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Aluminum Concentrations in Drinking Water and

Risk of Alzheimer's Disease

Christopher N. Martyn,1 David N. Coggon,1 Hazel Inskip,1 Robert F. Lacey,2 and

Wendy F. Young2

To investigate the relation of aluminum and silicon in drink? of the nervous system. All subjects in the study were between
ing water to risk of Alzheimer's disease, we carried out a 42 and 75 years of age. There was little association between
case-control study in eight regions of England and Wales. Alzheimer's disease and higher aluminum or lower silicon
Subjects were identified from the records of neuroradiology concentrations in drinking water when cases were compared
centers, and diagnoses were confirmed by a review of hospital with any of the control groups. The results indicate that any
case-notes. Exposure to aluminum and silicon in drinking risk of Alzheimer's disease from aluminum in drinking water at
water was estimated from residential histories of 106 men with concentrations below 0.2 mg per liter is small, and they give no
Alzheimer's disease, 99 men with other dementing illnesses, support for a protective role of silicon. (Epidemiology 1997;8:
226 men with brain cancer, and 441 men with other diseases 281-286)

Keywords: aluminum, silicon, Alzheimer's disease, dementia, case-control study.

Although there is little doubt that, in some circum? risk5,11-13but have used recent measurements of alumi?
stances, aluminum is neurotoxic,1 its role in the etiology num concentrations in drinking water to estimate expo?
of Alzheimer's disease remains controversial. Aluminum sure. Water treatment processes and the distribution of
has been detected in both senile plaques and neurofi- output from treatment plants may have changed over
brillary tangle-bearing neurons in the brains of people time, and, if so, current concentrations of aluminum will
with Alzheimer's disease,2,3 and several epidemiologic be a poor reflection of the aluminum content of water in
studies have shown an association between concentra? the past.
tions of aluminum in drinking water and risk of Alzhei? A further difficulty is the fact that only a small frac?
mer's disease.4"12 But there are difficulties in inferring tion of the total dietary intake of aluminum is derived
causation from this evidence. The accumulation of alu? from drinking water.14 This fact implies that the relation
minum in plaques and tangle-bearing neurons may not of Alzheimer's disease to aluminum in drinking water
be a primary event in the pathogenesis of the disease, may be indirect. It could, for example, reflect an inverse
and none of the epidemiologic studies can be interpreted relation between aluminum and silicon in water sup?
without reservation. plies. Birchall15 has proposed, on theoretical grounds,
Most of the early epidemiologic studies were ecologic that dietary silicon, especially where^ it occurs in drink?
in design, and, although they indicate that rates of ing water at concentrations greaterman 100 jLtmol per
Alzheimer's disease vary among populations according liter of silicic acid, may prevent ^he absorption of alu?
to the concentrations of aluminum in their water supply, minum from the gastrointestinal tract and facilitate its
they do not address the risk of disease in individuals.4,6"10 excretion by the kidney. This idea is supported by ex?
Three case-control studies have investigated individual periments with tracer doses of an aluminum isotope in
which simultaneous ingestion of silicic acid reduced
uptake from the gut.16
Fromthe MedicalResearchCouncilEnvironmental
EpidemiologyUnit (Uni?
GeneralHospital,Southampton,and To explore further the relation of Alzheimer's disease
versityof Southampton),
Southampton
2WaterResearchCentre,Medmenham,Marlow,Bucks,UnitedKingdom. to aluminum and silicon in drinking water, we have
carried out a case-control study in which we assessed
N. Martyn,MRCEnvironmental
Addressreprintrequeststo: Christopher Epi?
exposures from historical measurements of aluminum
demiologyUnit, SouthamptonGeneralHospital,SouthamptonS016 6YD,
UnitedKingdom. and silica in water supplies.

This studywasmainlyfundedby the MedicalResearchCouncil.The involve-


ment of the WaterResearchCentrewas madepossibleby fundingfromthe
FoundationforWaterResearch. Methods
We compared cases of Alzheimer's disease with three
12, 1996;finalversionacceptedNovember22, 1996.
SubmittedFebruary
sets of controls: patients with other types of dementia,
Inc.
Resources
? 1997by Epidemiology patients with brain cancer, and patients with various

281

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282 MARTYN ET AL Epidemiology May 1997, Volume 8 Number 3

TABLE 1. Distribution of Subjects by Neuroradiology Center and Diagnosis reported addresses, with dates
of residence but without infor?
mation about diagnosis, was
sent to the investigators at the
Water Research Centre, Med-
menham, who compiled data
on concentrations of aluminum
and molybdate-reactive silica
in drinking water by making
inquiries to water suppliers and
by referring to existing databas?
es.717 This effort entailed deter-
mining the water supply zone
in which each address was lo?
cated, identifying the source
and treatment works that had
other neurologic disorders. Subjects were identified from supplied that zone, and then investigating the history of
the computerized tomographic (CT) records of eight plant operation, the mixing of supplies, and the avail?
neuroradiology centers. In each center, we searched files ability of analytical data. These data were usually de?
retrospectively over a defined period (Table 1) to ascer- rived from samples of water leaving the water treatment
tain all men born during the period 1916-1945 with a works, but in some areas, we referred also to assays of
possible diagnosis of dementia or primary brain cancer. samples from the distribution system. Where possible,
For each possible case of dementia, we also selected the we gathered quantitative data for aluminum back to
next man in the file who was born during the same 1974. For periods before this, or when quantitative data
5-year period and had a diagnosis other than dementia, were lacking, we used historical information about treat?
malignant brain tumor, epilepsy, or chronic disabling ment processes and distribution of water supply to decide
disease. whether extrapolation from the available data could be
We next reviewed the hospital notes of these poten? justified. We aimed to estimate the average aluminum
tial cases and controls. Hospital notes could not be concentration for each address and period of residence.
located for 561 (20%), and we excluded these men from Unlike aluminum, silicon is not of operational signif?
further study, as well as all private patients and patients icance in the water supply, and its concentration is
who lived outside the normal catchment area of the monitored less frequently. Although silicon is present in
neuroradiology center. We also excluded those men drinking water in the form of silicic acid, concentrations
whose provisional diagnosis of dementia or brain cancer were usually measured as mg per liter of molybdate-
from the radiology files was not confirmed, and those reactive silica. Where possible, we obtained a single
whose diagnosis had first been made before the period of estimate of the average concentration for each address at
case ascertainment (that is, non-incident cases). For the which subjects had lived since age 25 years. These esti?
subjects who remained, we abstracted further informa? mates were based predominantly on recent measure?
tion, including the diagnosis, address, name and address ments.
of the next of kin, and name and address of the general Subjects were classified according to the concentra?
practitioner. The patients with dementia were classified tion of aluminum in their water supply after age 25 years,
as cases if their hospital notes indicated that a firm averaged over the years for which data were available,
clinical diagnosis of Alzheimer's disease had been made. and according to whether estimated silica concentra?
Cases of dementia were also considered to have Alzhei? tions at addresses occupied after age 25 years were con-
mer's disease if the CT scan was normal or showed only sistently above or below 6 mg per liter (equivalent to 100
cerebral atrophy without evidence of infarction, pro? jLtmol per liter of silicic acid) or fell on both sides of this
vided that the case notes recorded a progressive deteri- threshold. We examined associations of Alzheimer's dis?
oration in at least two areas of cognition and no other ease with aluminum and silicon in water by logistic
cause for dementia was found. We excluded subjects regression with adjustment for age at the time ofthe CT
whose hospital notes indicated that they suffered only scan (treated as a continuous variable), neuroradiology
from impairment of memory. center, and distance of residence at the time of diagnosis
With permission from the general practitioner, we from the neuroradiology center (<10 km or ^10 km).
sent a short postal questionnaire either to the patient
himself or, if he had died or was severely incapacitated,
to his next of kin. Patients who completed their own Results
questionnaires were encouraged to seek help from a From the hospital records, we identified 155 patients
member of their family, if needed. Among other things, with Alzheimer's disease who met the criteria for inclu?
the questionnaire asked for the addresses of all houses at sion in the study, together with 179 controls with other
which the patient had lived for at least 3 years since age dementias, 442 controls with brain cancer, and 720
25, with the dates of residence. A list of the 2,347 other controls. Questionnaires were returned for 872
Epidemiology May 1997, Volume 8 Number 3 ALUMINUM AND ALZHEIMER'S DISEASE 283

TABLE 2. Characteristics of Subjects by Diagnosis naires were completed, the


most frequent diagnoses were
cerebrovascular disease (195
men), benign tumors (36
men), and migraine or head?
ache (30 men).
Table 2 gives further infor?
mation about the 872 respond?
ers who were inciuded in the
analysis. On average, the pa?
tients with Alzheimer's disease
were a little older than the
three control groups. Most of
the controls with brain cancer
had died, and information was
therefore provided by their
next of kin. Likewise, most of
the questionnaires for patients
with dementia were completed
by or with help from a relative.
A higher proportion of brain
cancer controls lived more
* Distanceof currentresidence than 10 km from their neuro?
fromneuroradioiogy
centercouldnotbe classified
fortwomenbecausetheiraddresses
wereincomplete. radioiogy center. Data on alu?
minum and silicon in water
supplies were available for at
men, giving an overall response rate of 58%. Table 1 least one period of residence for more than 80% of
shows the distribution of responders by diagnosis and subjects; and for about half of the men, the information
neuroradioiogy center. The response rate was highest for covered more than 90% of their lifetime since age 25
patients with Alzheimer's disease (68%) and lowest for years.
controls with brain cancer (51%). The main reasons for Among those subjects for whom information could be
the incomplete response were failure to obtain permis- obtained, aluminum levels in water supplies, averaged
sion from the general practitioner for an approach to the over the years for which data were available, ranged from
patient or his next of kin (303 subjects), difficulty in 0.004 to 0.481 mg per liter, with a median of 0.043 mg
tracing the patient or next of kin (112 subjects), and per liter. Table 3 shows the risk of Alzheimer's disease
refusal by the patient or next of kin (209 subjects). associated with four levels of aluminum. There was no
Among the 441 "other controls" for whom question? tendency for risk to increase with aluminum concentra-

TABLE 3. Association of Alzheimer's Disease with Aluminum in Water Supply

* Oddsratiosadjustedforage,neuroradioiogy center(<10 kmor ^10 km);95%CI = 95%confidenceinterval.


center,anddistanceof residencefromneuroradioiogy
t Referentcategory.
284 MARTYN ET AL Epidemiology May 1997, Volume 8 Number 3

TABLE 4. Association of Alzheimer's Disease with Silicon in Water Supply*

* The analysiswasrestrictedto menwithwaterconcentrations


of molybdate-reactive
silicaconsistentlyabove6 mgperliter(thatis, exposed)or consistentlybelow
6 mgperliter(thatis, unexposed).
t Oddsratiosadjustedforage,neuroradioiogy
center,anddistanceof residencefromneuroradioiogycenter(<10 kmor ^10 km);95%CI = 95%confidenceinterval.

tion, either when levels were averaged over all years for ing in places where the concentration of silica in water
which data were available, or when analysis was re? was above 6 mg per liter as compared with men consis?
stricted to levels encountered at least 10 years before tently exposed to concentrations below this threshold.
diagnosis, or less than 10 years before diagnosis. In There was no clear indication that higher concentra?
comparisons with the control group of "other diagnoses," tions of silica were associated with reduced risk, but
trends were, if anything, in the reverse direction. Nor confidence intervals were wide.
was any association observed in subgroup analyses lim? Table 5 summarizes the relation between Alzheimer's
ited to men living within 10 km of the neuroradioiogy disease and aluminum in men whose water supply con?
center and to those whose data on aluminum were more tained molybdate-reactive silica at concentrations con?
than 90% complete (detailed results are available from sistently lower than 6 mg per liter. If anything, the
the authors on request). association was inverse.
Average levels of silicon in water, expressed as units of
molybdate-reactive silica, ranged from 1.2 to 23.0 mg per
liter and were inversely related to average aluminum Discussion
concentrations (correlation coefficient after logarithmic This study provides no evidence that risk of Alzheimer's
transformations to normalize data = ?0.46). Table 4 disease is increased by aluminum in drinking water at
shows risk estimates for Alzheimer's disease in men liv- average concentrations up to about 0.2 mg per liter (the

TABLE 5. Association of Alzheimer's Disease with Aluminum in Water Supply When Silicon Content Was Low*

ComparisonGroup

* The analysiswasrestrictedto menwhosewatersupplycontainedmolybdate-reactivesilicaat concentrations


consistentlylessthan6 mgperliter.
t Oddsratiosadjustedforage,neuroradiology
center,anddistanceof residencefromneuroradiologycenter(<10 kmor ^10 km);95%CI = 95%confidenceinterval.
$ Referentcategory.
Epidemiology May 1997, Volume 8 Number 3 ALUMINUM AND ALZHEIMER'S DISEASE 285

mean level in the highest category analyzed). Nor does it as compared with less than 0.01 mg per liter.7 The
indicate that concentrations of silicon in drinking water prevalence of Alzheimer's disease was also positively
above 6 mg per liter of molybdate-reactive silica exert a related to water aluminum concentrations in a French
protective effect. study,6 although only where the pH of the water was less
There are obvious difficulties in a case-control study than 7.3.10 Against this, two studies (one in the north-
of dementia that relies on people's memory to establish west of England and one in Switzerland) found no rela?
exposures, and there was no ideal control group for such tion between the prevalence of cognitive impairment
a study. The probiems lie in the extent to which controls and aluminum in water supply.19,20
are representative of the population at risk of becoming The largest of the three case-control studies carried
cases, and in obtaining information of comparable qual? out so far gave an odds ratio of 1.5 for Alzheimer's
ity from cases and controls. We therefore opted for three disease or presenile dementia in those living in areas of
separate control groups. Patients with other types of Ontario where the water aluminum concentration was
dementia provided a similar quality of information to ^0.20 mg per liter as compared with areas where the
cases and are likely to have been referred for investiga? aluminum concentration was <0.01 mg per liter.5 A
tion in a comparable manner. Nevertheless, their expo? second case-control study, also carried out in Ontario,
sures to aluminum and silicon may not have been rep? reported an odds ratio of 1.86 for symptoms of impaired
resentative, since aluminum could in theory influence mental functioning where concentrations of aluminum
the course of other dementias as well as Alzheimer's in the drinking water supply at the subject's place of
disease. Because most of the controls with brain cancer residence were above the 50th centile.11,12 In contrast, a
were deceased and histories were obtained from their case-control study in northern England found no rela?
next of kin, they, too, provided data of comparable tion between Alzheimer's disease and aluminum in
quality to cases. Referral practices for brain cancer, how? drinking water,13 although it did suggest a protective
ever, differed from those for dementia, and their expo? effect of silicon.21
sures may have been unrepresentative even when dis? The inconsistency of our results with those of most
tance of residence from the neuroradioiogy center was earlier studies is unlikely to be explained by the biases
taken into account. The controls with other neurologic that we have discussed. It is possible that exposure to
diagnoses were perhaps more likely to have representa? aluminum only causes Alzheimer's disease after a latent
tive exposures, but most were still alive and able to period, but we found no evidence to support this. If
answer the questionnaire themselves rather than by anything, the relation was in the reverse direction, an
proxy. observation that we cannot explain. Nor was the disease
The consistent lack of support for the study hypoth- related to recent exposure to aluminum, as in some of
eses with all three control groups, each with their dif? the earlier investigations.
ferent potentials for bias, allows conclusions to be more We cannot rule out an important association of Alz?
confident. Still, other possible sources of bias must also heimer's disease with aluminum in drinking water at
be considered. Cases were identified on the basis of very high concentrations, but our findings indicate that
clinical diagnoses, which may not always have been any relation at levels below 0.2 mg per liter is weak. Nor
correct, and any resultant misclassification will have do we find any evidence to support a protective effect of
tended to obscure associations. Also, full residential his? silicon at concentrations of molybdate-reactive silica in
tories could not be obtained for all subjects, and infor? excess of 6 mg per liter.
mation about aluminum and silicon concentrations in
water was not available for all addresses and all time
periods. An earlier ecologic study that found a positive Acknowledgments
geographical correlation between Alzheimer's disease Obtainingdetailedinformationon aluminumand silicon concentrations in
and aluminum in water used similar diagnostic criteria drinkingwaterwouldnot have been possiblewithoutthe cooperationof the
watercompanies. Almostwithoutexception,theytookgreattroubleto provide
and cruder data on water quality.7 Moreover, analyses the informationwe required,
andwe areindebtedto them.We arealsograteful
restricted to men for whom data on aluminum and to the manyneuroradiologists,
neurologists,
neurosurgeons, andgeneralpracti-
silicon were more than 90% complete produced results tionerswho gaveus accessto theirrecordsand permissionto approachtheir
patients.We hopethattheywillunderstand thatconstraints of spacepreventus
similar to those for all subjects. acknowledging themindividuallyhere.We shouldalsoliketo thankthe staffof
Nine other studies have investigated aluminum in the medicalrecordsdepartments of the hospitalsin the studyandthe research
assistants
andcomputingstaffat the MedicalResearchCouncilEnvironmental
drinking water and risk of dementia or Alzheimer's dis? Epidemiology Unit fortheirhelp.
ease. In Norway, mortality from dementia correlated
geographically with the concentration of aluminum in
water supplies,8,9 and in Newfoundland, death from de-
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