Alzheimer'S Disease and Aluminium

 

The possible role of aluminium in thc aetiopathogenesis of Alzheimer's disease (AD) is one of the more controversial issues in clinical neuroscience. Recent advances in understanding the molecular pathology of this disorder and the finding that some familial forms of presenile AD are associated with a mutation in the b-amyloid precursor protein (APP) gene have not resolved the problem, since many elderly cases appear to be sporadic, and the finding of discordance in monozygotic twin pairs argues strongly for the importance of environmental factors. While over 20 risk factors for AD have been claimed the evidence for most of these is weak except in the case of age and familial history. Aluminium (Al ) is known to be encephalopathic in special circumstances, such as renal failure or following massive occupational exposure, but there is no firm evidence implicating this metal in the aetiology or pathogenesis of AD.

 

 

Historical Perspective

 

The first suggestion that Al might be involved in the pathogenesis of AD came with the finding of extensive neurofibrillary changes in the spinal cord and various cortical regions of rabbits injected with Al salts and with the discovery of similar changes and cognitive deficits in cats treated in this manner. Subsequently, it was reported that the Al content of the neocortex was significantly elevated in AD with some patients showing increases to levels known to induce encephalopathy in susceptible animal species. Evidence that Al was responsible for dialysis encephalopathy, or dialysis dementia as it was also called was considered by some to lend support to the aluminium hypothesis' of AD. However there are fundamental problems with such an interpretation of these early data. The neurofibrillary changes induced by Al in animals consist of straight 10 mm filaments and involve neurofilament proteins, unlike the paired helical filaments characteristic of the human tangle, first described by Kidd and which contain the microtubule-associated protein tau, as a major component.  Furthermore, neurofibrillary tangles (NFTs) are not found extensively in the spinal cord in AD, and animals treated with Al do not develop b-amyloid­ containing neuritic plaques. Although an age-related in­crease in the Al content of the brain in the elderly was subsequently shown, a significant increase in AD compared with age-matched controls was not confirmed.  In addition, although the clinical features of dialysis encephalopathy include progressive dementia there are focal neurological symptoms which readily differenti­ate this condition from AD, and the majority of neuropatho­logical studies in this condition have failed to find senile plaques and NETs, the hallmark lesions of AD.

 

More recent suggestions that Al may be implicated in the aetiopathogenesis of AD have been based on other lines of evidence, notably: (i) claims that Al accumulates in those brain regions which are selectively vulnerable in AD and that the transport of Al may be defective in this disorder. (ii) the association of Al with senile plaques and NETs. (iii) the finding of premature b-amyloid deposition in the brains of chronic renal dialysis patients, (iv) epidemiological stud­ies, and (v) preliminary evidence that treatment with the chelating agent, desferrioxamine (DFO) can retard the rate of behavioural decline in AD.

 

Uptake of Aluminium by the Brain

 

Although aluminium is the most abundant metal in the earth's crust, it is largely present in highly insoluble forms such as aluminosilicates which are not bioavailable. It has no known role as an essential trace element and its natural abundance contrasts with the small amount (30-50 mg present in the human body, reflecting: (i) the insolubility of most naturally occurring forms of Al, (ii) the gastrointestinal barrier to the absorption of soluble species. and (iii) the efficiency with which the kidneys excrete Al in healthy individuals. Dietary sources of Al include food addi­tives, naturally occurring forms present in sources such as tea (which is rich in Al), drinking water (especially where aluminium is used as a flocculation agent to remove organic residues), and relatively large amounts associated with medications such as antacids or buffered aspirin. Little is known about the mechanisms of Al absorption from the gastrointestinal tract, or the chemical interactions with other dietary constituents which may affect these processes. al­though it is clear that the relative amounts of Al present in various dietary sources do not necessarily reflect their bioavailability.  Plasma concentrations of Al in normal subjects are in the range of 1-10 pg/I, and most if not all plasma Al is bound to the iron-transpoiting protein. trans­ferrin. There is no convenient isotope of Al, but used gallium, which also binds with high affinity to transferrin, as a marker of Al transport in the rat. The uptake of 67Ca into brain was found to be unidirectional and to correspond largely with the distribution of transferrin receptors.

 

Accumulation of 67Ca was highest in regions such as the cortex, hippocampus and amygdala, areas containing the highest densities of transferrin receptors and which are selectively vulnerable in AD. The uptake of Al by the human brain appears to be similar, as evidenced by a recent study in patients with chronic renal failure who are unable to excrete Al and are regularly treated with large doses of Al-containing compounds to prevent hyperphosphataemia. By using imaging secondary ion mass spectrometry, the presence of numerous, focal concentrations of Al has been shown in the brains of such patients.  This uptake appeared to reflect the distribution of pyramidal cells and other neurones with a high requirement for iron in the synthesis of respiratory chain enzymes, and which have high densities of transferrin receptors on the cell surface

 

It appears that transferrin-mediated uptake into brain is the major route of entry of Al, even when the gastrointestinal barrier is bypassed, since iron-deficient rats receiving Al by intraperitoneal injection showed greater cerebral accumulation than control animals given Al by the same route, presumably, due to increased synthesis of brain transferrin receptors. It has been suggested recently that the plasma binding of 67Ca (and by implication Al) to transferrin is defective in AD and Down's syndrome, and that this might lead to the abnormal accumulation of Al in AD.  However, this study was carried out under conditions which were markedly suboptimal for metal ion-binding to transferrin, and it has also been criticized on other grounds. These findings need to be replicated with a more rigorous investigation.

 

The observation that Al salts applied to the olfactory mucosa in experimental animals can result in the transloca­tion of Al into the brain [24], and the predominant occur­rence of Alzheimer-type neuropathological changes in re­gions connected with the olfactory system, have led to the suggestion that the olfactory route could be important for the entry of this agent. However, the recent report of NETs in brain regions normally connected to the olfac­tory bulb in a patient with congenital olfactory dysgenesis, who had never developed an olfactory bulb or olfactory tracts, makes this hypothesis difficult to sustain.

 

Plaques

 

Several groups have reported the association of Al with senile plaques and NFTs, the two diagnostic, neuropatho­logical lesions of AD. However, negative findings have also been reported and there is neither general agreement that this association is consistent nor specific. Thus, Perl and Brody have claimed that the Al content of NFT-bearing neurones in the hippocampus in AD is significantly in­creased compared with that of adjacent neurones without tangles, and Candy et al have suggested that a focal deposit of Al in the form of aluminosilicates is a consistent feature of the central region of the core of senile plaques. Some groups have failed to detect Al associated with these lesions and, although negative evidence is more difficult to interpret - especially when standards suitable for imaging microanalysis have not been used, it can be argued that the presence of Al does not prove the involvement of this element in the pathogenesis of plaques and tangles. A more important issue is, rather, whether such lesions appear prematurely in patients known to be exposed chronically to high levels of aluminium. This question was addressed recently in a postmortem study of the brains of patients with chronic renal failure who did not have dialysis encephalopathy.  Increased immunostaining with an antibody to APP was found in cortical pyramidal neurones in the majority of patients, and such changes were not evident in age-matched control subjects. Furthermore, one third of the dialysis patients had high densities of amor­phous b-amyloid deposits in the cerebral cortex, including patients below the age at which such changes normally occur, except in presenile AD or Down's syn­drome. Although APP is a cell stress' protein and dialysis patients suffer from many metabolic abnormalities, similar changes have not been found in patients with hepatic encephalopathy and it is remarkable that intracellular stain­ing for APP occurs in a neuronal population which selec­tively accumulates Al. The data suggest that chronic accumulation of Al in neurones may lead to increased synthesis or abnormal processing of APP, and, in some individuals, the extracellular deposition of b-amyloid fi­brils. Cortical NFTs were not observed in any of the dialysis patients studied, suggesting that it is unlikely that Al plays any direct role in NFT formation.

 

Epidemiological Studies

 

Normal dietary intake of Al is small (10-20 mg/day) com­pared with amounts ingested as antacid medication (50-1000 mg/day) but, surprisingly, there have been few epide­miological studies which have investigated antacid use as a risk factor for AD. Excluding studies which were small, with low statistical power to detect such an association, one investigation has reported negative results, and two have reported evidence of a weak positive relationship; overall, however, it does not appear that antacid usage is a significant risk-factor for AD. In contrast to these data, studies from four different countries have suggested a positive association between exposure to Al in water and AD, while one has reported negative findings. Aluminium in drinking water accounts for far less than 5% of dietary intake of Al, even in heavily treated supplies, and the data indicate either that Al in water is particularly bioavailable, or that some other factor in water is responsi­ble for this association. While there is no strong evidence to support the view that Al in water is more bioavailable than Al from many other sources, Birehall and Chappell have noted that a broad inverse correlation exists between dissolved silicon (in the form of silicic acid) and Al in water, and that a possible explanation for these epidemiological data is that high levels of silicic acid may prevent the absorption of Al not just from water but also from other dietary sources. Heavy industrial exposure to Al powder may also be significant. A recent Canadian study reported that miners exposed to finely milled Al powder to prevent silicotic lung disease showed evidence of a dose-related cognitive decline.

 

Effects of Chelation Therapy

 

A crucial test of the “aluminium hypothesis” would be to determine whether the removal of this metal by chelation therapy has any effect on the progression of AD. Crapper MeLachlan have recently reported the results of such a study, in which intramuscular injections of the trivalent ion-specific chelator, DFO, were used to treat AD patients over a period of 24 months. Treatment with DFO led to a significant reduction of approximately 50% in the rate of decline of daily living skills. Although the authors point out that the therapeutic effects of DFO could be due to mechanisms other than Al chelation, such as a reduction in iron-mediated free radical formation, these preliminary data clearly justify further clinical trials with DEG and other chelating agents in the treatment of AD.

 

Discussion and Conclusions

 

Alzheimer's disease is a heterogeneous disorder and there is strong evidence for the involvement of both genetic and environmental risk factors in its development. While it is clear that aluminium is neurotoxic in certain conditions, such as dialysis encephalopathy, there is no conclusive evidence that Al is a significant risk factor in the aetiopatho­genesis of AD.

 

Aluminium is abundant in the environment, occurring in many different chemical forms, and relatively little is known about the factors which determine its bioavailability. Alu­minium absorbed from the gastrointestinal tract is largely,if not totally, bound to transferrin and slow accumulation in the nervous system occurs via transferrin-mediated trans­port. Accumulation is most marked in regions containing neurones with high densities of transferrin receptors, in­cluding areas that are selectively vulnerable in AD.

 

The study in patients exposed to high blood levels of aluminium because of chronic renal failure suggests that intracellular accumulation of Al may lead to altered neuronal synthesis or processing of the b-APP and, in some patients, diffuse deposits of b-amyloid in the cerebral cor­tex. A mutation in the APP gene is responsible for some forms of familial AD, suggesting that the pathogenic sequence in AD is abnormal synthesis/metabolism of APP which leads to b-amyloid deposition and, eventually, tangle formation, neuronal dysfunction and cell death. Such a sequence is supported by findings that the direct intracer­ebral injection of b-amyloid in the rat causes neurodegenerative changes, including neuronal loss, de­generating neuritic processes and the appearance of Alz-50 immunoreactive proteins which characterise the NFT-bear­mg neurone in AD. It is possible, therefore, that Al may contribute to or accelerate this cascade in AD, but the absence of neurofibrillary changes in renal dialysis patients indicates that Al does not directly lead to NFT formation. A further possibility is that chronic accumula­tion of Al by the brain may be partly responsible, in a less specific way, for the attrition of neuronal populations. This could contribute to age-related memory dysfunction and reduce the threshold for the manifestation of clinical deficits produced by more specific disease-related processes, such as b-amyloid deposition and NET formation.

Although several studies have shown a geographical correlation between the prevalence of AD and the concen­tration of Al in water supplies, it is possible, even likely, that this association reflects exposure to other environmental factors, such as dissolved silicon, which may limit the bioavailability of Al from all dietary sources.

 

A single study with the chelating agent DFO in AD suggests that such treatment may help to slow the deterio­ration in living skills; further therapeutic trials with chelating agents are required.

 

A cautious interpretation of the above conclusions would suggest that it maybe appropriate to limit Al intake in foods, fluids and medicines, and also where heavy occupational exposure is involved. However, there is as yet no direct evidence that such steps would reduce the risk of AD or slow progression of the disorder. Further research is required before any consensus on the value of such measures is likely to emerge.