Bioavailable Aluminum: Its Effects on Human Health

JR Walton, Australian Institute for Biomedical Research, Sydney, NSW, Australia

& 2011 Elsevier B.V. All rights reserved.

pathologies associated with chronic kidney failure. The

Abbreviations
final part discusses neurodegenerative diseases that may
AD Alzheimer disease
develop from chronic, routine exposure to low-dose Al3.
Al3 aluminum
These are more contentious. However, by considering
Al(OH)2H2PO4 aluminum hydroxyapatite
Alzheimer disease (AD) in some detail, it can assist
ALSPD amyotrophic lateral sclerosis
in determining whether Al3 is involved in chronic
and parkinsonism-dementia of
neurodegenerative conditions.
Guam
APP amyloid precursor protein
BMAA b-methylamino-L-alanine
Ca2 calcium
Diseases from Occupational Al3
CO carbon monoxide
Exposure
CO2 carbon dioxide
In the aluminum industry, the main workers with ex-
DBA/2, CH/2, A/J, inbred mouse strains
posure to aluminum dust and fumes are those employed
BALB/c, C57BL/6
in potrooms, foundries, and production of finely pow-
DFO deferoxamine
dered aluminum. Many reports have linked occupational
Fe2 ferrous iron
Al3 exposure to pulmonary fibrosis and potroom
Fe3 ferric iron
asthma. Authorities in Germany, Great Britain, Australia,
GVD granulovacuolar degeneration
and New Zealand recognize a causal relationship be-
HF hydrogen fluoride
tween these respiratory diseases and occupational Al3
IRP iron regulatory protein
exposure. In the United States, this relationship is yet
LD50 lethal dose, 50%
to be fully recognized, possibly because modernization
Mg2 magnesium
measures taken by the US aluminum industry have re-
MPTP 1-methyl-4-phenyl-1,2,3,6-
duced incidence of these diseases. Before the modern-
tetrahydropyridine
ization, 76.6% (95/124) of US workplace air samples
NFT neurofibrillary tangle
tested had concentrations of total dust (alumina and
PKC protein kinase C
fluorides), carbon dioxide (CO2), carbon monoxide (CO),
PP2A protein phosphatase 2A
sulfur dioxide (SO2), hydrogen fluoride (HF), and phenol
SO2 sulfur dioxide
above the recommended standards. After modernization,
TPN total parenteral nutrition
23.8% (57/240) of samples exceeded these levels. Sim-
US FDA United States Food and Drug
ultaneous exposure to such complex mixes of air pollu-
Administration
tants obscures the involvement of Al3 in occupational
diseases.
At least 29 reports from eight industrialized countries
have also described damage to cognitive function,
Introduction motor control, and peripheral nerves from occu-
pational Al3 exposure via dusts, fumes, or skin contact.
Toxic metals commonly provoke several different path- The use of McIntyre powder exemplifies relatively
ologies, depending on exposure level, exposure duration, uncomplicated occupational Al3 exposure. This alu-
route of uptake, subject age, comorbidities, and other minum powder was designed to bind with silica dust
conditions. Bioavailable aluminum (Al3) is no different. in the lung to form aluminosilicate and protect miners
A number of human health conditions are either caused from silicosis, a severe lung disease caused by silicon
by or associated with Al3 exposure and the affected dust. Between 1944 and 1979, 29 000 Canadian gold
subjects range in age from premature infants to the eld- miners were given millions of 10-min treatments,
erly. The first part of this article concerns respiratory inhaling high levels of aluminum powder at 353 mg m3
and neurological diseases attributable to occupational of air.
Al3 exposure. The second part deals with diseases that Subsequently, a research study tested the null hypoth-
arise from medical treatments that involve Al3. Here, esis that there are no cognitive differences between miners
the main focus is on dialysis encephalopathy and other exposed and those not exposed to McIntyre powder.

331
332 Bioavailable Aluminum: Its Effects on Human Health
Unexposed nickel and copper miners served as controls.
Altogether, 607 miners completed three different stand-
ard cognitive tests, measuring short-term memory and
other properties. Of the 261 miners exposed to McIntyre
powder, 13% showed cognitive impairment compared to
5% of the 346 controls. Importantly, those exposed to
McIntyre powder for 1020 years were 3.1 times more
likely to score poorly on cognitive function tests. Those
exposed Z20 years were 4.5 times more likely than
controls to show this effect. Thus, length of exposure to
this aluminum powder significantly correlates with cog-
nitive impairment.
Diseases Related to Medical Treatments
that Involve Al3
There is no doubt that aluminum has made many posi-
tive contributions to health. For example, it increases
efficacy in vaccines where it serves as an adjuvant that
enhances the bodys immune response to the active agent.
Aluminum antacids provide relief from indigestion, and
most large urban water utilities use alum (aluminum
sulfate) to clarify their drinking water supplies. Alu-
minum is a useful component of phosphate binders,
buffered aspirins, antimicrobials and antidiarrheals; irri-
gants for bladder hemorrhage and vaginal douches;
topical powders and creams for diaper rash, athletes foot,
and anorectal pruritis; and toothpastes, dental cements,
styptic pencils, cosmetics, deodorants and sunscreens.
Aluminum is also used in alloy form for some prosthetic
hip, shoulder, and knee replacements. However, in some
individuals, repetitious usage of Al3-containing prod-
ucts has negative side-effects, with toxic reactions ran-
ging from irritation to organ failure.
Al3 and Immune Reactions
Contact sensitivity to Al3 occasionally occurs, mostly
after vaccination or hyposensitization therapies utiliz-
ing aluminum compounds. Injected aluminum hydroxide,
aluminum phosphate, or alum, either in conjunction with
antigen extracts or in an adsorbed vaccine, can cause
granulomas. Routine application of aluminum-containing
antiperspirants may lead to axillary eczema or rashes;
otitis externa has resulted from aluminum acetate ear-
drops. Aluminum allergy is most common in pediatric
patients.
Al3 and Intravenous Feeding
The gastrointestinal tract normally excludes much Al3
but it is bypassed in patients receiving long-term total
parenteral nutrition (TPN). Intravenous feeding solu-
tions commonly contain Al3-contaminated ingredients,
some at relatively high levels. Reports dating from 1982
describe patients on long-term TPN, from premature
infants to adults, routinely exposed to Al3 at levels
sufficiently high to cause clinical signs of toxicity. Some
have developed encephalopathy or osteomalacia despite
having normal kidney function before treatment with
long-term TPN.
Parenterally fed infants have a higher risk for Al3
damage due to their immature bloodbrain barrier and
kidneys. Diagnostic techniques used to evaluate bone
Al3 content in adults are inappropriate for infants.
Therefore, these neonates may have more Al3 toxicity
than currently recognized. For these reasons, the United
States Food and Drug Administration (US FDA) amen-
ded its regulations in 2004 to require labeling of Al3
content in TPN products.
Al3-associated Mortality
Toxicity signs from very high Al3 exposure are fairly
consistent across species. These include decreased ap-
petite, poor digestion with reduced bodyweight gain,
disturbed mineral metabolism (low phosphate absorption,
hypercalcemia, and reduced bone mineralization), and
Al3 accumulation in body tissues.
Some humans abuse aluminum antacid self-medi-
cation. To illustrate, a case history concerns a mother
who admitted to taking many 200 mg aluminum antacid
tablets each day throughout her pregnancy. Her daughter
had poor growth, anemia, impaired bone mineralization,
and abnormal bone development, all consistent with Al3
toxicity. Her mental development failed to progress
after age 2 months and she died at age 9 years with a
neurodegenerative disease. Her brain showed marked
cortical atrophy with focal astrogliosis of the hippo-
campus. Gestational Al3 neurotoxicity has been con-
firmed in fetuses and offspring of pregnant Al3-exposed
rats, mice, and rabbits.
Several reports in the literature have also described
Al3 toxicity from Al3-containing products used in
medical procedures. For example, encephalopathy and
death have resulted from aluminum cement used for
bone reconstruction in otoneurosurgery and from alum
irrigation of hemorrhaging bladders.
Chronic Kidney Failure
In the United States, the 2005 prevalence rate for patients
with end-stage kidney failure was 514 688. Kidney failure
patients are unable to actively excrete the Al3 they
absorb, and are thus prone to elevated levels of plasma
Al3, tissue Al3, and Al3-associated diseases. The latter
include (1) dialysis encephalopathy (dialysis dementia);
(2) bone disease (mainly fractures, vitamin D-resistant
osteomalacia, and aplastic bone disease); (3) parathyroid
disease; (4) microcytic anemia; (5) amyloidosis; and
 Bioavailable Aluminum: Its Effects on Human Health
(6) kidney disease itself (as Al3 is a nephrotoxin, it can
exacerbate kidney disease).
Al3 and dialysis encephalopathy
Kidney failure patients are unable to effectively excrete
phosphate. High levels of blood phosphate increase their
risk for bone disease, heart disease, and death. In the
1960s, aluminum hydroxide was widely prescribed as a
phosphate binder to limit phosphate absorption. By the
early 1970s, bone fractures and outbreaks of dialysis
encephalopathy (dialysis dementia) began to occur. This
was shown to result from high Al3 content in buffers
and tap waters used for the dialysate, aluminum-based
phosphate binders, and corrosion of aluminum com-
ponents in dialysis equipment. In one example of many,
six patients undergoing hemodialysis in a Netherlands
hospital developed dialysis encephalopathy. An investi-
gation determined the boiler used to heat their dialysis
water contained two aluminum anodes (combined weight
of 32.4 kg) that completely dissolved over a 2-year period.
Children dialyzed for impaired kidney function have also
developed encephalopathy secondary to Al3 toxicity.
In healthy adult humans, plasma Al3 levels are
usually approximately 6 mg ll and brain Al3 content
less than 2.0 mg g1 dry brain weight. In renal failure
patients, cognitive impairment is associated with plasma
Al3 values greater than 60 mg ll. Dialysis encephal-
opathy can occur with plasma Al3 levels ranging
between 80 and 800 mg ll. Al3 concentrations in the
cerebral cortex of dialysis encephalopathy patients are
also high, averaging between 10 and 25 mg g1 dry brain
weight.
The clinical course for dialysis encephalopathy in-
volves: (1) a 612-month asymptomatic period; (2) loss of
short-term memory and associative learning; (3) alter-
ations in muscle tone, motor control disorders resem-
bling motor dyspraxia; and eventually (4) myoclonic jerks
and seizures that, if left untreated, result in death. Many
dialysis patients exhibit the early protein changes (oxi-
dation and hyperphosphorylation) that precede the for-
mation of amyloid plaques and neurofibrillary tangles
(NFTs), respectively. These are neuropathological
hallmarks of AD. The affected brain regions in dialysis
encephalopathy and its animal models are basically
the same that are affected in AD. Some dialysis patients
are reported to exhibit fully formed plaques and tangles
but these features do not consistently occur in this
patient population that is generally younger than the
Alzheimer population and has different Al3 exposure
characteristics and comorbidities. To simulate Al3 levels
that occur in dialysis encephalopathy, cat and rabbit
brains have been injected with Al3 into the lateral
ventricles. These animals exhibit a similar clinical pro-
gression to dialysis encephalopathy, ending in convul-
sions and death.
333
Since Alfrey et al. published their landmark paper
naming Al3 as the probable cause of dialysis en-
cephalopathy, measures have been implemented to re-
duce Al3 exposure in patients with chronic kidney
disease. These include reverse osmosis filtration to re-
move Al3 from dialysis fluid, avoidance of aluminum-
based phosphate binders, and chelation treatments. Such
measures have greatly reduced the occurrence of dialysis
encephalopathy.
Deferoxamine (DFO) is a chelating agent that forms
much stronger complexes with the trivalent metals alu-
minum (Al3) and iron (Fe3) than with calcium (Ca2)
and most other metal ions. A DFO infusion test is
sometimes performed in preference to routine serum
or plasma Al3 measurements to assess the bodys alu-
minum load. DFO therapy has been extensively used
to treat kidney patients with high Al3 burdens. Up to
5 mg kg1 bodyweight of parenteral DFO is sufficient to
substantially lower plasma Al3 levels, generally leading
to improvements in short-term memory and intellectual
function.
Al3, bone, and parathyroid diseases
The detrimental effects of aluminum in bone are com-
plex and may affect osteoblast/osteoclast coupling, dis-
rupt the calcium/vitamin D/parathyroid hormone axis,
and interfere with bone mineralization by inhibiting
hydroxyapatite formation. Aluminum deposition in bone
is associated with vitamin D-resistant osteomalacia,
aplastic bone disease, and fractures. Patients with plasma
Al3 levels greater than 30 mg l1 have increased risk for
bone disease, especially osteomalacia, despite having
normal plasma magnesium (Mg2) and Ca2 levels.
Even low levels of accumulated Al3 disrupt bone
Ca metabolism. Al3 inhibits the formation of 1,25-
2
(OH)2-vitamin D. Precipitation of aluminum hydro-
xyapatite (Al(OH)2H2PO4) in bone tissue interferes
with the orderly, controlled deposition and dissolution
of calcium hydroxyapatite, even at Al3 concentrations as
low as 0.1 mM. Aluminum deposition in bone increases
fragility and susceptibility to fracture. For example,
regular usage of aluminum-based antacids increases the
risk of a first vertebral fracture in women aged 65 or older.
A rat model for human osteomalacia and parathyroid
suppression involves kidney surgery and repeated intra-
peritoneal Al3 injections (9.25 mg over 33 days). This
results in profound osteomalacia similar to the human
condition characterized by unmineralized osteoid, de-
creased bone formation, lower bone resorption, and de-
pressed parathyroid activity.
Several reports describe transient stimulation by Al3
on bone growth while others show Al3 inhibits bone
growth. These apparently contradictory observations are
reconciled by the finding that osteoblast response to Al3
is biphasic. Cultured osteoblasts initially undergo cell
334 Bioavailable Aluminum: Its Effects on Human Health
division in response to Al3 in their growth medium.
After accumulating Al3, osteoblasts develop metabolic
abnormalities and exhibit growth inhibition. A similar
response occurs at the molecular level where Al3 ini-
tially stimulates mRNA synthesis and then inhibits it.
Likewise, in human kidney disease and its animal models,
high plasma Al3 levels initially stimulate parathyroid
activity, resulting in hyperparathyroidism. As Al3
accumulates in parathyroid cells, hypoparathyroidism
eventually develops. Recognition of this biphasic nature
is important to understanding Al3 toxicity.
Al3 and microcytic anemia
Some kidney failure patients are anemic. Blood Al3 is
almost equally partitioned between red blood cells and
plasma. Erythrocytes contain 4 nM 2,3-diphosphoglycerate,
a potentially strong Al3 binder. Al3 competition with
hemoglobin for 2,3-diphosphoglycerate adversely affects
oxygen transport in erythrocytes, resulting in microcytic
anemia.
Al3 and systemic amyloidosis
Amyloidosis, characterized by deposits of b-2-micro-
globulin in multiple tissue locations, increases with
time on dialysis. This amyloid protein is structurally
distinct from cerebral b-amyloid protein, yet both are
demonstrated by Congo red staining and thioflavin
S immunofluorescence. A study showed deposits of
b-2-microglobulin in 9/22 sternoclavicular biopsies. The
amyloidosis-affected dialysis patients were older than
those without amyloidosis, had been on dialysis longer,
and demonstrated a significantly higher plasma Al3
burden in response to challenge by DFO infusion.
Al3 and nephrotoxicity
Aluminums nephrotoxicity largely derives from the
kidneys role in routine Al3 handling. Micropuncture
Figure 1 Adult rat kidney processed with the modified Walton stain for Al3. (a) Proximal convoluted tubules show magenta droplets
indicative of filterable Al3 (arrowhead). (b) Renal cells of proximal convoluted tubules in aged rat kidney have pale pink cytoplasm
(arrowhead), indicating dispersed Al3. Some exhibit nuclei that stain pink-magenta for Al3. Scale 10 mm.
studies and histological staining for Al3 show that it is
reabsorbed in droplet form in the proximal convoluted
tubules (Figure 1(a)). In aged kidney tissue of Al3-ex-
posed rats, the proximal tubule cells eventually show
nuclear and cytoplasmic Al3 staining in nondroplet
form (Figure 1(b)).
Stained for Al3, kidney tissue from a stillborn human
fetus is Al3-negative (Figure 2(a) and 2(b)). In contrast,
a strong Al3 staining response occurs throughout the
deteriorated kidney tissue of an adult human who died
with chronic kidney failure (Figure 2(c) and 2(d)).
Long-Term Routine Exposure of Humans
to Low-Dose Aluminum
Although contentious, there is evidence that certain
neurodegenerative conditions develop from chronic
exposure to low-dose Al3, in particular, Alzheimers
disease (AD), amyotrophic lateral sclerosis and parkin-
sonism-dementia of Guam (ALS/PD) and some cases of
Parkinson disease. In most humans, the main route and
sources for aluminum exposure involves oral ingestion
of processed foods and beverages that contain Al3 in the
form of additives. Americans (representative of people
living in modern urban society) are estimated to ingest
110 mg Al3 each day from fresh vegetables, fresh fruits,
unprocessed meats, and fish. In addition, 50% of them
ingest up to 24 mg Al3 per day in the form of additives,
45% consume 2495 mg Al3 per day, and the remaining
5% consume more than 95 mg Al3 per day. These es-
timates take into account the extent of aluminum addi-
tive usage by the food industry.
Many precooked processed foods contain aluminum
(Table 1), in amounts typically ranging between o0.1
and 22 mg kg1. A small Al3 increase occurs in food
cooked in aluminum pots but it is minor compared to
 Bioavailable Aluminum: Its Effects on Human Health
Figure 2 Human kidney tissue processed with the modified Walton stain for Al3. (a) This kidney tissue, obtained from a stillborn human fetus, shows a glomerulus and surrounding tubules
that are completely Al3-negative. Blood cells in the glomerulus are aluminum-negative, staining bright turquoise (e.g., arrow). (b) Kidney tubules (arrowhead) from this fetus are also Al3-
negative. (c) Kidney tissue from an adult human who died with end-stage kidney failure. Blood cells in the glomerulus (e.g., arrow) stain bright magenta for Al3. The nuclei of glomerular cells
stain for Al3, whereas their cytoplasms are Al3-negative. (d) Kidney tubules (arrowhead) from the same patient are comprised of deteriorated cells that are entirely Al3-stained.
Scale 10 mm.

335
336 Bioavailable Aluminum: Its Effects on Human Health
Table 1 Common sources of aluminum additives and contaminants
Aluminum compound Purpose
Aluminum lake dyes Coloring agent for nonliquid products
Aluminum maltolate Flavor enhancer
Aluminum silicates Anticaking agent
Aluminum sulfate (alum), aluminum Coagulant, acidifying agent, firming agent
ammonium sulfate, potassium
aluminum sulfate, sodium aluminum
sulfate
Polyaluminum chloride Coagulant
Sodium aluminum phosphate, basic Emulsifier, easy melting, meat-binding
agent
Sodium aluminum phosphate, acidic Leavening agent
Aluminum hydroxide (contaminant)
Aluminosilicate (natural contaminant)
Miscellaneous uses of aluminum compounds are as follows: to strengthen dough, swell pastas, bleach flour and cheeses, ingredient in reconstituted
vegetable protein, stabilizers, thickeners, texturizers, and buffers.
amounts contributed by aluminum additives. Also, car-
bonated drinks and beer are subject to Al3 contamin-
ation, if stored for more than a few months in aluminum
cans, from corrosion of the inner protective lining. For
example, soft drink Al3 rose from 0.16 to 250 mg l1
when cans were stored for up to 173 days; Al3 in beer
increased from 50 to 547 mg l1 when cans were stored at
room temperature for 5 months.
Most large cities use rapid water filtration to clarify
their drinking water supply. This process requires add-
ition of a coagulant. Alum and polyaluminum chloride
are widely used for this purpose although iron salts are
also used effectively. Coagulants clarify water by binding
to organic matter and aggregating suspended particles
that can harbor bacteria. This causes the particles to
settle, facilitating their removal by filtration. Metal-based
coagulants are able to clarify (without disinfecting) the
brackish drinking water available in some developing
countries.
Before treatment, total Al3 concentrations in water
sources range from undetectable to more than 1 mg l1.
Addition of aluminum-based coagulants reduces the
total Al3 concentration while significantly increasing the
level of monomeric inorganic Al3 in drinking water,
a form significantly more bioavailable than the poorly
absorbable aluminosilicate clay particulates and colloids
that they effectively remove. For example, a drinking
Food examples
Cereals, snack foods, jams, margarine,
maraschino cherries, artificially colored
oranges, cake mixes, ice cream,
candies, fruit yoghurts, margarine,
vitamin pills, medicinal capsules
Blueberry muffins
Table salt, nondairy creamer, pancake
mix, cocoa mix, corn chips
Drinking water treatment; food dyes;
adjuvant in vaccines; baking powder
(e.g., 70 mg Al3 per teaspoon),
chocolate cake (e.g., 515 mg Al3 per
slice); free-rising flour, pickles, frozen
strawberries, candied fruits
Drinking water treatment
Blue cheese, gongonzola, provolone,
Swiss processed American cheese
(e.g., 14 mg Al3 per 20 g slice),
luncheon meats
Self-rising flour; biscuit, pancake, cake,
muffin, and doughnut mixes; yeast
doughs
Infant soymilk formulas (e.g., 460
930 mg l1)
Calcium supplements from crushed
oyster shells (e.g., 12 mg Al3 per day)
water analysis involving water from three treatment
plants showed inorganic monomeric Al3 accounted
for 449% of the total dissolved Al3 in pretreatment
water. After polyaluminum chloride treatment, this
fraction increased to 4188% of the total dissolved Al3.
A survey of 186 water supplies showed alum-treated
water had a median Al3 concentration of 112 mg l1
compared to 43 mg l1 in drinking water without coagu-
lant treatment. Some brands of bottled water also have a
high aluminum content, suggesting clarification with
alum treatment.
Since most humans living in modern urban society
routinely ingest dietary Al3, and many drink alum-
treated water, their tissues gradually accumulate Al3
over time. The total body Al3 content for humans has
been estimated at 300 mg. Tissues of elderly individuals
contain more Al3, presumably because of their longer
Al3 exposure. When stained for Al3, aged human
hippocampal pyramidal neurons show Al3 accumulation
either in their nucleolus, throughout their nucleus,
throughout their entirety or, where present, in NFTs.
Alzheimer Disease
AD is a condition that makes its sufferers mentally
incompetent as they progressively lose self-help skills.
 Bioavailable Aluminum: Its Effects on Human Health
Eventually, some become unable to recognize their own
reflection in a mirror. Overt deterioration in mental
function occurs slowly, typically over 1020 years after
behavioral change first becomes apparent. Compared
with dialysis encephalopathy, AD is much more gradual.
An early onset inherited form of AD occurs before age
65 years but late-onset AD accounts for 95% of all cases,
affecting approximately 5% of humans aged 65 years and
1525% of those aged 85 years or older.
Distinguishing neuropathological hallmarks of the AD
brain are cerebral atrophy involving neuron loss, astro-
gliosis in the hippocampus and cerebral cortex, NFTs,
extracellular senile plaques with amyloid cores, granu-
lovacuolar degeneration (GVD) in the hippocampus,
microtubule disappearance, and synapse loss. Dementia
severity increases with the extent of synapse loss and, to a
lesser extent, with NFT numbers.
Historical Background
AD was unknown in the nineteenth century. A British
Medical Council Health Survey published in 1889
described overall health assessments by family doctors
of nearly 900 patients, 80 years and older, including 74
centenarians. This report clearly states that 2/74 or 2.7%
of the centenarians showed any type of dementia. Then,
as now, dementias associated with alcohol abuse and
syphilis were prevalent. Contrastingly, in 2000, 15/17 or
88% of the centenarians in three Dutch towns were
diagnosed with dementia, mostly AD, and the other two
could not be examined.
In 1906, when Alzheimer delivered his historic paper
to a group of German psychiatrists, he stated: The case
presented even in the clinic such a different picture, that
it could not be categorized under known disease head-
ings, and also anatomically it provided a result that
departed from all previously known disease pathology.
The first case was a 51-year-old resident of Frankfurt-
am-Main. After moving to Munich, Alzheimer reviewed
at least two other brains sent from Frankfurt-am-Main
with the same diagnosis. Interestingly, due to droughts
in the early 1880s, Frankfurt-am-Main was one of
the first cities in Europe to consider rapid water filtration,
a process that requires addition of a coagulant such
as alum.
In 1925, AD was described in The Lancet as a rare
disease. In 1934, the number of recorded cases was 90.
By 2003, AD prevalence had risen to 4.5 million in the
United States alone and 18 million cases worldwide
Unlike today, AD intially applied only to patients under
65 years of age. The steep increase in AD prevalence over
the 20th century includes a vast number of middle-aged
individuals whose AD cannot be reasonably explained by
increase in genetic mutation rate, population size, or
population aging.
337
Epidemiological Findings
Studies of AD concordance in identical twins indicate
that AD causality is partly genetic and partly environ-
mental. Since AD prevalence is much higher in affluent
industrialized countries than in developing geographical
regions, AD has been described as a disease of indus-
trialized countries.
Thirteen epidemiological studies have investigated
whether there is a relationship between long-term ex-
posure to Al3 in drinking water and AD or dementia.
Nine have shown a positive relationship. The two most
robust of these human studies compare drinking water
supplies with Al3 levels above and below the cut-off
value of 100 mg l1. A prospective study that followed
2698 cognitively normal subjects aged 65 years or older,
with 8 years of follow-up, revealed the relative risk of AD
increased to 2.14 for those who drank water containing
more than 100 mg Al3 ll compared to those who drank
water containing less Al3. In another major study, almost
600 subjects brains were autopsied to ensure correct
classification. To the extent possible, 10-year residential
histories were obtained since many people with AD
die in nursing homes within localities different from
their main Al3 exposure. This study showed a dose-
dependent relationship. Similar to the prospective study,
it concluded people who routinely drink water con-
taining 4100 mg Al3 ll have a risk for AD 2.5 times
higher than those who drink water containing less Al3.
The risk increases to 4.4 and 7.6 times for those who
drink water with Al3 concentrations in excess of cut-off
levels at 150 and 175 mg ll, respectively.
Two of the four negative studies involved only early
onset AD subjects. A third compared results from two
water supplies where both had relatively low Al3 con-
centrations (not exceeding 100 mg ll). In the fourth
study, the water supply had only been alum-treated since
the year patient recruitment for the study began.
To date, a single preliminary study has examined the
putative relationship between ingestion of food with
aluminum additives and AD. When adjusted for covari-
ates, this retrospective casecontrol study found humans
whose dietary history indicated routine consumption of
foods high in aluminum additives were 8.6 times more
likely to develop AD than those with a low dietary intake
of aluminum additives.
As shown for dialysis encephalopathy, chelation
treatment using DFO can reduce Al3 concentrations in
AD-affected brains, for example, from 4.1 mg g1 to near
normal levels of 2.7 mg g1 dry weight (po.05). This
observation furnished the basis for a 2-year, prospective,
randomized controlled clinical trial to learn whether
Al3 removal slows AD progression. Forty-eight AD
subjects, given intramuscular DFO injections twice daily,
had lower plasma and brain Al3 concentrations, and
338 Bioavailable Aluminum: Its Effects on Human Health
were reported to have improved short-term memory
and intellectual functioning. Oral placebo and untreated
controls declined twice as rapidly as the DFO-injected
group in performance tests of daily living skills (docu-
mented on video tape) and in the progression of their
motor dyspraxia (where one knows what one wants to do
but cannot control ones body to achieve it). After 5 years,
there were nine deaths in the control (non-treated) group
and one in the DFO-treatment group. Despite these
promising results, confirmatory trials have not been
performed, largely due to the labor-intensive protocol.
Intramuscular DFO injection of rabbits, with NFTs in-
duced in their brains by intraventricular Al3 injection,
significantly mitigated their neuropathology compared
to controls. This experiment suggested a confirmatory
human trial could succeed with fewer DFO injections.
Tissue Al3 Levels and AD
Plasma 26Al measurements taken after consuming a
standardized 26Al dose at either dietary or pharma-
ceutical levels have shown subjects who develop AD
absorb significantly more 26Al than age-matched non-
demented controls. Consistent with these findings, six
out of seven studies in peer-reviewed journals reported
AD patients have significantly higher basal plasma or
serum Al3 levels than nondemented controls. The
single negative study is statistically underpowered. Thus,
plasma or serum Al3 measurements made under con-
trolled conditions may be useful for predicting indi-
viduals at higher risk for AD.
As the human brain ages, Al3 preferentially accu-
mulates in large pyramidal neurons to a much greater
extent than in surrounding neuropil. More than 12
laboratories in seven countries, employing a variety of
analytical techniques, have reported in peer-reviewed
journals that certain brain regions of AD patients have
higher Al3 concentrations than those of age-matched
controls. In AD-affected brain regions, controls typically
contain 12 mg Al3 g1 dry brain weight, whereas AD
patients have 35 mg Al3 g1 dry brain weight, and
patients dying with dialysis encephalopathy have Z10 mg
Al3 g1 dry brain. Thus, between each of these
categories, there is a two- to threefold difference. Al3
concentrations that occur in AD cortical tissue are
neurotoxic for laboratory cats and rabbits. Recordings
from single neurons in cat visual cortex containing 4.7 mg
Al3 g1 dry brain weight show altered electrical spike
activity. Al3 toxicity and LD50 (lethal dose in 50% of
rabbits given an intracerebral Al3 injection), occurs
at a brain aluminum concentration of 5.5 mg Al3 g1
(dry weight). In vitro, media containing between 1 and
50 mM Al3 are toxic to primary neural cells.
Al3 content is significantly higher in the temporal
cortex than in the frontal cortex of AD brain, consistent
with the extent of neuropathological change that
occurs in these regions. At Al3 concentrations found in
AD-affected brain, Al3 binds to heterochromatin of
cultured human neural cells and represses gene activity.
Neurons in AD-affected regions characteristically exhibit
chromatin condensation and repressed or aberrant gene
activity. AD brain samples contain approximately 17
times more aluminum per gram DNA in highly con-
densed heterochromatin than in other cell fractions and
almost twice as much aluminum per gram DNA than
controls.
A few studies have been unable to show quantitative
difference in brain Al3 content between aged humans
with AD and aged nondemented controls. It has been
suggested that this may result from technical difficulties
involved in detecting low levels of nonuniformly dis-
tributed Al3 in a biological matrix or dissecting out
small samples that include pyramidal neurons with
minimal extracellular matrix.
Al3 Disregulation of Iron Metabolism
Free Al3 and free iron are both toxic to neurons.
Intracellular Al3 is free to participate in, and interfere
with, cellular reactions. In contrast, iron levels in neurons
are normally controlled by iron regulatory proteins
(IRPs) that sense the free iron concentration in cells. If
too high, IRP-1 up-regulates the synthesis of ferritin, a
protein that binds excess iron and allows only a small
transit pool of unbound iron to be freely available for
cytoplasmic reactions. If low, IRP-2 responds by up-
regulating the synthesis of transferrin receptors to in-
crease iron uptake.
Experiments with Al3-loaded rats and Al3-loaded
cell cultures have shown Al3 accumulation in neurons
dramatically interferes with their iron metabolism. Al3
stabilizes IRP-2, preventing its breakdown. This pro-
motes the synthesis of transferrin receptors and blocks
the synthesis of ferritin. Such interference makes
more free iron available in neurons where Al3 has
accumulated, thus increasing their risk for oxidative
damage. Al3 amplifies iron-initiated lipid peroxidation
several-fold.
Human brains affected by AD have disregulated
iron metabolism. IRP-2 fails to degrade in neurons,
showing striking increase. Consequently, free iron attains
toxic levels, causing oxidative damage via the Fenton
reaction. This has been described as one of the
earliest features of AD. 4-Hydroxynonenal and the iso-
prostane 8,12-iso-iPF2a-VI markers of oxidative dam-
age are present at significantly higher levels in AD
brain than in control brains. Both markers have also
been identified in rodent brains after long-term low-dose
Al3 exposure.
 Bioavailable Aluminum: Its Effects on Human Health 339

Al3 Involvement in Amyloid Plaque Formation
Ample published data describe Al3 involvement in
amyloid plaque formation:
1. Gene microarrays show Al3 up-regulates expression
of the gene for amyloid precursor protein (APP) in
primary cultures of human neural cells.
2. Nanomolar amounts of Al3 inhibit the activation of
protein kinase C (PKC) by 90%. This enzyme allows
APP cleavage via its nonamyloidogenic a-secretase
pathway as opposed to its b-amyloidogenic pathway.
Al3 inhibition of PKC activity can reasonably explain
why Al3 increases b-amyloidogenesis in cultured
neuroblastoma cells.
3. Al3 accelerates the in vitro formation of an aberrant
splicing isoform of presenilin-2 that also occurs in AD
neural tissue.
4. In vitro studies with circular dichroic spectroscopy
have shown human b-amyloid exposed to Al3 at
brain-relevant levels becomes altered from a soluble
form with random structure to a fibrillar precipitate
with b-pleated structure.
5. Amyloid142 oligomers are stabilized by, and increase
in, the presence of aluminum. These are regarded by
some as the most toxic form of amyloid.
6. Al3 induces b-amyloid fibrils to aggregate as in AD
plaque formation.
7. b-Amyloid aggregates induced by Al3 exposure stain
with both Congo red and thioflavin S as in AD
plaques.
8. Plaque formation is species-specific but mice, trans-
genic for human APP, develop more and larger
amyloid plaques in their brains after consuming a diet
supplemented by Al3 for 1 year than their transgenic
counterparts that ingest the diet without added Al3.
This change is countered by vitamin E, indicating
Al3 stimulates amyloidogenesis via a mechanism
involving free radical production and oxidative stress.
Al3 Involvement in Neurofibrillary Tangle
Formation
Human NFTs develop within aluminum-rich cyto-
plasmic areas of pyramidal neurons (Figure 3(a) and
3(b)) located in specific brain regions including: the
neocortex (particularly layers II and V), hippocampal
formation, entorhinal cortex, amygdala, olfactory bulb,
substantia nigra, basal nucleus of Meynert, dorsal raphe
nucleus, and locus coeruleus. These cells all have high
densities of transferrin receptors. The same regions ac-
cumulate Al3 in dialysis encephalopathy and in Al3-
injected rabbit brains where NFTs form.
Evidence from in vivo and in vitro studies has shown
Al3 inhibits the activity of protein phosphatase 2A
(PP2A). Inhibition of PP2A activity is an early feature of
NFT formation in AD. Kinases add phosphates to protein
and PP2A is the main phosphatase in neurons that
removes phosphates. Inhibited PP2A activity results
in hyperphosphorylation of cellular proteins (mainly
neurofilament and microtubule-associated proteins such
as tau). As hyperphosphorylated tau proteins accumulate,
they aggregate and polymerize to form the so-called
paired helical filaments of NFTs, which are actually
single filaments with a twisted ribbon structure.

Figure 3 AD hippocampal neurons stained for Al3 with the modified Walton stain. (a) This pretangle neuron has a deep purple
(Al3-rich) region in its cytoplasm (arrow). Reproduced from Walton JR (2010) Evidence for participation of aluminum in neurofibrillary
tangle formation and growth in Alzheimers disease. Journal of Alzheimers Disease 22: 6572, with permission from IOS Press.
(b) Another neuron has an NFT (arrow) within Al3-rich cytoplasm. Scale 5 mm.
340 Bioavailable Aluminum: Its Effects on Human Health
Hyperphosphorylated tau and microtubule-associated
proteins are unable to assemble and maintain micro-
tubules, leading to microtubule loss in cells that contain
NFTs or that otherwise stain for Al3.
Much importance has been given to the difference
between NFTs in AD brains and NFTs induced by Al3
injection into animal brains. This difference is probably
species-specific and/or temporal, given that the former
can be decades old and the latter are newly formed.
In the presence of Al3, neurofilament proteins in
rabbit neurons become hyperphosphorylated, aggregate,
and orient into filaments with characteristic region-
specific NFT shapes (flame-shaped in hippocampus,
skein-like in cerebral cortex). As tau becomes increasingly
available and hyperphosphorylated over the next few days,
the levels of hyperphosphorylated tau, ApoE, and other
NFT-associated proteins gradually increase in the nascent
animal NFTs. Hence, human animal NFTs and Al3-
induced animal NFTs are more similar than commonly
assumed.
Al3 and Other Hallmarks of AD
Laboratory animals given a series of intraperitoneal Al3
injections or that have long-term oral Al3 exposure at
human-relevant dietary levels develop GVD in their
hippocampal neurons. Hippocampal GVD was recog-
nized as a characteristic of the AD brain several years
after Alzheimer described his first case. Whether affected
neurons contain one to several large vacuoles or many
small ones, each vacuole has a single granule. The
granules contain Al3 (Figure 4) and abnormal proteins
such as hyperphosphorylated tau.
Al3 exposure results in synapse loss in the cerebral
cortex of experimental animals. In humans, loss of synapse
density correlates with AD severity more strongly than
either NFTs or plaques. Al3 also interferes with activity
of neurotransmitters, for example, decreasing cholinergic
activity in cat, rabbit, and rat cortex by 3658%.
Figure 4 Human hippocampal neuron with Al3 staining of the
nucleus and granules in large GVD vacuoles. Scale 5 mm.
GeneEnvironment Interaction in AD
In aluminum absorption studies conducted in outbred
species, some individuals typically absorb two to three
times more Al3 than others (e.g., Figure 5). The genes
presumed to account for this difference are yet to be
identified. As described earlier, humans that develop AD
generally absorb more Al3 than nondemented controls.
Supporting evidence that genotype affects aluminum
absorption comes from subjects with Downs syndrome
who have three copies of chromosome 21. They have
higher basal serum Al3 levels and absorb four and
six times more Al3 than age-matched controls from
standardized pharmaceutical Al3 and dietary Al3
doses, respectively. Moreover, all Downs syndrome pa-
tients develop AD neuropathology by age 40 years.
As aluminum is an important influence in AD neuro-
pathology, this early tendency to develop plaques and
tangles may stem from their abnormally efficient Al3
absorption.
Further evidence that the genetic constitution affects
Al3 uptake comes from experiments using five different
inbred mouse strains. The DBA/2 and C3H/2 strains
were shown to have higher brain Al3 concentrations
than the A/J, BALB/c, and C57BL/6 strains after all
consumed 260 mg Al kg1 diet for 28 days.
4
A
No silicon
B
+ silicon
3 C
Plasma 20Al (pg/l)
D
2
E
1
A
C
B
D
E
0
0 1 2 3 4 5 6
Time after drink (hrs)
Figure 5 Plasma Al3 concentrations from some subjects
peak higher than those from others after consuming a drink
containing a standard Al3 dose. With silica added to the drink,
the amounts of Al3 absorbed were in a similar ranking order, at
lower levels, respectively. Reproduced with permission from
Edwardson JA et al. (1993) Effect of silicon on gastrointestinal
absorption of aluminium. The Lancet 342: 211212.
 Bioavailable Aluminum: Its Effects on Human Health 341

Al3 and Dementia than elsewhere. The affected humans characteristically

developed motoneuron disease with extrapyramidal
Al3 is capable of causing dementia (e.g., as in dialysis
neuron degeneration. Their central nervous system ex-
encephalopathy). Many experiments with young animals
hibited NFTs with elevated concentrations of Al3 and
have demonstrated that subacute Al3 exposure impairs
Ca2 in the absence of amyloid deposition and senile
memory and learning abilities, provided the exposure
plaques.
duration is sufficient. These high-dose studies demon-
ALS/PD may result from a basic imbalance in mineral
strate Al3 neurotoxicity, yet have limited relevance for
metabolism where chronic Ca2 and Mg2 deficiency
neurodegenerative diseases. Recently, long-term longi-
induces secondary hyperparathyroidism that in turn en-
tudinal studies have been performed using rats trained
hances Al3 absorption. In support of this, a condition
to perform a hippocampal-dependent continuous alter-
resembling ALS develops in monkeys exposed to a Ca2-
nation spatial memory T-maze task. Such tests are often
and Mg2-deficient diet containing excess aluminum.
taken as indicators of working memory performance.
The monkeys develop muscle atrophy, spinal neurons
These rats were chronically exposed, throughout middle
with eccentric nucleoli, and NFTs in swollen axons as in
age and old age, to Al3 in amounts equivalent to total
ALS. An Al3-induced myelopathy in rabbits also has
dietary Al3 levels that humans routinely ingest from
ALS features.
their food and drinking water. Seventy percent of animals
In Guam, approximately 30% of the indigenous
that consumed Al3 in an amount equivalent to the high
Chamorros with ALS/PD had subtle abnormalities in
end of the human dietary Al3 range (i.e., 1.68 mg kg1
Ca2 and vitamin D metabolism. Even at pH 7, Guam
bodyweight per day) attained significantly lower mean
water elutes unusually high Al3 levels from soil, par-
scores on this task in old age than in middle age
ticularly in the southwestern high-incidence region
and exhibited behaviors analogous to those seen in
of the island. In affected humans, excess Al3 could
humans with dementia. The accompanying QuickTime
reach the central nervous system via the respiratory tract,
movies compare the T-maze performances of a rat from
nasal-olfactory pathway, or gastrointestinal tract either by
this longitudinal study in middle age and old age, when
the eating of plants that concentrate aluminum or by
showing signs of cognitive deterioration.
drinking and washing food in Al3-contaminated river
This cognitive change that develops in animals with
water during the rainy season.
long-term Al3 exposure at human-relevant levels is age-
Cases from the Kii peninsula have exhibited re-
associated, slowly developing, and progressive. As men-
markably high neocortical and spinal cord bulk Al3
tioned, for species reasons, the rat brains lack amyloid
concentrations, up to 23 times higher than control tissue.
plaques and NFTs. However, they develop the same
Affected residents of southern Irian Jaya appear to have a
early changes (namely oxidative damage, up-regulated
physiological disorder for aluminum processing as they
expression of the APP gene, low PP2A activity, and
absorb much more aluminum than controls. Their aver-
hyperphosphorylated tau) that precede and give rise to
age serum Al3 concentration was 29 mg l1 compared
amyloid plaques and NFTs in human brains. They also
with 7 mg l1 for age- and sex-matched healthy relatives
show GVD and other hallmarks of AD neuropathology
and 6 mg l1 for healthy Caucasian controls.
such as microtubule disappearance and synapse loss.
It is also possible that b-methylamino-L-alanine
The lowest observed adverse effect level for Al3 in
(BMAA), a neurotoxin from the palm Cycas circinalis, may
this animal model is 0.49 mg kg1 bodyweight per day,
contribute to the condition in Guam because BMAA has
consumed over a time equivalent to 40 human years.
been found in brain tissue of some ALS patients. As a
Approximately 50% of Americans are estimated to
result of economic development and westernization, the
consume aluminum above this level. No effect was seen
native populations have experienced changes in their
at 0.36 mg kg1 bodyweight per day (equivalent to the
local water supplies, dietary habits, and dependence
low end of the human dietary aluminum range).
on locally grown food. Concurrently, the prevalence of
ALS/PD in these regions has greatly diminished.
Amyotrophic Lateral Sclerosis and
Parkinsonism-Dementia of Guam
Parkinson Disease
For approximately 30 years (mid-1950s to 1985), a ring
of islands in the western Pacific Ocean namely Guam Parkinson disease is a neurodegenerative disorder that
in the Mariana Islands, southern Irian Jaya of Indonesia, particularly affects the sufferers speech and motor skills,
and the Kii peninsula of Japan was known to have characterized by tremor of the face, hands, and jaw,
high-incidence foci of either ALS/PD or ALS only muscle rigidity, and slow physical movement. This results
among the native populations. A register indicated that from decreased stimulation by the basal ganglia on the
incidence rates for this region were 501000 times higher motor cortex due to death of neurons in the substantia
342 Bioavailable Aluminum: Its Effects on Human Health
nigra and globus pallidus that normally synthesize
and secrete epinephrine and, in particular, dopamine.
Parkinson disease apparently results from multiple cau-
ses, including head injury, encephalitic virus, exposure to
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, a
heroin-like opiate contaminant), and certain pesticides.
Al3 toxicity may be involved in Parkinson disease
because some Parkinson patients develop AD-type de-
mentia. Also, the catechol moiety of the catecholamine
neurotransmitters epinephrine and dopamine is a po-
tentially important Al3-binding site. Although epi-
nephrine and dopamine are poor Mg2 binders at
millimolar levels, they bind Al3 at nanomolar levels. In
Parkinson brains, the substantia nigra and locus ceruleus
exhibit high Al3 and Fe3 concentrations in neurome-
lanin granules and in Lewy bodies, abnormal hallmarks
of dead and dying neurons. Evidence for Al3-dis-
regulated iron metabolism is that neurons in relevant
regions of Parkinson brains have excessively high iron
levels, yet fail to increase their ferritin levels. The re-
sulting oxidative damage could contribute to neuronal
death in the substantia nigra and other brain regions
affected in Parkinson disease.
Conclusions
In its metallic form, aluminum has conferred many
benefits to modern society, even making mass air travel
possible. However, bioavailable Al3 in the body is re-
active, toxic, and causal to, or at least involved in, a
number of disease conditions. Health problems associated
with occupational Al3 exposure and medical treatments
containing Al3 products are well documented. There
are suitable non-Al3 alternatives for many of these
products. Current research indicates chronic Al3 ex-
posure, primarily from aluminum additives in the diet,
water, and other ingested or injected products, adds to the
bodys Al3 burden, and contributes over time to neuro-
degenerative conditions.
See also: Bioavailable Aluminum: Its Metabolism and
Effects on the Environment.
Further Reading
Alfrey AC, LeGendre GR, and Kaehny WD (1976) The dialysis
encephalopathy syndrome; possible aluminum intoxication. The
New England Journal of Medicine 294: 184--188.
Alzheimer A (1907) Ueber eine eigenartige Erkrankung der Hirnrinde.
Zentralblatt fur Nervenheilkunde und Psychiatrie 30: 177--179;
Allgemeine Zeitschrift fur Psychologie 64: 146147.
Alzheimer A (1911) Uber eigenartige Krankheitsfalle des spateren
Alters. Zeitschrift fur die gesamte Neurologie und Psychiatrie 4:
356--385.
Baker MN (1981) The Quest for Pure Water: The History of Water
Purification from the Earliest Records to the Twentieth Century, 2nd
edn., vol. 1. Denver: American Water Works Association.
Exley C, Price NC, Kelly SM, and Birchall JD (1993) An interaction
of beta-amyloid with aluminium in vitro. FEBS Letters 324:
293--295.
Flaten TP (2001) Aluminium as a risk factor in Alzheimers disease,
with emphasis on drinking water. Brain Research Bulletin 55:
187--196.
Greger JL (1993) Aluminum metabolism. Annual Review of Nutrition 13:
42--63.
Humphrey GM (1889) Old Age: The Results of Information received
Respecting Nearly Nine Hundred Persons who had Attained the Age
of Eighty Years, including Seventy-Four Centenarians. Cambridge:
Macmillan and Bowes.
McLachlan DRC (1995) Aluminium and the risk for Alzheimers disease.
Environmetrics 6: 233--275.
Miu AC and Benga O (2006) Aluminum and Alzheimers disease: A new
look. Journal of Alzheimers Disease 10: 179201.
Rifat SL, Eastwood MR, McLachlan DR, and Corey PN (1990) Effect
of exposure of miners to aluminium powder. Lancet 336:
1162--1165.
Savory J, Exley C, Forbes WF, et al. (1996) Can the controversy of the
role of aluminum in Alzheimers disease be resolved? What are the
suggested approaches to this controversy and methodological
issues to be considered? Journal of Toxicology and Environmental
Health 48: 615--635.
Walton JR (2007) An aluminum-based rat model for Alzheimers
disease exhibits oxidative damage, inhibition of PP2A activity,
hyperphosphorylated tau, and granulovacuolar degeneration.
Journal of Inorganic Biochemistry 101: 1275--1284.
Walton JR (2009) Brain lesions comprised of aluminum-rich cells that
lack microtubules may be associated with the cognitive deflicit of
Alzhemer disease. Neurotoxicology, doi: 10.1016/j.neuro.
2009.06.010.
Walton JR (2009) Functional impairment in aged rats chronically
exposed to human range dietary aluminium equivalents.
Neurotoxicology 30: 182--193.
Relevant Websites
http://books.google.com/books?id iNzG8PoyW4AC&pg RA1-
PA113&lpg RA1-PA113&dq %22tea leaves%22 and
aluminum or aluminium&source web&ots 7WxXttkJh0&sig-
C4kQk8P685KwbuBxHLmkUlwF1ns#PRA1-PA113,M1
Encyclopedia of Food and Color Additives, George A. Burdock.
http://www.usrds.org
United States Renal Data System.