Method:
Unmatched case - control study conducted at Alexandria
University Hospital, comparing patients with a clinical diagnosis of
Alzheimer's disease (NINCDS-ADRDA diagnostic criteria) and two control
groups, in respect of their serum aluminium levels using Atomic Absorption
Spectrophotometry.
Results:
There was a statistically significant difference between
serum aluminium levels in Alzheimer's disease and other dementias and non
dementing controls (P<.05). No difference was found between serum
aluminium levels in other dementias and non dementing controls. Serum
aluminium levels and the age distribution among patients with Alzheimer's
disease showed a statistically significant positive correlation.
Conclusion:
The study finding of a significant increase in the serum
aluminium level in patients with Alzheimer's disease supports the
hypothesis that aluminium may be implicated in Alzheimer's disease in some
form. Whether aluminium is an etiological factor in Alzheimer's disease
or its presence is simply the result of age and changes in renal functions
among Alzheimer's disease patients needs further assessment.
KEY POINTS
Although available evidence for the role of aluminium in the pathogenesis
of Alzheimer's disease over the last 36 years has remained largely
circumstantial and unconfirmed, the aluminium hypothesis has not been
rejected.
The statistically significant increase in the serum
aluminium level among cases of Alzheimer's disease compared to other
dementias and non dementing controls raises the question again about the
role of aluminium as an etiological factor in the pathogenesis of
Alzheimer's disease.
The small sample size, imposed mainly by the limited
availability and cost of the Atomic Absorption Spectrophotometry, also the
poor matching of the study groups are likely to reduce the study power and
its inferential value.
Prospective studies are necessary to examine the incidence
of Alzheimer's disease in high risk population exposed to neurotoxins such
as aluminium. A non-invasive, cost effective method to screen patients
with Alzheimer's disease for clinical aluminium exposure and the risk of
possible aluminium related cognitive changes may be the way forward.
Key words:
Alzheimer's disease
Aluminium hypothesis
Alzheimer's disease and aluminium
aluminium in dementia
Introduction:
Since early reports of the experimentally
induced neurofibrillary degeneration1, a link between
Alzheimer's disease and aluminium has been suspected. Although
experimentally induced neurofibrillary degeneration provides some evidence
for such link as, electron microscopy studies have shown that aluminium-induced
tangles consist of bundles of normal neurofilaments which is in contrast
with neurofibrillary tangles in Alzheimer's disease containing paired
helical fibrils of abnormal tau protein2. Epidemiological
studies of exposure to aluminium in drinking water3,4,5 have
claimed a positive association between aluminium concentration in water
and incidence of Alzheimer's disease. Evidence that aluminium dust can be
transported to the brain directly via nasal olfactory pathway6
suggests that the nasal olfactory route is another source of aluminium
intake in occupational exposure. Chronic exposure to aluminium and its
possible neurotoxicity has been reported7 who showed that
exposed miners were almost two times more cognitively impaired than the
unexposed miners. Salib & Hillier8 found no evidence to
support any association between aluminium occupation and the risk of
Alzheimer's disease later in life. Broe et al9 Faltten et al10
found no increase in the incidence of Alzheimer's disease in high risk
population such as patients consuming large amounts of aluminium
containing antacids. However, serum aluminium was not checked in any of
the above studies.
Although available evidence for the role
of aluminium in the pathogenesis of Alzheimer's disease over the last 36
years has remained largely circumstantial and unconfirmed, the aluminium
hypothesis has not been rejected11,12,13.
It is generally accepted that factors that
govern the bioavailability, neurotoxicity and the effect of chronic low
dose exposure to aluminium compounds, remain unclear11
In this study, serum aluminium levels in
patients with clinically diagnosed Alzheimer's disease, other dementias
and a non dementing controls of similar age and sex, was examined to see
whether there is any significant difference between the three groups and
between dementia syndrome as a whole and normal aging.
Method:
An unmatched case - control study
conducted at Alexandria University Hospital, comparing Egyptian patients
with a clinical diagnosis of Alzheimer's disease and two control groups,
in respect of their serum aluminium using Atomic Absorption
Spectrophotometry.
Diagnostic criteria used in the study are
those of:
NINCDS - ADRDA 'Alzheimer's disease and Related disorders
Association - National institute of Neurological and Communicative
Disorders and Stroke'14. The information needed to apply these criteria is
obtained by standard methods of examination, medical history, Neurological
and Psychiatric examination, Neuro- psychological and laboratory studies.
Patients were assessed and assigned to one of three categories;
1) Alzheimer's disease (Group I):
Probable or possible Alzheimer's disease (using NINCDS-ADRDA criteria)
2) Other dementias (Group II):
Dementias other than Alzheimer's disease (with mini mental state
examination15 < 17 and either a Hachiniski ischaemic score16
>7 or an identified other causes other than vascular. Patients who were
receiving or known to have received dialysis were not included.
3) Non dementing controls (Group III) :
No dementia (MMSE > 23).
All patients were selected from the
Outpatient Clinics and Inpatient Units of Alexandria University Hospitals.
The non dementing controls with similar age and sex, were selected from
the same area of residence in Alexandria and its outskirts.
The renal functions of all subjects was
satisfactory. None of the patients were on dialysis nor were they on
antacid medication.
Analytical procedure
Serum aluminium level was estimated by
Atomic Absorption Spectrophotometry performed at the University Hospital
Department of Biochemistry.
In the flameless type of Atomic Absorption
Spectrophotometry, the sample is dispensed into a small graphic tube which
can be heated electrically. By increasing the temperature stepwise, the
process of drying, thermal pre-treatment of the matrix and dissociation
into free atoms (atomisation) can be separated. During the drying and
thermal pre-treatment stages, an inert pruge gas stream is passed through
the tube to remove solvent and matrix vapours. Blood samples were
collected in the mornings as advised by the Biochemistry Department of
the Alexandra University Hospital, serum was separated and kept in the
freezer till all samples were collected and ready for analysis.
Operating Parameters
Wave length:
309 nm
Slit setting:
0.7 nm
Lights source:
Hollow cathode lamp
Tube/site:
Pyro/platform
Pre-treatment temperatures: 1700 c
Atomisation temperature: 2500 c
Techniques: Flameless
Analysis: Analyze the sample
versus the standard and reagent blank.
Calculations: Serum aluminium ug/L: ug/mlx1000
Normal range: <40 ug/L
Results:
The study sample included 44 patients
categorised in the following groups:
Group I
Alzheimer's disease
15 patients
Group II
Multi-infarct dementia
6 patients
Parkinson's dementia
4 patients
Miscellaneous (Pick's
4 patients
dementia, symptomatic dementia
and huntington's dementia)
Group III
Non dementing controls from the
15 subjects
same area of residence in Alexandria.
Group I (Alzheimer's disease) had a mean
level of 33.67 + 11.9 ug/L, ranging from 20 to 58 ug/L.
In Group II (other dementias) mean
aluminium level was 25.27 + 4.8 ug/L, ranging from 20 to 35 ug/L.
Group III (non dementing controls) had a mean level of 25.78 + 10 ug/L,
ranging from 16 to 30 ug/L. Table 1 summarises means of age and serum
aluminium in the three groups.
Graph 1 illustrates mean serum levels in
the study groups by Gender with significant difference between group means (ANOVA
F 6.5 P<0.001 & Kruskal Wallis P<.05). Using U-Mann Whitney and also t-test
for 2 independent samples, there was statistically significant difference
between serum aluminium levels Group I (Alzheimer's disease) and Group II (other
dementias) and non dementing controls (P<.05). No difference was found
when comparing Group II (other dementias) and Group III (Control group)
P=0.8. Graph 2 shows a positive correlation between serum aluminium and
age in the entire sample (r= 0.309 P=.07). Serum aluminium levels and the
age distribution among patients with Alzheimer's disease showed that there
was a statistically significant increase in the serum aluminium level with
the progress of age for Alzheimer's disease group (Correlation co efficient
r=0.5223 (P<.05) as in Graph 3, but not for other dementia or non dementing
control group (r=0.03 P=0.8 and r=0.354 P=0.06 respectively).
The Difference between the distribution of
serum aluminium Levels in patients with dementia as a whole (Group I & Group
II combined) and those of the non dementing control group was found to be
statistically significant (P<0.05) with higher mean in the dementia syndrome.
The difference was found in male and female patients.
Tables 2 & 3 show the significant
difference between aetiological categories in respect of age and serum
aluminium levels.
Discussion:
1. Methodological limitations
1. The small sample size, imposed mainly
by the limited availability and cost of the Atomic Absorption
Spectrophotometry, also the poor matching of the study groups are likely to
reduce the study power and its inferential value.
2. A proportion of the Alzheimer's
disease cases as well as controls are expected to have been incorrectly
classified. It is possible that some Alzheimer's disease cases and other
dementias may have had a combined aetiology.
3. The patients with Alzheimer's disease
that were admitted to the study may have differed considerably from all
incident or prevalent patients with Alzheimer's disease in respect of some
attributes.
4. Although the study groups came from a
social environment with similar exposure opportunity, they may have been
selected probably due to an advanced condition than those who were not
referred to due to other medical or social problems.
5. It is possible that the increase in
serum aluminium might have occurred at sometime before or even after the
onset of cognitive decline. There is also the possibility that serum
aluminium may not accurately reflect brain aluminium.
6. There was clear difference in age
between the groups and also high standard deviation of age means within
groups. Therefore, it is possible that the differences in serum aluminium
levels between the study groups may have been attributed, at least partly,
to the age difference rather than pathophysiology.
2. Interpretation of findings;
The statistically significant increase in
the serum aluminium level among cases of Alzheimer's disease compared to
other dementias and non dementing controls raises the question again about
the role of aluminium as an etiological factor in the pathogenesis of
Alzheimer's disease. The findings are in keeping with 3 other studies;
Kellet et al17 and Naylor et al18 reported significant
increase in aluminium levels in the serum and whole blood of Alzheimer's
disease patients. Zapatero et al19 reported significant
difference in serum aluminium in patients with Alzheimer's disease and age
matched control group. The difference was not statistically significant
when cases with Alzheimer's disease were compared with dementias due to
other causes which was not confirmed in our study. Zapatero et al19
also observed that serum aluminium increased with age which they attributed
to enhanced gastric permeability or increased metal accumulation with age.
Shore et al20 and Pailler et al21,
did not find elevated aluminium plasma levels in patient with Alzheimer's
disease. serum, CSF or hair in patients with Alzheimer's disease. Also
Mackenzie et al22 did not find any changes in serum aluminium in
patients with epilepsy whose temporal lobectomies showed senile plaques
lesions related to early stage of Alzheimer's disease. The study finding of
the significant increase in the serum aluminium level in Alzheimer's disease
supports the hypothesis that aluminium may be implicated in Alzheimer's
disease in some form, and thus adds to the puzzle of "aluminium-Alzheimer
link", The increase in serum aluminium with age for whatever reason may
suggest that aluminium compounds should be limited in older people because
of the physiological accumulation of the metal during their life time19.
Whether aluminium is an etiological factor in Alzheimer's disease or its
presence is simply the result of abnormal brain cellular metabolism among
Alzheimer's disease patients needs further assessment23.
Although chronic exposure to aluminium is hypothesised to be a risk factor
for the development of Alzheimer;s disease, it is unfortunate that the
official values for aluminium in drinking water of the Egyptian regions
where the sample members originated, were not available to add to the
interpretation of findings.
However, findings of studies of exposure
to aluminium in drinking water3,4,5 which claimed positive
association between aluminium concentration in water and incidence of
Alzheimer's disease have not been conclusive.
Alzheimer's disease has no confirmed
aetiology but there is strong evidence for the involvement of both genetic
and environmental risk factors in its development. The interaction of
hereditary and environmental factors such as aluminium in the aetiology of
Alzheimer's disease is an area that future studies should pay special
attention. Prospective studies are necessary to examine the incidence of
Alzheimer's disease in high risk population exposed to neurotoxins such as
aluminium. A non-invasive, cost effective method to screen patients with
Alzheimer's disease for clinical aluminium exposure and the risk of possible
aluminium related cognitive changes may be the way forward.
"The possibility of a causal link between
aluminium and Alzheimer's disease must be kept open until uncertainty about
neuropathological evidence is resolved "
Sir
Richard Doll12 (1993)
*Correspondence:
18 Broughton Close, Appleton,
Warrington WA6 3DR
Tel: 01925 664123, Fax: 01925 664145
References:
1. Wisniewski,H.
Klatzo I.
(1965) Experimental production of neurofibrillary
degeneration..Neuropathology and experimental neurology.1965; 27:
187- 199.
2. Munoz-Garcia
(1986
An immunocytochemical comparison of cytoskeletal proteins in
aluminium-induced and Alzheimer-type neurofibrillary tangles.
Acta Neuropathology Vol
70,pp 243-248
3. Martyn,C.N.;Barker,D.
et al.(1989) Geographical relation between Alzheimer's disease and Aluminium
in drinking water. The Lancet. No.8629,Jan 1989.p.59-62.
4. Michel, P.
et al. (1990) Study of the relationship between aluminium concentration in
drinking water and risk of Alzheimer's disease: IN Basic mechanism,
Diagnosis and therapeutic strategies. Iqbal K. John Wiley,
Chichester91.
5. Neri, LC.
(1991) Aluminium, Alzheimer's disease and drinking water.
The Lancet
vol 338:August 10,1991.
6. Perl,D.P., Good,
P.
(1987) Uptake of aluminium into CNS along nasal Olfactory pathways.The
Lance May 2, 1987.
7. Rifat,S.
Eastwood
et al. (1990) Effect of exposure of miners to aluminium
powder. The Lancet No. 8724 Nov1990 p. 59-62.
8. Salib E, Hillier
(1996)
A case-control study of Alzheimer's disease and aluminium
occupation British Journal of Psychiatry 168(2) 244-9
9. Broe GA,
Henderson AS, Creasey H et al (1990) A case-control study of Alzheimer's disease in Australia
Neurology Nov 1990; 40(11): 1698-707
10. Fallten TP.,
Glattre E., Viste A et al (1991)
Mortality from dementia among gastroduodenal ulcer
patients. J Epidemiol nad Community health 45(3):203-206
11. Doll R. (1993)
Review: Alzheimer's disease and environmental aluminium. Age & ageing
1993; 22: 138-53.
12. Rifat,S.
Aluminium hypothesis lives. The Lancet Vol 343 Jan 94
13. Salib E (1989)
Alzheimer's disease and the aluminium connection: A literature review
Int J of Psychiatry in Clinical Practice Vol 2 pp 181-188
14. Mckhann,G.;Drachman,D
et al. (1984) Clinical diagnosis of Alzheimer's disease. Report of the
NINCDS-ADADA, Task force on Alzheimer's disease. Neurology. 1984; 34:
939-944.
15. Folstein MF
et al (1975) The mini mental state examination . A practical method for
grading the cognitive state of patients for clinician
J.Psych Res
1975,12:189-98.
16. Hachiniski VC
et al(1975) . Cerebral blood flow in dementia.
Arch. Neurology.
32:632:637.
17. Kellet JM,
Taylor A and Oram JJ (1989)
Serum aluminium in Alzheimer's disease Lancet 1,682 (1986)
18. Naylor GJ,
Smith AH, McHarg A (1989)
Serum aluminium in Alzheimer's disease
Trace Elements Med
6, 93-95
19. Zapatero MD,
Garcia DJ, Pascual F et al (1995) Serum aluminium levels in Alzheimer's disease and other
senile dementia Biological Trace elements Research Vol 47 235-240
20. Shore D., Wyatt
RJ (1983)
Aluminium and Alzheimer's disease.
J of nervous and mental disease
171(9): 553-8
21.Pailler FM.,
Bequet D., Corbe H et al (1995) Aluminium. hypothetic cause of Alzheimer's disease.
Presse. Med
1995 Mar 11;24(10): 489-90.
22. Mackenzie IR.,
Mclachlan RS., Kubu CS et al (1996) Prospective neuropsychological assessment of nondemented
patients with biopsy proven senile plaques. Neurology 1996; 46(2):
425-9
23. Mclachlan DR.,
Bergeron C., Smith JE et al (1996) Risk of neuropathologically confirmed Alzheimer's disease
and residual aluminium in municipal drinking water employing weighted
residential histories. Neurology 1996; 46(2):401-5
Table 1 Mean age and serum aluminium in the study groups
|
|
Mean age |
Mean Aluminium (ug/L) |
|
Group I
Alzheimer's disease |
66.20 (sd 9.1)
range 55-88
|
33.67 sd 11.9
(20-58 ug/L) |
|
Group II
Other dementias |
63.60 (sd 11.2)
range 40-86 |
25.27 sd 4.8
(16-30 ug/L)
|
|
Group III
Non dementing
|
59.93 (sd 7.4)
range 45-70 |
25.78 sd 10
(20-35 ug/L)
|
Table 2
The significant differences in age between different groups
with significance level: 0.05
|
|
MID |
PD |
MIS |
Control |
|
AD
Mean 66.2 years
Range 50=88 years
SD 9 years |
<0.05 |
>0.05 |
<0.05 |
<0.05 |
|
MID
Mean 75.3 years
Range 60-86 years
SD 8.6 years |
|
<0.05 |
<0.05 |
<0.05 |
|
PD
Mean 62.3 years
Range 55-67 years
SD 5.3 years |
|
|
>0.05 |
>0.05 |
|
MIS
53 years
Range 40-67 years
SD 11.7 years |
|
|
|
>0.05 |
AD: Alzheimer's disease
MID: Multi infarct dementia
PD: Dementia in Parkinsons disease
MIS: Miscellaneous
* controls Mean 59.9 years
Range 45-70
SD 7.4 years
Table 3
The significant differences in serum aluminium between
different groups with significance level: 0.05
|
|
MID |
PD |
MIS |
* Control |
|
AD
Mean 33.6 ug/L
Range 20-58 ug/L
SD 11.86 ug/L |
<0.05 |
>0.05 |
>0.05 |
<0.05 |
|
MID
Mean 24.8 ug/L
Range 20-32 ug/L
SD 4.4 ug/L |
|
>0.05 |
>0.05 |
>0.05 |
|
PD
Mean 26 ug/L
Range 21-30g/L
SD 3.9 ug/L |
|
|
>0.05 |
>0.05 |
|
MIS
Mean 32.8 ug/L
Range 20-51 ug/L
SD 12 ug/L |
|
|
|
>0.05 |
AD: Alzheimer's disease
MID: Multi infarct dementia
PD: Dementia in Parkinsons disease
MIS: Miscellaneous
* Controls Mean 25.5 ug/L
Range 16-30 yg/L
SD 4.8 ug/L
