Alzheimer's disease (AD) is the most common type of dementia in the elderly, with a rapidly increasing prevalence. In the past three decades, we have witnessed remarkable advances in our understanding of AD, both in terms of the disease course and its symptoms.
About 20 genes have been identified to be associated with an altered risk for late onset AD (LOAD), which could potentially serve as new therapeutic candidates. However, the risk variability and limited power of allelic risk candidates have led to the conclusion that there must be other factors, such as toxic exposure and environmental factors, significantly contributing to the risk of developing LOAD.
One of the most compelling pieces of data, supporting nongenetic modulators, emerged from the fact that monozygotic twins are discordant for AD and/or age when the symptoms present.
Head trauma is widely recognized as the only accepted classic exogenous environmental risk factor for AD. Some of the phylogenic AD risk factors include: body mass, cholesterol level, blood pressure, glucose homeostasis and exercise.
Furthermore, environmental toxins such as trace metals or DDT have been reported to have roles in AD. Transcription of the AD amyloid precursor protein gene has been shown to be regulated by acute phase reactant molecules that could lead to a rapid increase of the precursor protein following chemical or traumatic injury.
Metals (copper and iron) have been reported to have pro-oxidantal effects under oxidative stress. A high concentration of serum copper was detected in AD group as compared to the control group in recent studies.
Aluminum is also among the metals with potential link to AD. Three routes have been reported for aluminum to enter the brain from the systemic circulation, including: blood-brain barrier (BBB), nasal-olfactory pathway and cerebrospinal fluid (CSF). Any potential structural or functional changes in BBB could relate to aluminum accumulation in AD.
Aluminum can be found in drinking water, aluminum containers, aluminum foil used in food packaging, food and drugs, such as antacids. In other studies, higher aluminum levels were reported to be correlated with dietary habits and usage of aluminum cookware.
Temporal cortex and hippocampus, which have been reported to be significantly involved in AD, were found to have high aluminum contents in these reports. At the subcellular level, aluminum has selectivity for cytosolic, mitochondrial, lysosomal and nuclear compartments. Furthermore, it has a low DNA and high RNA binding affinity.
On the other hand, the alterations of a single metal could affect the total elemental and charge distribution pattern of the nervous system. Therefore, the trace elemental homeostasis plays a crucial role in the normal brain function.
Aluminum could potentially replace divalent metals (Ca, Mg, Zn), which could lead to toxic effects. Aluminum can also inhibit or activate certain enzymes by ion exchange mechanisms.
On the other hand, neurons have been reported to be highly vulnerable to free radicals. Oxidative damage has been evidenced in AD. Aluminum has been reported as a contributing factor to the oxidative stress due to reactive oxygen species (ROS) generation. Furthermore, aluminum can potentially modify the biophysical properties of membranes that could lead to functional impairment of neurons.
In conclusion, aluminum can be highlighted as one of the etiological factors in the pathology of Alzheimer's disease. Further systematic studies of the trace metal profile in the human body will further elucidate the detailed pathways of metal effect on the AD process.
