine. PLoS One 3, e2954.
[121] Exley C (2009) Aluminium and medicine. In Molecular and
Supramolecular Bioinorganic Chemistry: Applications in
Medical Sciences, Merce ALR, Felcman J, Recio MAL, eds,
Nova Biomedical Books, New York, pp. 45-68.
[122] Blaylock RL (2004) Excitotoxicity: a possible central mech-
anism in fluoride neurotoxicity. Fluoride 37, 264-277.
[123] Gherardi RK (2003) Lessons from macrophagic myofasci-
itis: towards definition of a vaccine adjuvant-related
syndrome. Rev Neurol (Paris) 159, 162-164.
[124] Gherardi RK, Coquet M, Cherin P, Belec L, Moretto P,
Dreyfus PA, Pellissier JF, Chariot P, Authier FJ (2001)
Macrophagic myofasciitis lesions assess long-term persis-
tence of vaccine-derived aluminium hydroxide in muscle.
Brain 124, 1821-1831.
[125] Authier FJ, Cherin P, Creange A, Bonnotte B, Ferrer X,
Abdelmoumni A, Ranoux D, Pelletier J, Figarella-Branger
D, Granel B, Maisonobe T, Coquet M, Degos JD, Gherardi
RK (2001) Central nervous system disease in patients with
macrophagic myofasciitis. Brain 124, 974-983.
[126] Exley C, Swarbrick L, Gherardi RK, Authier FJ (2009) A
role for the body burden of aluminium in vaccine-associated
macrophagic myofasciitis and chronic fatigue syndrome.
Med Hypotheses 72, 135-139.
[127] Israeli E, Agmon-Levin N, Blank M, Shoenfeld Y (2009)
Adjuvants and autoimmunity. Lupus 18, 1217-1225.
[128] Shoenfeld Y, Agmon-Levin N (2010) ‘ASIA’ – Autoim-
mune/inflammatory syndrome induced by adjuvants.
J Autoimmun, [Epub ahead of print] doi:10.1016/
j.jaut.2010.07.003.
[129] Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA
(2007) Aluminum adjuvant linked to Gulf War illness
induces motor neuron death in mice. Neuromolecular Med
9, 83-100.
L. Tomljenovic / Aluminum and Alzheimer’s Disease 593
[130] Pennington JA,Jones JW (1989) Dietary intake of aluminum
In Aluminum and health: a critical review, Gitelman HJ, ed.,
Dekker, New York, pp. 67-101.
[131] Xiong JS, Branigan D, Li M (2009) Deciphering the MSG
controversy. Int J Clinical Exp Med 2, 329-336.
[132] Gonzalez-Burgos I, Velazquez-Zamora DA, Beas-Zarate C
(2009) Damage and plasticity in adult rat hippocampal
trisynaptic circuit neurons after neonatal exposure to glu-
tamate excitotoxicity. Int J Dev Neurosci 27, 741-745.
[133] Deloncle R, Fauconneau B, Piriou A, Huguet F, Guillard
O (2002) Aluminum L-glutamate complex in rat brain cor-
tex: in vivo prevention of aluminum deposit by magnesium
D-aspartate. Brain Res 946, 247-252.
[134] Deloncle R, Guillard O, Huguet F,Clanet F (1995) Modifica-
tion of the blood-brain barrier through chronic intoxication
by aluminum glutamate. Possible role in the etiology of
Alzheimer’s disease. Biol Trace Elem Res 47, 227-233.
[135] Nayak P, Chatterjee AK (2003) Dietary protein restric-
tion causes modification in aluminum-induced alteration in
glutamate and GABA system of rat brain. BMC Neurosci
4,4.
[136] Cunat L, Lanhers MC, Joyeux M, Burnel D (2000) Bioavail-
ability and intestinal absorption of aluminum in rats: effects
of aluminum compounds and some dietary constituents.
Biol Trace Elem Res 76, 31-55.
[137] Mundy WR, Freudenrich TM, Kodavanti PR (1997)
Aluminum potentiates glutamate-induced calcium accu-
mulation and iron-induced oxygen free radical formation
in primary neuronal cultures. Mol Chem Neuropathol 32,
41-57.
[138] Sorenson JR, Campbell IR, Tepper LB, Lingg RD (1974)
Aluminum in the environment and human health. Environ
Health Perspect 8, 3-95.
[139] Exley C (2004) Aluminum in antiperspirants: more than just
skin deep. Am J Med 117, 969-970.
[140] Guillard O, Fauconneau B, Olichon D, Dedieu G, Deloncle
R (2004) Hyperaluminemia in a woman using an aluminum-
containing antiperspirant for 4 years. Am J Med 117, 956-
959.
[141] Graves AB, White E, Koepsell TD, Reifler BV, van
Belle G, Larson EB (1990) The association between
aluminum-containing products and Alzheimer’s disease.
J Clin Epidemiol 43, 35-44.
[142] FDA DHHS (2003) Skin Protectant Drug Products for
Over-the-Counter Human Use, Final Monograph. Fed
Regist 68, 34273-34290.
[143] Alzheimer Society of Canada, Alzheimer’s Disease,
Causes of Alzheimer’s Disease, http://www.alzheimer.ca/
english/disease/causes-alumi.htm, Last updated March
2009, Accessed on August 4, 2010.
[144] Polizzi S, Pira E, Ferrara M, Bugiani M, Papaleo A, Albera
R, Palmi S (2002) Neurotoxic effects of aluminium among
foundry workers and Alzheimer’s disease. Neurotoxicology
23, 761-774.
[145] Sinczuk-Walczak H, Szymczak M, Razniewska G, Matczak
W, Szymczak W (2003) Effects of occupational exposure
to aluminum on nervous system: clinical and electroen-
cephalographic findings. Int J Occup Med Environ Health
16, 301-310.
[146] Joshi JG (1991) Neurochemical hypothesis: participation
by aluminum in producing critical mass of colocalized errors
in brain leads to neurological disease. Comp Biochem Phys-
iol C 100, 103-105.
[147] Shafer TJ, Mundy WR (1995) Effects of aluminum on
neuronal signal transduction: mechanisms underlying dis-
ruption of phosphoinositide hydrolysis. Gen Pharmacol 26,
889-895.
[148] Mundy WR, Kodavanti PR, Dulchinos VF, Tilson HA
(1994) Aluminum alters calcium transport in plasma mem-
brane and endoplasmic reticulum from rat brain. J Biochem
Toxicol 9, 17-23.
[149] Macdonald TL, Humphreys WG, Martin RB (1987) Promo-
tion of tubulin assembly by aluminum ion in vitro. Science
236, 183-186.
[150] McLachlan DRC, Farnell BJ (1986) Cellular mechanisms
of aluminium toxicity. Ann Ist Super Sanita 22, 697-702.
[151] Siegel N, Haug A (1983) Aluminum interaction with
calmodulin. Evidence for altered structure and function
from optical and enzymatic studies. Biochim Biophys Acta
744, 36-45.
[152] Roskams AJ, Connor JR (1990) Aluminum access to the
brain: a role for transferrin and its receptor. Proc Natl Acad
SciUSA87, 9024-9027.
[153] Silva VS, Duarte AI, Rego AC, Oliveira CR, Goncalves PP
(2005) Effect of chronic exposure to aluminium on isoform
expression and activity of rat (Na+/K+)ATPase. Toxicol Sci
88, 485-494.
[154] Exley C, Price NC, Birchall JD (1994) Aluminum inhibi-
tion of hexokinase activity in vitro: a study in biological
availability. J Inorg Biochem 54, 297-304.
[155] Lukiw WJ (2001) Aluminum and gene transcription in
the mammalian central nervous system-implications for
Alzheimer’s Disease. In Aluminium and Alzheimer’s Dis-
ease: The science that describes the link, Exley C, ed.,
Elsevier Science, Amsterdam, pp. 147-169.
[156] McLachlan DRC, Dam TV, Farnell BJ, Lewis PN (1983)
Aluminum inhibition of ADP-ribosylation in vivo and
in vitro.Neurobehav Toxicol Teratol 5, 645-647.
[157] Lukiw WJ, LeBlanc HJ, Carver LA, McLachlan DR, Bazan
NG (1998) Run-on gene transcription in human neocortical
nuclei. Inhibition by nanomolar aluminum and implica-
tions for neurodegenerative disease. J Mol Neurosci 11,
67-78.
[158] Cherroret G, Desor D, Hutin MF, Burnel D, Capolaghi B,
Lehr PR (1996) Effects of aluminum chloride on normal and
uremic adult male rats. Tissue distribution, brain choline
acetyltransferase activity, and some biological variables.
Biol Trace Elem Res 54, 43-53.
[159] King RG (1984) Do raised brain aluminium levels in
Alzheimer’s dementia contribute to cholinergic neuronal
deficits? Med Hypotheses 14, 301-306.
[160] King RG, Sharp JA, Boura AL (1983) Aluminium, choline
transportation and Alzheimer’s disease. Med J Aust 2, 606-
607.
[161] Huber CT, Frieden E (1970) The inhibition of ferroxidase by
trivalent and other metal ions. J Biol Chem 245, 3979-3984.
[162] Abdel-Ghany M, el-Sebae AK, Shalloway D (1993) Alu-
minum-induced nonenzymatic phospho-incorporation into
human tau and other proteins. J Biol Chem 268, 11976-
11981.
[163] Banks WA, Kastin AJ (1989) Aluminum-induced neu-
rotoxicity: alterations in membrane function at the
blood-brain barrier. Neurosci Biobehav Rev 13, 47-
53.
[164] Nehru B, Anand P (2005) Oxidative damage following
chronic aluminium exposure in adult and pup rat brains.
J Trace Elem Med Biol 19, 203-208.
[165] Jing Y, Wang Z, Song Y (2004) Quantitative study of
aluminum-induced changes in synaptic ultrastructure in
rats. Synapse 52, 292-298.
594 L. Tomljenovic / Aluminum and Alzheimer’s Disease
[166] Bondy SC, Ali SF, Guo-Ross S (1998) Aluminum but not
iron treatment induces pro-oxidant events in the rat brain.
Mol Chem Neuropathol 34, 219-232.
[167] Jope RS, Johnson GV (1992) Neurotoxic effects of dietary
aluminium. Ciba Found Symp 169, 254-262; discussion
262-257.
[168] Johnson GV, Watson AL Jr, Lartius R, Uemura E, Jope RS
(1992) Dietary aluminum selectively decreases MAP-2 in
brains of developing and adult rats. Neurotoxicology 13,
463-474.
[169] Bowdler NC, Beasley DS, Fritze EC, Goulette AM,
Hatton JD, Hession J, Ostman DL, Rugg DJ, Schmittdiel
CJ (1979) Behavioral effects of aluminum ingestion on
animal and human subjects. Pharmacol Biochem Behav
10, 505-512.
[170] Thorne BM, Donohoe T, Lin KN, Lyon S, Medeiros DM,
Weaver ML (1986) Aluminum ingestion and behavior in the
Long-Evans rat. Physiol Behav 36, 63-67.
[171] Pivnick EK, Kerr NC, Kaufman RA, Jones DP, Chesney
RW (1995) Rickets secondary to phosphate depletion. A
sequela of antacid use in infancy. Clin Pediatr (Phila) 34,
73-78.
[172] Fewtrell MS, Bishop NJ, Edmonds CJ, Isaacs EB, Lucas
A (2009) Aluminum exposure from parenteral nutrition in
preterm infants: bone health at 15-year follow-up. Pediatrics
124, 1372-1379.
[173] Candy JM, Oakley AE, Mountfort SA, Taylor GA, Morris
CM, Bishop HE, Edwardson JA (1992) The imaging and
quantification of aluminium in the human brain using
dynamic secondary ion mass spectrometry (SIMS). Biol Cell
74, 109-118.
[174] Lukiw WJ, Krishnan B, Wong L, Kruck TP, Bergeron C,
Crapper McLachlan DR (1992) Nuclear compartmentaliza-
tion of aluminum in Alzheimer’s disease (AD). Neurobiol
Aging 13, 115-121.
[175] Yokel RA, Allen DD, Ackley DC (1999) The distribution
of aluminum into and out of the brain. J Inorg Biochem 76,
127-132.
[176] Exley C, Burgess E, Day JP, Jeffery EH, Melethil S, Yokel
RA (1996) Aluminum toxicokinetics. J Toxicol Environ
Health 48, 569-584.
[177] French P, Gardner MJ, Gunn M (1989) Dietary aluminium
and Alzheimer’s disease. Food Chem Toxicol 27, 495-496.
[178] Wenk GL, Stemmer KL (1981) The influence of ingested
aluminum upon norepinephrine and dopamine levels in the
rat brain. Neurotoxicology 2, 347-353.
[179] Abreo K (2001) Aluminum-induced bone disease: impli-
cations for Alzheimer’s disease. In Aluminium and
Alzheimer’s Disease: The science that describes the link,
Exley C, ed., Elsevier Science, Amsterdam, pp. 37-59.
[180] D’Haese PC, Couttenye MM, De Broe ME (1996) Diagno-
sis and treatment of aluminium bone disease. Nephrol Dial
Transplant 11(Suppl 3), 74-79.
[181] Ebersole PS, Hess PA, Luggen AS (2004) Age-related
changes: renal changes. In Toward Healthy Aging: Human
Needs and Nursing Response, Ledbetter MS, Gower LK,
eds, Mosby Inc. St Louis, MO, p. 89.
[182] Lukiw WJ, Kruck TP, McLachlan DR (1989) Linker
histone-DNA complexes: enhanced stability in the pres-
ence of aluminum lactate and implications for Alzheimer’s
disease. FEBS Lett 253, 59-62.
[183] McLachlan DRC, Lukiw WJ, Mizzen CA, Kruck TP (1989)
Chromatin structure in Alzheimer’s disease: effect on 5
leader sequence for NF-L gene and role of aluminum. Prog
Clin Biol Res 317, 1061-1075.
[184] McLachlan DRC, Lukiw WJ, Kruck TP (1989) New evi-
dence for an active role of aluminum in Alzheimer’s disease.
Can J Neurol Sci 16, 490-497.
[185] McLachlan DRC, Lukiw WJ, Kruck TPA(1990) Aluminum,
altered transcription, and the pathogenesis of Alzheimer’s
disease. Env Geochem Health 12, 103-114.
[186] Mann DM (1996) Pyramidal nerve cell loss in Alzheimer’s
disease. Neurodegeneration 5, 423-427.
[187] Heckers S, Geula C, Mesulam MM (1992) Acetylcholin-
esterase-rich pyramidal neurons in Alzheimer’s disease.
Neurobiol Aging 13, 455-460.
[188] Salimi I, Friel KM, Martin JH (2008) Pyramidal tract stim-
ulation restores normal corticospinal tract connections and
visuomotor skill after early postnatal motor cortex activity
blockade. J Neurosci 28, 7426-7434.
[189] Elston GN (2003) Cortex, cognition and the cell: new
insights into the pyramidal neuron and prefrontal function.
Cereb Cortex 13, 1124-1138.
[190] Connor JR, Snyder BS, Arosio P, Loeffler DA, LeWitt
P (1995) A quantitative analysis of isoferritins in select
regions of aged, parkinsonian, and Alzheimer’s diseased
brains. J Neurochem 65, 717-724.
[191] Favarato M, Mizzen CA, McLachlan DR (1992) Resolu-
tion of serum aluminum-binding proteins by size-exclusion
chromatography: identification of a new carrier of aluminum
in human serum. J Chromatogr 576, 271-285.
[192] Day JP, Barker J, Evans LJA, Perks J, Seabright PJ,
Ackrill P, Lilley JS, Drumm PV, Newton GWA (1991)
Aluminium absorption studied by 26Al tracer. Lancet 337,
1345.
[193] Favarato M, Mizzen C, Kruck TPA (1990) Chromatographic
resolution of aluminum binding components in human
serum. Neurobiol Aging 11, 315.
[194] Beardmore J, Exley C (2009) Towards a model of non-
equilibrium binding of metal ions in biological systems.
J Inorg Biochem 103, 205-209.
[195] Moos T, Morgan EH (2000) Transferrin and transferrin
receptor function in brain barrier systems. Cell Mol Neu-
robiol 20, 77-95.
[196] Morris CM, Candy JM, Kerwin JM, Edwardson JA (1994)
Transferrin receptors in the normal human hippocampus
and in Alzheimer’s disease. Neuropathol Appl Neurobiol
20, 473-477.
[197] Pardridge WM, Eisenberg J, Yang J (1987) Human blood-
brain barrier transferrin receptor. Metabolism 36, 892-
895.
[198] Sakajiri T, Yamamura T, Kikuchi T, Ichimura K, Sawada
T, Yajima H (2009) Absence of binding between the human
transferrin receptor and the transferrin complex of biological
toxic trace element, aluminum, because of an incomplete
open/closed form of the complex. Biol Trace Elem Res 136,
279-286.
[199] Ha-Duong NT, Hemadi M, Chikh Z, Chahine JM (2008)
Kinetics and thermodynamics of metal-loaded transferrins:
transferrin receptor 1 interactions. Biochem Soc Trans 36,
1422-1426.
[200] Hemadi M, Miquel G, Kahn PH, El Hage Chahine JM
(2003) Aluminum exchange between citrate and human
serum transferrin and interaction with transferrin receptor 1.
Biochemistry 42, 3120-3130.
[201] Smans KA, D’Haese PC, Van Landeghem GF, Andries LJ,
Lamberts LV, Hendy GN, De Broe ME (2000) Transferrin-
mediated uptake of aluminium by human parathyroid cells
results in reduced parathyroid hormone secretion. Nephrol
Dial Transplant 15, 1328-1336.
L. Tomljenovic / Aluminum and Alzheimer’s Disease 595
[202] McGregor SJ, Brock JH, Halls D (1991) The role of trans-
ferrin and citrate in cellular uptake of aluminium. Biol Met
4, 173-175.
[203] McGregor SJ, Naves ML, Birly AK, Russell NH, Halls D,
Junor BJ, Brock JH (1991) Interaction of aluminium and
gallium with human lymphocytes: the role of transferrin.
Biochim Biophys Acta 1095, 196-200.
[204] Abreo K, Jangula J, Jain SK, Sella M, Glass J (1991) Alu-
minum uptake and toxicity in cultured mouse hepatocytes.
J Am Soc Nephrol 1, 1299-1304.
[205] Fleming J, Joshi JG (1987) Ferritin: isolation of aluminum-
ferritin complex from brain. Proc Natl Acad Sci U S A 84,
7866-7870.
[206] Dedman DJ, Treffry A, Candy JM, Taylor GA, Morris
CM, Bloxham CA, Perry RH, Edwardson JA, Harrison PM
(1992) Iron and aluminium in relation to brain ferritin in
normal individuals and Alzheimer’s-disease and chronic
renal-dialysis patients. Biochem J 287(Pt 2), 509-514.
[207] Spada PL, Rossi C, Alimonti A, Bocca B, Ricerca BM, Bocci
MG, Carvelli M, Vulpio C, Luciani G, De Sole P (2009)
Iron, zinc and aluminium ferritin content of hemodialysis
hyperferritinemic patients: comparison with other hyperfer-
ritinemic clinical conditions and normoferritinemic blood
donors. Clin Biochem 42, 1654-1657.
[208] Brewer GJ (2007) Iron and copper toxicity in diseases of
aging, particularly atherosclerosis and Alzheimer’s disease.
Exp Biol Med (Maywood) 232, 323-335.
[209] Alexandrov PN, Zhao Y, Pogue AI, Tarr MA, Kruck TP,
Percy ME, Cui JG, Lukiw WJ (2005) Synergistic effects
of iron and aluminum on stress-related gene expression in
primary human neural cells. J Alzheimers Dis 8, 117-127;
discussion 209-115.
[210] Smith MA, Harris PL, Sayre LM, Perry G (1997) Iron
accumulation in Alzheimer disease is a source of redox-
generated free radicals. Proc Natl Acad Sci U S A 94,
9866-9868.
[211] Exley C (2004) The pro-oxidant activity of aluminum. Free
Radic Biol Med 36, 380-387.
[212] Verstraeten SV, Golub MS, Keen CL, Oteiza PI (1997)
Myelin is a preferential target of aluminum-mediated oxida-
tive damage. Arch Biochem Biophys 344, 289-294.
[213] Khan A, Dobson JP, Exley C (2006) Redox cycling of iron
by Abeta42. Free Radic Biol Med 40, 557-569.
[214] Floyd RA (1999) Antioxidants, oxidative stress, and degen-
erative neurological disorders. Proc Soc Exp Biol Med 222,
236-245.
[215] Olanow CW (1993) A radical hypothesis for neurodegener-
ation. Trends Neurosci 16, 439-444.
[216] Pandya JD, Dave KR, Katyare SS (2004) Effect of long-
term aluminum feeding on lipid/phospholipid profiles of
rat brain myelin. Lipids Health Dis 3, 13.
[217] Sokoloff L (1981) Relationships among local functional
activity, energy metabolism, and blood flow in the central
nervous system. Fed P roc 40, 2311-2316.
[218] Maker HS, Clarke DD, Lajtha AL (1972) Intermediary
metabolism of carbohydrates and amino acids. In Basic Neu-
rochemistry, Siegal GL, Albers RW, Katzman R, Agranoff
BW, eds, Little, Brown and Co., Boston, pp. 279-307.
[219] Johnson GV, Jope RS (1986) Aluminum impairs glucose
utilization and cholinergic activity in rat brain in vitro.Tox-
icology 40, 93-102.
[220] McLachlan DRC, Dalton AJ (1973) Alterations in short-
term retention, conditioned avoidance response acquisition
and motivation following aluminum induced neurofibrillary
degeneration. Physiol Behav 10, 925-933.
[221] Hellwig B (1993) How the myelin picture of the human
cerebral cortex can be computed from cytoarchitectural data.
A bridge between von Economo and Vogt. J Hirnforsch 34,
387-402.
[222] Lintl P, Braak H (1983) Loss of intracortical myelinated
fibers: a distinctive age-related alteration in the human
striate area. Acta Neuropathol 61, 178-182.
[223] Grant P, Pant HC (2000) Neurofilament protein synthesis
and phosphorylation. J Neurocytol 29, 843-872.
[224] Shea TB, Beermann ML (1994) Respective roles of neurofil-
aments, microtubules, MAP1B, and tau in neurite outgrowth
and stabilization. Mol Biol Cell 5, 863-875.
[225] Jicha GA, Weaver C, Lane E, Vianna C, Kress Y, Rockwood
J, Davies P (1999) cAMP-dependent protein kinase phos-
phorylations on tau in Alzheimer’s disease. J Neurosci 19,
7486-7494.
[226] Blanchard BJ, devi Raghunandan R, Roder HM, Ingram
VM (1994) Hyperphosphorylation of human TAU by
brain kinase PK40erk beyond phosphorylation by cAMP-
dependent PKA: relation to Alzheimer’s disease. Biochem
Biophys Res Commun 200, 187-194.
[227] el-Sebae AH, Abdel-Ghany ME, Shalloway D, Abou Zeid
MM, Blancato J, Saleh MA (1993) Aluminum interaction
with human brain tau protein phosphorylation by various
kinases. J Environ Sci Health B 28, 763-777.
[228] Markesbery WR (1999) The role of oxidative stress in
Alzheimer disease. Arch Neurol 56, 1449-1452.
[229] Markesbery WR, Carney JM (1999) Oxidative alterations in
Alzheimer’s disease. Brain Pathol 9, 133-146.
[230] Gomez M, Esparza JL, Nogues MR, Giralt M, Cabre M,
Domingo JL (2005) Pro-oxidant activity of aluminum in the
rat hippocampus: gene expression of antioxidant enzymes
after melatonin administration. Free Radic Biol Med 38,
104-111.
[231] Pratico D, Uryu K, Sung S, Tang S, Trojanowski JQ,
Lee VM (2002) Aluminum modulates brain amyloidosis
through oxidative stress in APP transgenic mice. FASEB
J16, 1138-1140.
[232] Bondy SC, Liu D, Guo-Ross S (1998) Aluminum treatment
induces nitric oxide synthase in the rat brain. Neurochem Int
33, 51-54.
[233] Pratico D, Rokach J, Lawson J, Fitzgerald GA (2004) F2-
isoprostanes as indices of lipid peroxidation in inflammatory
diseases. Chem Phys Lipids 128, 165-171.
[234] Pratico D, Clark CM, Lee VM, Trojanowski JQ, Rokach
J, Fitzgerald GA (2000) Increased 8,12-iso-iPF2alpha-VI
in Alzheimer’s disease: correlation of a noninvasive index
of lipid peroxidation with disease severity. Ann Neurol 48,
809-812.
[235] Pratico D, V MYL, Trojanowski JQ, Rokach J, Fitzgerald
GA (1998) Increased F2-isoprostanes in Alzheimer’s dis-
ease: evidence for enhanced lipid peroxidation in vivo.
FASEB J 12, 1777-1783.
[236] Wu J, Du F, Zhang P, Khan IA, Chen J, Liang Y (2005)
Thermodynamics of the interaction of aluminum ions with
DNA: implications for the biological function of aluminum.
J Inorg Biochem 99, 1145-1154.
[237] Lukiw WJ, Percy ME, Kruck TP (2005) Nanomolar alu-
minum induces pro-inflammatory and pro-apoptotic gene
expression in human brain cells in primary culture. J Inorg
Biochem 99, 1895-1898.
[238] Ripovi D, Platilova V,Strunecka A, Jirak R, Hoschl C (2000)
Cytosolic calcium alterations in platelets of patients with
early stages of Alzheimer’s disease. Neurobiol Aging 21,
729-734.
596 L. Tomljenovic / Aluminum and Alzheimer’s Disease
[239] Grammas P, Roher AE, Ball MJ (1994) Increased accu-
mulation of cAMP in cerebral microvessels in Alzheimer’s
disease. Neurobiol Aging 15, 113-116.
[240] Young-Pearse TL, Chen AC, Chang R, Marquez C, Selkoe
DJ (2008) Secreted APP regulates the function of full-length
APP in neurite outgrowth through interaction with integrin
beta1. Neural Dev 3, 15.
[241] De Strooper B, Annaert W (2000) Proteolytic processing and
cell biological functions of the amyloid precursor protein.
J Cell Sci 113 (Pt 11), 1857-1870.
[242] Bell KF, Zheng L, Fahrenholz F, Cuello AC (2008)
ADAM-10 over-expression increases cortical synaptogen-
esis. Neurobiol Aging 29, 554-565.
[243] Alzheimer’s Association (alz.org), Alzheimer Myths, http://
www.alz.org/alzheimers disease myths about alzheimers
.asp, Last Updated January 4, 2010, Accessed on August 4,
2010.
[244] Alzheimer’s Association (alz.org), Association responds to
USA TODAY letter to the editor, http://www.alz.org/news
and events alzheimer news 02-02-2005.asp, Last Updated
December 22, 2006, Accessed on August 4, 2010.
[245] McLachlan DRC (1995) Aluminium and the risk for
alzheimer’s disease. Environmetrics 6, 233-275.
[246] McLachlan DRC, Kruck TP, Lukiw WJ, Krishnan SS (1991)
Would decreased aluminum ingestion reduce the incidence
of Alzheimer’s disease? CMAJ 145, 793-804.
[247] Perl DP (2001) The association of aluminum and neu-
rofibrillary degeneration in Alzheimer’s Disease, a personal
perspective. In Aluminium and Alzheimer’s Disease: The
science that describes the link, Exley C, ed., Elsevier Sci-
ence, Amsterdam, pp. 133-147.
[248] Altmann P (2001) Aluminium induced disease in subjects
with and without renal failure-does it help us understand the
role of aluminium in Alzheimer’s Disease? In Aluminium
and Alzheimer’s Disease: The Science that Describes the
Link, Exley C, ed., Elsevier Science, Amsterdam, pp. 1-37.
[249] Golub MS (2001) Behavioral studies in animals: past
and potential contribution to the understanding of the
relationship between aluminium and Alzheimer’s Dis-
ease. In Aluminium and Alzheimer’s Disease: The Science
that Describes the Link, Exley C, ed., Elsevier Science,
Amsterdam, pp. 169-189.
[250] Pendlebury WW, Beal MF,Kowall NW,Solomon PR (1988)
Neuropathologic, neurochemical and immunocytochemi-
cal characteristics of aluminum-induced neurofilamentous
degeneration. Neurotoxicology 9, 503-510.
[251] Rozas VV, Port FK, Easterling RE (1978) An outbreak of
dialysis dementia due to aluminum in the dialysate. J Dial
2, 459-470.
[252] Flendrig JA, Kruis H, Das HA (1976) Aluminium intox-
ication: the cause of dialysis dementia? Proc Eur Dial
Transplant Assoc 13, 355-368.
[253] McLachlan DRC, Tomko GJ (1975) Neuronal correlates of
an encephalopathy associated with aluminum neurofibril-
lary degeneration. Brain Res 97, 253-264.
[254] Platt B, Carpenter DO, Busselberg D, Reymann KG, Riedel
G (1995) Aluminum impairs hippocampal long-term poten-
tiation in rats in vitro and in vivo.Exp Neurol 134, 73-
86.
[255] Beal MF, Mazurek MF, Ellison DW, Kowall NW, Solomon
PR, Pendlebury WW (1989) Neurochemical characteristics
of aluminum-induced neurofibrillary degeneration in rab-
bits. Neuroscience 29, 339-346.
[256] Zatta P, Ibn-Lkhayat-Idrissi M, Zambenedetti P, Kilyen M,
Kiss T (2002) In vivo and in vitro effects of aluminum on
the activity of mouse brain acetylcholinesterase. Brain Res
Bull 59, 41-45.
[257] Moraes MS, Leite SR (1994) Inhibition of bovine brain
acetylcholinesterase by aluminum. Braz J Med Biol Res 27,
2635-2638.
[258] Patocka J, Bajgar J (1987) Aluminium activation and inhi-
bition of human brain acetylcholinesterase in vitro. Inorg
Chim Acta 135,161-163.
[259] Lai JC, Guest JF,Leung TK, Lim L, Davison AN (1980) The
effects of cadmium, manganese and aluminium on sodium-
potassium-activated and magnesium-activated adenosine
triphosphatase activity and choline uptake in rat brain synap-
tosomes. Biochem Pharmacol 29, 141-146.
[260] Cucarella C, Montoliu C, Hermenegildo C, Saez R, Manzo
L, Minana MD, Felipo V (1998) Chronic exposure to alu-
minum impairs neuronal glutamate-nitric oxide-cyclic GMP
pathway. J Neurochem 70, 1609-1614.
[261] Meiri H, Banin E, Roll M, Rousseau A (1993) Toxic effects
of aluminium on nerve cells and synaptic transmission. Prog
Neurobiol 40, 89-121.
[262] Rao KS (1990) Effects of aluminium salts on synaptosomal
enzymes – an in vitro kinetic study. Biochem Int 22, 725-
734.
[263] Wong PC, Lai JC, Lim L, Davison AN (1981) Selective
inhibition of L-glutamate and gammaaminobutyrate trans-
port in nerve ending particles by aluminium, manganese,
and cadmium chloride. J Inorg Biochem 14, 253-260.
[264] Altindag ZZ, Baydar T, Engin AB, Sahin G (2003) Effects
of the metals on dihydropteridine reductase activity. Toxicol
In Vitro 17, 533-537.
[265] Shafer TJ, Nostrandt AC, Tilson HA, Mundy WR (1994)
Mechanisms underlying AlCl3 inhibition of agonist-
stimulated inositol phosphate accumulation. Role of
calcium, G-proteins, phospholipase C and protein kinase C.
Biochem Pharmacol 47, 1417-1425.
[266] Shafer TJ, Mundy WR, Tilson HA (1993) Aluminum
decreases muscarinic, adrenergic, and metabotropic
receptor-stimulated phosphoinositide hydrolysis in hip-
pocampal and cortical slices from rat brain. Brain Res 629,
133-140.
[267] Cochran M, Elliott DC, Brennan P, Chawtur V (1990) Inhi-
bition of protein kinase C activation by low concentrations
of aluminium. Clin Chim Acta 194, 167-172.
[268] Koenig ML, Jope RS (1987) Aluminum inhibits the fast
phase of voltage-dependent calcium influxes into synapto-
somes. J Neurochem 49, 316-320.
[269] Siegel N, Suhayda C, Haug A (1982) Aluminum changes the
conformation of calmodulin. Physiol Chem Phys 14, 165-
167.
[270] Beal MF, Hyman BT, Koroshetz W (1993) Do defects in
mitochondrial energy metabolism underlie the pathology of
neurodegenerative diseases? Trends Neurosci 16, 125-131.
[271] Drago D, Cavaliere A, Mascetra N, Ciavardelli D, di Ilio
C, Zatta P, Sensi SL (2008) Aluminum modulates effects of
beta amyloid(1-42) on neuronal calcium homeostasis and
mitochondria functioning and is altered in a triple transgenic
mouse model of Alzheimer’s disease. Rejuvenation Res 11,
861-871.
[272] Lipman JJ, Colowick SP, Lawrence PL, AbumradNN (1988)
Aluminum induced encephalopathy in the rat. Life Sci 42,
863-875.
[273] Li X, Zheng H, Zhang Z, Li M, Huang Z, Schluesener
HJ, Li Y, Xu S (2009) Glia activation induced by periph-
eral administration of aluminum oxide nanoparticles in rat
brains. Nanomed Nanotech Biol Med 5, 473-479.
L. Tomljenovic / Aluminum and Alzheimer’s Disease 597
[274] Muma NA, Troncoso JC, Hoffman PN, Koo EH, Price
DL (1988) Aluminum neurotoxicity: altered expression of
cytoskeletal genes. Brain Res 427, 115-121.
[275] McLachlan DRC, Krishnan SS, Quittkat S (1976) Alu-
minium, neurofibrillary degeneration and Alzheimer’s
disease. Brain 99, 67-80.
[276] Humphreys WG, Macdonald TL (1988) The effects on tubu-
lin polymerization and associated guanosine triphosphate
hydrolysis of aluminum ion, fluoride and fluoroaluminate
species. Biochem Biophys Res Commun 151, 1025-1032.
[277] Shea TB, Beermann ML, Nixon RA (1995) Aluminum
treatment of intact neuroblastoma cells alters neurofilament
subunit phosphorylation, solubility, and proteolysis. Mol
Chem Neuropathol 26, 1-14.
[278] Shin RW, Kruck TP, Murayama H, Kitamoto T (2003)
A novel trivalent cation chelator Feralex dissociates binding
of aluminum and iron associated with hyperphosphorylated
tau of Alzheimer’s disease. Brain Res 961, 139-146.
[279] Shin RW, Lee VM, Trojanowski JQ (1994) Aluminum mod-
ifies the properties of Alzheimer’s disease PHF tau proteins
in vivo and in vitro.J Neurosci 14, 7221-7233.
[280] Yamamoto H, Saitoh Y, Yasugawa S, Miyamoto E (1990)
Dephosphorylation of tau factor by protein phosphatase 2A
in synaptosomal cytosol fractions, and inhibition by alu-
minum. J Neurochem 55, 683-690.
[281] Exley C (2006) Aluminium and iron, but neither copper
nor zinc, are key to the precipitation of beta-sheets of
Abeta {42}in senile plaque cores in Alzheimer’s disease.
J Alzheimers Dis 10, 173-177.
[282] Exley C, Price NC, Kelly SM, Birchall JD (1993) An inter-
action of beta-amyloid with aluminium in vitro. FEBS Lett
324, 293-295.
[283] Fasman GD, Perczel A, Moore CD (1995) Solubilization of
beta-amyloid-(1-42)-peptide: reversing the beta-sheet con-
formation induced by aluminum with silicates. Proc Natl
Acad SciUSA92, 369-371.
[284] Exley C, Korchazhkina OV (2001) Promotion of forma-
tion of amyloid fibrils by aluminium adenosine triphosphate
(AlATP). J Inorg Biochem 84, 215-224.
[285] Kawahara M, Kato M, Kuroda Y (2001) Effectsof aluminum
on the neurotoxicity of primary cultured neurons and on
the aggregation of beta-amyloid protein. Brain Res Bull 55,
211-217.
[286] Drago D, Bettella M, Bolognin S, Cendron L, Scancar J,
Milacic R, Ricchelli F,Casini A, Messori L, Tognon G, Zatta
P (2008) Potential pathogenic role of beta-amyloid(1-42)-
aluminum complex in Alzheimer’s disease. Int J Biochem
Cell Biol 40, 731-746.
[287] Mills J, Laurent Charest D, Lam F, Beyreuther K, Ida N,
Pelech SL, Reiner PB (1997) Regulation of amyloid pre-
cursor protein catabolism involves the mitogen-activated
protein kinase signal transduction pathway. J Neurosci 17,
9415-9422.
[288] Nitsch RM, Slack BE, Wurtman RJ, Growdon JH (1992)
Release of Alzheimer amyloid precursor derivatives stim-
ulated by activation of muscarinic acetylcholine receptors.
Science 258, 304-307.
[289] Xu H, Greengard P, Gandy S (1995) Regulated formation of
Golgi secretory vesicles containing Alzheimer beta-amyloid
precursor protein. J Biol Chem 270, 23243-23245.
[290] Arribas J, Massague J (1995) Transforming growth factor-
alpha and beta-amyloid precursor protein share a secretory
mechanism. J Cell Biol 128, 433-441.
[291] Sakamoto T, Saito H, Ishii K, Takahashi H, Tanabe S,
Ogasawara Y (2006) Aluminum inhibits proteolytic degra-
dation of amyloid beta peptide by cathepsin D: a potential
link between aluminum accumulation and neuritic plaque
deposition. FEBS Lett 580, 6543-6549.
[292] Alfrey AC (1986) Dialysis encephalopathy. Kidney Int Suppl
18, S53-S57.
[293] Alfrey AC (1978) Dialysis encephalopathy syndrome. Annu
Rev Med 29, 93-98.
[294] Alfrey AC, LeGendre GR, Kaehny WD (1976) The dialysis
encephalopathy syndrome. Possible aluminum intoxication.
N Engl J Med 294, 184-188.
[295] Wisniewski HM, Sturman JA, Shek JW (1982) Chronic
model of neurofibrillary changes induced in mature rabbits
by metallic aluminum. Neurobiol Aging 3, 11-22.
[296] Petit TL, Biederman GB, McMullen PA (1980) Neu-
rofibrillary degeneration, dendritic dying back, and
learning-memory deficits after aluminum administration:
implications for brain aging. Exp Neurol 67, 152-162.
[297] McLachlan DC (1973) Experimental neurofibrillary degen-
eration and altered electrical activity. Electroencephalogr
Clin Neurophysiol 35, 575-588.
[298] Klatzo I, Wisniewski H, Streicher E (1965) Experimen-
tal production of neurofibrillary degeneration. I. Light
microscopic observations. J Neuropathol Exp Neurol 24,
187-199.
[299] Shigematsu K, McGeer PL (1992) Accumulation of amy-
loid precursor protein in damaged neuronal processes and
microglia following intracerebral administration of alu-
minum salts. Brain Res 593, 117-123.
[300] Hewitt CD, Herman MM, Lopes MB, Savory J, Wills
MR (1991) Aluminium maltol-induced neurocytoskeletal
changes in fetal rabbit midbrain in matrix culture. Neu-
ropathol Appl Neurobiol 17, 47-60.
[301] Wisniewski H, Narkiewicz O, Wisniewska K (1967) Topog-
raphy and dynamics of neurofibrillar degeneration in
aluminum encephalopathy. Acta Neuropathol 9, 127-133.
[302] Savory J, Huang Y, Wills MR, Herman MM (1998) Rever-
sal by desferrioxamine of tau protein aggregates following
two days of treatment in aluminum-induced neurofibril-
lary degeneration in rabbit: implications for clinical trials
in Alzheimer’s disease. Neurotoxicology 19, 209-214.
[303] Selkoe DJ, Liem RK, Yen SH, Shelanski ML (1979)
Biochemical and immunological characterization of neu-
rofilaments in experimental neurofibrillary degeneration
induced by aluminum. Brain Res 163, 235-252.
[304] Gambetti P, Autilio-Gambetti L, Perry G, Shecket G,
Crane RC (1983) Antibodies to neurofibrillary tangles of
Alzheimer’s disease raised from human and animal neuro-
filament fractions. Lab Invest 49, 430-435.
[305] Walton JR (2007) An aluminum-based rat model for
Alzheimer’s disease exhibits oxidative damage, inhibition
of PP2A activity, hyperphosphorylated tau, and granulovac-
uolar degeneration. J Inorg Biochem 101, 1275-1284.
[306] Exley C, Esiri MM (2006) Severe cerebral congophilic
angiopathy coincident with increased brain aluminium in
a resident of Camelford, Cornwall, UK. J Neurol Neurosurg
Psychiatry 77, 877-879.
[307] Yumoto S, Kakimi S, Ohsaki A, Ishikawa A (2009) Demon-
stration of aluminum in amyloid fibers in the cores of senile
plaques in the brains of patients with Alzheimer’s disease.
J Inorg Biochem 103, 1579-1584.
[308] Walton JR, Diamond TH, Kumar S, Murrell GA (2007)
A sensitive stain for aluminum in undecalcified cancellous
bone. J Inorg Biochem 101, 1285-1290.
[309] Kruck TP, Cui JG, Percy ME, Lukiw WJ (2004) Molecu-
lar shuttle chelation: the use of ascorbate, desferrioxamine
598 L. Tomljenovic / Aluminum and Alzheimer’s Disease
and Feralex-G in combination to remove nuclear bound alu-
minum. Cell Mol Neurobiol 24, 443-459.
[310] Bertholf RL, Roman JM, Brown S, Savory J, Wills
MR (1984) Aluminum hydroxide-induced osteomalacia,
encephalopathy, and hyperaluminemia in CAPD. Treatment
with desfenioxamine. Perit Dial Int 4, 30-32.
[311] Williams P, Khanna R, Crapper McLachlan DR (1981)
Enhancement of aluminum removal by desfemoxamine in
a patient on continuous ambulatory peritoneal dialysis with
dementia. Perit Dial Int 1, 73.
[312] Flarend R (2001) Absorption of aluminum from antiperspi-
rants and vaccine adjuvants. In Aluminium and Alzheimer’s
Disease: The Science that Describes the Link, Exley C, ed.,
Elsevier Science, Amsterdam, pp. 75-97.
[313] Flarend R, Bin T, Elmore D, Hem SL (2001) A prelim-
inary study of the dermal absorption of aluminium from
antiperspirants using aluminium-26. Food Chem Toxicol 39,
163-168.
[314] Autret-Leca E, Bensouda-Grimaldi L, Jonville-Bera AP,
Beau-Salinas F (2006) Pharmacovigilance of vaccines. Arch
Pediatrie 13, 175-180.
[315] Koo WW, Kaplan LA, Krug-Wispe SK (1988) Aluminum
contamination of infant formulas. J Parenter Enteral Nutr
12, 170-173.
[316] CDC, Recommended Immunization Schedule for Per-
sons Aged 0 Through 6 Years, United States 2010,
http://www.cdc.gov/vaccines/recs/schedules/default.htm,
Last updated June 15 2010, Accessed on August 4, 2010.
[317] Srinivasan PT, Viraraghavan T, Subramanian KS (1999)
Aluminium in drinking water: an overview. Water S.A. 25,
47-55.
... A smaller amount enters through the skin, such as in antiperspirants. These routes would put aluminum into the circulatory system relatively quickly, and most of this aluminum is typically rapidly removed by the kidneys (Tomljenovic 2011). This study used rats exposed to drinking water containing aluminum to study the neurotoxicity of aluminum since oral exposure is closer to the way that the body experiences aluminum exposure. ...
... In this study, neonatal rats were exposed to Al by parental lactation for 3 weeks and then fed with distilled water containing 0.0 g/L, 2.0 g/L, 4.0 g/L, and 8.0 g/L Al chloride (AlCl 3 ) for 12 weeks. The available literature clearly shows that the neurotoxicity of aluminum in the CNS manifests itself in symptoms such as deficits in learning, memory, concentration, speech, and psychomotor control, as well as increased seizure activity and altered behavior (i.e., confusion, anxiety, repetitive behaviors, and sleep disturbances) (Tomljenovic 2011). Al sequesters different transport mechanisms to traverse brain barriers actively, and incremental acquisition of small amounts of Al over a lifetime favors its selective accumulation in brain tissues. ...
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Aluminum (Al) is a neurotoxin that gradually accumulates in the brain in human life, resulting in oxidative brain injury related to Alzheimer’s disease (AD) and other diseases. In this study, the learning and memory of rats exposed to different aluminum concentrations (0.0 g/L, 2.0 g/L, 4.0 g/L, and 8.0 g/L) were studied, and the learning and memory of rats were observed by shuttle box experiment. With hematoxylin and eosin staining, Western blot, immunofluorescence, and RT-PCR, the morphology of nerve cells in the hippocampus of rat brain were observed, and the levels of activator protein-1 (AP-1) gene and protein, nerve growth factor (NGF), neurotrophin-3 (NT3), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) gene and protein level, etc. The experimental results showed that subchronic aluminum exposure damaged learning and memory in rats. The cognitive function damage in rats was more evident after increasing the aluminum intake dose. The more aluminum intake, the more pronounced the histological changes in the hippocampus will be. The expression level and protein content of neurotrophic factors in the hippocampus of rats showed a negative correlation with aluminum intake. In this experiment, we explored the mechanism of aluminum exposure in learning and memory disorders, and provided some data reference for further elucidation of the damage mechanism of aluminum on the nervous system and subsequent preventive measures.
... L'absorption d'Al peut représenter un risque pour la santé de l'organisme humain (Becaria et al., 2002). Parmi les effets toxiques de l'Al, on peut citer les lésions pulmonaires (Taiwo et al., 2014), les anomalies osseuses , l'immunotoxicité (Zhu et al., 2014), les troubles neurologiques (Morris et al., 2017), etc. Selon Rondeau et al. (2008) et Tomljenovic (2011), il y a eu des suggestions indiquant une relation entre l'Al et la démence d'Alzheimer. Une influence directe de l'augmentation de l'absorption d'Al sur l'apparition d'une maladie n'a cependant été démontrée que pour quelques maladies, dont l'encéphalopathie de dialyse, l'ostéomalacie, l'anémie et l'aluminose (Harrington et al., 1994;Becaria et al., 2002;Chappard et al., 2016). ...
... Par ailleurs, l'Al a été introduit comme adjuvant dans les vaccins en 1926 par Glenny et al. (Marrack et al., 2009). L'hydroxyde d'Al, le phosphate d'Al, le sulfate de potassium d'Al (alun) et le silicate d'Al (zéolite) sont utilisés dans la préparation d'un certain nombre de vaccins pour adsorber les composants antigéniques et servir d'adjuvant qui améliore la réponse immunitaire en stimulant la production d'anticorps (Lione, 1985a;Barbaud et al., 1995;Tomljenovic, 2011). Par ailleurs, l'Al entre dans la composition de nombreux produits cosmétiques, pour diverses fonctions (antitranspirant dans les déodorants, abrasif dans les produits dentaires et les produits pour le visage et le corps, agent de viscosité dans les produits de soins et de maquillage, et absorbant dans les masques pour le visage). ...
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Full-text available
Omniprésent dans notre vie quotidienne, l’aluminium (Al) est l’un des éléments traces métalliques les plus dangereux pour la santé humaine. Nous y sommes exposés quotidiennement, par l’alimentation, l’application d’antitranspirants, l’utilisation d’antiacides, la vaccination, etc. L’exposition est donc inévitable, et chaque jour des taux modérés de ce métal pénètrent dans l’organisme et sont capables de s’accumuler dans certains organes. Malgré cela, la majorité de la population humaine n’est pas à risque évident de toxicité aluminique, puisque notre corps est équipé de plusieurs mécanismes qui ne permettent pas une absorption et une accumulation faciles, et facilitent son élimination. Par conséquent, une très faible quantité d’Al atteindra les différents organes et tissus (poumons, foie, cerveau, etc.). Une exposition élevée à l’Al entraîne des effets toxiques pulmonaires, gastro-intestinaux, cardiovasculaires, hématologiques, musculosquelettiques, neurologiques, hépatopancréatiques, etc. Les populations les plus exposées sont les patients dialysés, les consommateurs d’antiacides à long terme, et les professionnels de l’Al.
... Further, a few researchers (Tomljenovic, 2011;Bongiovani et al., 2016) stated that using alum and poly aluminium chloride for treating water via coagulation might lead to Alzheimer's; the treated water consists of chemical ionic residues that cause damage to health. In addition, these inorganic chemical coagulants showed a more remarkable performance for destabilizing suspended particles. ...
Article
Full-text available
Globalization and industrialization lead to the corresponding increase of effluents discharged into the nearest water bodies. The persistence of pollution in the ecological system has led to uncertainty about living habitats; drinking water safety has become a societal issue attached to great importance. As we increasingly become aware of environmental problems and their impacts on human life, we realize that current problem-solving using contemporary water treatment techniques cannot provide adequate solutions owing to their advantages and disadvantages. Nature-based solutions are required as they are the best alternative for treating polluted water. Conventional coagulation is not a new technique that has been utilized in ancient times and works as a sustainable solution for water treatment and reduces the costs associated with the other treatment methods. Even though these techniques have been practised since ancient times, there is still a need to explore more plants to identify coagulating properties. The current study aims to do the phytochemical and physicochemical screening of the plant-based materials to identify them as coagulants and compare their efficiencies with the conventional inorganic and animal-based coagulants; out of 18 plant-based materials, Moringa oleifera, Manihot esculenta and Pisum Sativum removed turbidity up to 100% are subjected to the FTIR, XRD, and SEM to analyze the functionalized groups responsible for the polymer formation and identify the interaction between the coagulator's and suspended particles. The results showed that plant-based materials could be promising solutions for water quality challenges.
... Cd is categorized as a carcinogenic agent. It is investigated that a serious element in low doses cause of its role compared to other essential elements such as Zn, Ca, Cu, and Fe [46]. The variety of impacts of Al (aluminum), Pb, Cr, etc., contains neurological disease, Alzheimer's, cardiovascular, and brain disorders [47]. ...
... Regarding AD, evidence that Al and other metals may cross the blood-brain barrier and accumulate in brain tissues provides a solid rationale for its association with TMs [17,18]. Human epidemiological studies have also shown that Pb and Cd, as well as Mn at high levels, are associated with impaired cognitive function and cognitive decline, suggesting a causal link with AD [19]. ...
Article
Full-text available
Many mechanisms have been related to the etiopathogenesis of neurodegenerative diseases (NDs) such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. In this context, the detrimental role of environmental agents has also been highlighted. Studies focused on the role of toxic metals in the pathogenesis of ND demonstrate the efficacy of treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (EDTA) in eliminating toxic metal burden in all ND patients, improving their symptoms. Lead, cadmium, aluminum, nickel, and mercury were the most important toxic metals detected in these patients. Here, I provide an updated review on the damage to neurons promoted by toxic metals and on the impact of EDTA chelation therapy in ND patients, along with the clinical description of a representative case.
... The 1980s and 1990s revealed a 75.7% increase in publications on the association between Al and AD with great emphasis on biochemical interactions [17][18][19][20][21]. However, most of the articles (n = 43) were published from 2000 to 2013 and provided evidence that Al can cause neurotoxicity, in particular after long-term exposure [12,[22][23][24]; in addition, Al can cross the blood-brain barrier and accumulate in neuronal cells [25,26]. Since the exposure form directly influences the absorption of Al [27,28], the consumption of drinking water with high Al concentrations increases the incidence of neurological diseases such as AD [29][30][31][32][33][34][35][36][37]. ...
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This study aimed to identify the landscape of current aluminum toxicity based on knowledge mapping of the 100 most-cited articles on toxicological aspects of aluminum in biological organisms. The research was searched in the Web of Science Core Collection (WoS-CC) with publications between 1945 and 2022. Data regarding authorship, title, journal, year of publication, citation count, country, keywords, study design, and research hotspots were extracted and all elected articles were analyzed. Our results showed that among the articles selected, literature review and in vivo studies were the most common study designs. The USA and England were found as the countries with most publications. Alzheimer’s disease (AD), aluminum, and neurotoxicity were found as the most frequent keywords. The articles most cited in world literature suggested that aluminum exposure is associated with Alzheimer’s disease, Parkinson’s disease (PD), dialysis encephalopathy, amyotrophic lateral sclerosis, neurodegeneration changes, cognitive impairment, such as bone damage, oxidative alterations, and cytotoxicity.
... Although whether low-dose aluminum exposure may contribute to AD development in humans remains controversial, accumulated experimental evidence has repeatedly demonstrated that chronic aluminum intoxication can reproduce the neuropathological hallmarks of AD (Tomljenovic 2011). We found that the p-tau/total tau ratios in the hippocampal tissue of aluminum-exposed rats and PC12 cells were higher than those of the control rats and control-treated cells, respectively; therefore, abnormal deposition of p-tau occurred. ...
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