Nonlinear dose-response of aluminium hydroxide adjuvant particles: selective low dose neurotoxicity.Toxicology http://dx.doi.org/10.1016/j.tox. 2016.11.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. An unusual neuro-toxicological pattern limited to a low dose of Alhydrogel ® was observed.Neurobehavioural changes, including decreased activity levels and altered anxiety-like behaviour, were observed compared to controls in animals exposed to 200 µg Al/kg but not at 400 and 800 µg Al/kg. Consistently, microglial number appeared increased in the ventral forebrain of the 200 µg Al/kg group. Cerebral Al levels were selectively increased in animals exposed to the lowest dose, while muscle granulomas had almost completely disappeared at 6 months in these animals.We conclude that Alhydrogel® injected at low dose in mouse muscle may selectively induce long-term Al cerebral accumulation and neurotoxic effects. To explain this unexpected result, an avenue that could be explored in the future relates to the adjuvant size since the injected suspensions corresponding to the lowest dose, but not to the highest doses, exclusively contained small agglomerates in the bacteria-size range known to favour capture and, presumably, transportation by monocyte-lineage cells. In any event, the view that Alhydrogel® neurotoxicity obeys "the dose makes the poison" rule of classical chemical toxicity appears overly simplistic.

Genetic predispositions associated with metabolism of the amyloid-␤ protein precursor underlie familial Alzheimer's disease; a form of dementia characterized by early disease onset and elevated levels of cortical amyloid-␤. Human exposure to aluminum is linked to the etiology of Alzheimer's disease and recent research measured a high content of aluminum in brain tissue in familial Alzheimer's disease. To elaborate upon this finding, we have obtained brain tissues from a Colombian cohort of donors with familial Alzheimer's disease. We have used established methods to measure the aluminum content of these tissues and we have compared the data with a recently measured dataset for control brain tissues. We report significantly higher levels of aluminum in brain tissues in donors with familial Alzheimer's disease than in control tissues from donors without neurological impairment or neurodegeneration. We have used aluminum-specific fluorescence microscopy along with complementary imaging for amyloid-␤ to demonstrate a very high degree of co-localization of these two risk factors in brain tissue in familial Alzheimer's disease. Aluminum and amyloid-␤ were co-located in senile plaques as well as vasculature, the latter resembling cerebral amyloid angiopathy. Aluminum was also found separately from amyloid-␤ in intracellular compartments including glia and neuronal axons. The research has identified an arguably unique association between high brain aluminum content and amyloid-␤ and allows postulation that genetic predispositions defining familial Alzheimer's disease underlie this relationship.

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A burgeoning number of studies are demonstrating aluminium in human brain tissue. While research has both quantified and imaged aluminium in human brain tissue in neurodegenerative and neurodevelopmental disease there are few similar data for brain tissue from non-neurologically impaired donors. We have used microwave assisted acid digestion and transversely heated graphite furnace atomic absorption spectrometry to measure aluminium in twenty brains from donors without recognisable neurodegenerative disease. The aluminium content of 191 tissue samples was invariably low with over 80% of tissues having an aluminium content below 1.0 μg/g dry weight of tissue. the data for these control tissues were compared with data (measured using identical procedures) for sporadic Alzheimer's disease, familial Alzheimer's disease, autism spectrum disorder and multiple sclerosis. Detailed statistical analyses showed that aluminium was significantly increased in each of these disease groups compared to control tissues. We have confirmed previous conclusions that the aluminium content of brain tissue in Alzheimer's disease, autism spectrum disorder and multiple sclerosis is significantly elevated. Further research is required to understand the role played by high levels of aluminium in the aetiology of human neurodegenerative and neurodevelopmental disease.

In this paper, I have summarized the experimental and largely clinical evidence that implicates aluminum as a primary etiological factor in Alzheimer’s disease. The unequivocal neurotoxicity of aluminum must mean that when brain burdens of aluminum exceed toxic thresholds that it is inevitable that aluminum contributes toward disease. Aluminum acts as a catalyst for an earlier onset of Alzheimer’s disease in individuals with or without concomitant predispositions, genetic or otherwise. Alzheimer’s disease is not an inevitable consequence of aging in the absence of a brain burden of aluminum.