The third-most abundant metal in the earth's crust, Aluminum (Al), is derived from mining cryolite and bauxite ore and enters the human body easily via the environment, diet or drugs1. Alzheimer's Disease is a senile neurodegenerative disease that affects human beings typically over 65 years of age1. A key biological question in the study of human health, is whether Aluminum exposure causes Alzheimer's Disease. Apart contributing to the diagnosis and cure for the disease that affects an estimated 24.3 million people globally2, the question posed can help understand other forms of senile dementia, since Alzheimer's Diseases makes up about 70% of all dementia that affects elderly people in Westernized countries1. Some major pathological features of Alzheimer's Disease include amyloid plaques and neurofibrillary tangles (NFTs)1. Amyloids are protein fragments normally produced by the body but their abnormal alteration to β-amyloid peptide fragments results in unhealthy accumulation between neurons which forms hard, insoluble plaques1, 3. NFTs are twisted, insoluble bundles of paired helical filaments, composed of microtubules that are made of tau protein3. Hyperphosphorylation of this tau protein disintegrates microtubules, causing terminal neurodegeneration1, 3. Clinically, this results in memory loss, impaired sense of judgment, and decline in cognition1, 3. The nature of correlation between Aluminum and Alzheimer Disease is under great debate.
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Some studies indicated that Aluminum may be linked to Alzheimer's Disease development. Aluminum affects biochemical processes, such as binding to inositol 1,4,5- triphosphate, which is part of the inositol pathway associated with memory formation4. Further still, elevated Aluminum levels were linked to a risk of Alzheimer's Disease in a study where the number of Alzheimer's Disease-affected individuals was greater in areas where drinking water contained elevated Aluminum levels (111 μg/L Al) versus areas containing 1.7 times lower (10 μg/L Al) levels of Aluminum3. Also, it was proposed that desferrioxamine (DFOA), a drug, reduced the progression of Alzheimer's Disease since it dissolved aggregated β-amyloid protein by chelating with Aluminum1, 3, 5. Next, functional impairment was observed in animal models, like an in vivo study where the intercranial injection of Aluminum in cats and rabbits resulted in memory defects in 7-10 days3. Another study showed that increased Aluminum concentration in drinking water corresponded to an increase in the number of aged rats with cognitive dysfunction6. These studies proved that elevated Aluminum levels were linked to interference in key biochemical processes and caused cognitive dysfunction in some animals.
However, some studies indicated that Aluminum may not be linked to Alzheimer's Disease development since it may just be present as a spectator element. This was noted when no neuronal damage was seen in cultured rat hippocampus and human cortical neurons exposed to Al3+ for under a week, which suggested that tau protein alterations were more likely caused by Calcium (Ca2+) and not Aluminum7. Also, the possibility that Aluminum sequestered in the brain as an immunological response cannot be ruled out7, 8. A joint effect possibility of a third factor causing both, Alzheimer's Disease and Aluminum accumulation, has not been ruled out either. Oxidative stress caused by free ferritin radicals was claimed to be initiated by Aluminum4, however DFOA treatment was found to directly target ferritin, and not chelate with Aluminum, thereby absolving Aluminum's role in oxidative stress7. Moreover, Aluminum must cross the gut-barrier and the blood brain barrier to be absorbed by the body, both of which are selectively permeable to it, depending on its species and its reaction with other ingested compounds, like citrate4. The above studies established no conclusive cause-and-effect link between Aluminum exposure and Alzheimer's Disease. In addition, it must be noted that differences in experimental design can potentially skew results. For instance, the results of a in vitro study that linked elevated Aluminum levels to the prevalence of amyloid plaque formation and tau protein accumulation are questionable because of its short three-week duration of observation. Yet another flaw was that the effects of Aluminum were tested on embryonic rat cortices rather than aged neurons, since Alzheimer's Disease is typically observed in aged human beings5. Interestingly, Alzheimer's Disease is not seen in any species other than human beings and so the use of animal models, despite their evolutionary proximity to human beings11, is questionable since animals like mice, chimpanzees and aged elephants lack neurofibrillary tangles (NFTs) and amyloid plaques5, 11, 12. Over reliance on cognitive damage assessment in animals through oxidative damage or tau protein changes then becomes doubtful.
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The nature of correlation between elevated Aluminum levels and Alzheimer's Disease is uncertain, although some studies suggest Aluminum as a causative factor8,15,17-19 while others do not6,9,10,16, supporting both sides of this argument10. The accuracy of results of some of these studies, however, is doubtful due to experimental flaws like lack of consistent Aluminum exposure, level of dosage, duration and method of exposure, lack of large group sizes, or the failure of animal models due to differences in immunological and pathophysiological responses between species10. Since human experimentation is unethical, animal models, more specifically, in vivo models are the next best choice researchers can opt for, since in vitro models have purified and controlled cell culture environments, where enzymes or cofactors that inhibit Aluminum could be denatured or absent. For instance, the intercranial injection of animals was not comparable to Aluminum consumed by humans through diet or drugs because it negates the role of such enzymes or cofactors, and possibly bypassed the gut barrier or blood brain barrier3, 4. In conclusion, Aluminum exposure and Alzheimer's Disease do seem to exhibit a correlation but the precise nature of it, including whether Aluminum is a causative factor of the disease, is far from ascertained.