2. Role of Copper in the Human Body

Copper is an element essential to the homeostasis of the human body due to its role in energy production, iron metabolism, neuropeptide activation, and connective tissue and neurotransmitter synthesis ^[9]. Copper’s most crucial property however is its role in cuproenzyme ceruloplasmin ^[10]. Ceruloplasmin is the major copper-carrying protein in the blood, accounting for over 95% of copper transport in human plasma ^[9][10]. Studies have also found that copper plays a crucial role in the formation of red blood cells, immune system function, brain development, gene expression, and other physiologic processes ^[9]. Through the use of ceruloplasmin transport, copper is able to reach the brain, which uses a significant portion of copper found in the body for brain development and regulation of the nervous system ^[6][9][10]. Copper is also significantly used in the liver to convert iron into its ferric form as well as absorb iron into the gut ^[6].

3. Common Forms of Copper Intake

Copper toxicity is an associated result of exposure to copper contaminated sources. Common exposure sites include water supplies, copper pipes, uncoated copper cookware, birth control, dietary supplements, food, and fungicides. Water supplies are often contaminated by farm operations and other industrial waste practices that become runoff and enter reservoirs and public wells ^[11]. This waster is then transported to nearby populations for consumption and other daily activities. Such an instance was accounted for in a 2016 journal highlighting the widespread water contamination of heavy metals, specifically copper and lead, in New South Wales, Australia ^[11]. This study analyzed tap water from 212 different homes in the region; of these samples, almost 100 percent tested positive for copper, with 5 percent testing positive for excess copper ^[11]. For the houses testing within the normal copper range, it was also found that drinking water contributed to 6 to 13 percent of the average daily intake of copper ^[11]. A high copper positive percentage was expected since many of these homes utilize copper pipes and fittings for water supply ^[11]. Subsequently, copper pipes are a great cause of concern regarding copper contamination as acidic water may cause erosion of the pipe or fitting, releasing copper particles directly into the water ^[11]. Therefore, this study concluded there is a great concern for copper levels due to their frequent occurrence at high concentrations, as this water is then used for drinking, washing of cookware, as well as for bathing, and personal hygiene, creating various opportunities for direct ingestion of copper contaminated water, increasing the prevalence of copper toxicity in the region ^[11]. Other sources of copper contamination include improperly coated copper cookware, such as pots and pans. If not coated with another non-reactive metal, copper from the cookware can enter food and therefore the human body. As copper levels in the body increase, excess copper begins to pool in tissues, leading to copper toxicity. Similar to copper pipes, unprotected copper cookware can corrode in the presence of acidic foods, resulting in another means of entry into the human body ^[5]. Copper toxicity can also be caused through the use of birth control, as it can raise copper levels, which also destroys Vitamin C, another essential nutrient for the human body’s optimal function ^[12]. Dietary supplements and other foods can also be a source of excess copper. The recommended daily dose of copper for those aged 19 and older is 900 mcg, with the upper limit at 10,000 mcg ^[6]. Overconsumption of copper supplements or foods high in copper content, such as legumes, mushrooms, chocolate, liver, and nuts and seeds, can result in copper toxicity when not consumed in moderation ^[6]. Copper sulfate, an inorganic copper and sulfur compound used as a fungicide and algaecide in swimming pools, creates a toxic environment for microorganisms that kill small plants and animals by shocking roots and causing copper toxicity, respectively ^[13]. Due to its multiple points of entry into the human body, copper contamination is a growing concern, especially considering the large quantities in which it is found in the activities of daily life.

4. Alzheimer’s Disease and Copper Pathways

The adult human brain contains approximately 100 billion neurons, directly correlating with brain mass. As healthy aging occurs, neurogenesis, the process of regeneration by neural plasticity, slows down, and neuron proliferation rate decreases ^[14]. Dementias, such as Alzheimer’s, can speed up neurodegenerative processes, causing memory loss, progressing to the point where the patient is no longer capable of independently performing activities of daily living. Referred to as cerebral atrophy, the loss of neurons decreases brain mass overall or in specific areas ^[15]. Alzheimer’s disease begins by targeting the hippocampus and entorhinal cortex located in the temporal lobe ^[1][16]. The temporal lobe is responsible for the connection of the network responsible for memory, navigation, and the perception of time ^[16]. The targeting of this region decreases the number of transmitters in the temporal lobe, causing neuron death and therefore size reduction, which can be seen on MRI scans of the brain ^[16]. A 2020 study found that the temporal lobe of those with Alzheimer’s disease decreases at a rate of 15.1 percent per year whereas the normal neurodegeneration rate is a significantly lower 1.5 percent ^[17]. The study concluded that cognitive decline and subsequent memory loss are a direct result of temporal lobe atrophy ^[17]. As the disease progresses, the cerebral cortex also becomes impaired ^[1][18]. The cerebral cortex is the outer layer of neural tissue located at the front of the head, covering the outer portion of the cerebrum ^[19]. The cerebrum controls language, reasoning, social behaviors, emotion, muscle movement, hearing, vision, and other sensory controls ^[1][19]. Alzheimer’s disease can also be characterized by neural mass loss and astrocytosis in the cerebral cortex ^[1][18]. A 2018 study found that about 25 percent of individuals who die by the age of 75 presented with substantial cerebral lesions resembling those of Alzheimer’s disease ^[18]. This study concluded that the identification of cellular brain structure is essential to understanding neurodegenerative disease progression ^[18]. The order of progression for Alzheimer’s disease begins in the hippocampus and expands outward to the temporal lobes, frontal lobes and prefrontal cortex, parietal lobes, occipital lobes, cerebellum, and finally the brainstem ^[20]. Once the disease reaches the brain stem, autonomous functions of the body will cease, ultimately proving fatal ^[20].

Copper toxicity results in the pooling of copper in different tissues of the body ^[3][5][21]. Prominent areas of copper pooling include the liver, brain, and eyes ^[5]. A 2013 study of male Wistar rats conducted by Pal et al. found copper toxicity effects on the rat brain include swelling and increased number of astrocytes, star-shaped glial cells, and copper deposition in the choroid plexus, which is located in close contact with the cerebral cortex ^[22][23]. The study concluded that copper toxicity in male Wistar rats causes impaired spatial memory and neuromuscular coordination, swelling of astrocytes, copper deposition in the choroid plexus, neuronal degeneration, and augmented levels of copper in the hippocampus ^[22]. This is a significant finding due to the implications of these symptoms; impaired spatial memory and neuromuscular coordination can result in difficulty walking and navigating, swelling of astrocytes can result in brain edema and fulminant hepatic failure, impairment of the choroid plexus can cause variations in the development of cerebrospinal fluid possibly leading to overproduction causing pressure in the brain, neuronal degeneration can lead to neuron death, and augmented levels on copper in the hippocampus can lead to various dementias ^{[24][25][26][27]}. Dementias may be a result of the various plaques copper can induce, the most prevalent of which are amyloid-beta plaques associated with Alzheimer’s disease ^[28]. Another 2018 study, conducted by Kardos et al., found copper levels to be significantly higher in the cerebellum, choroid plexus, ventricle system, and substantia nigra, a region of the midbrain ^[29]. This study also found that free excess copper often pools in the soma of cerebellar granule and cortical pyramidal neurons, as well as the hippocampus and spinal cord ^[29]. One 2012 study analyzed possible reasons for high copper levels in the brain and theorized that a high-fat diet caused an increase in copper levels, which they theorized was also correlated to an increased risk of Alzheimer’s disease ^[30]. The study found that the highest 20 percent of those with copper intake lost cognition at six times the rate of groups with lower copper consumption if they also had a high-fat diet ^[30]. The study hypothesized that the ingestion of free-floating copper from sources such as drinking water and copper supplements played a major factor in the onset of Alzheimer’s as it caused high levels of copper pooling in the brain ^[30]. This study concluded that there is a strong correlation between copper levels and the prevalence of Alzheimer’s disease ^[30]. It is believed this correlation exists due to the commonalities between affected areas by Alzheimer’s disease and copper toxicity ^[29][30]. Such common areas include the hippocampus, cerebral cortex, cerebellum, and brainstem, which affect memory, information processing, motor skills, and regulation of autonomous functions, respectively ^[20][29][30]. This supports the theory that copper may play a role in the onset of Alzheimer’s disease as these regions are also the pathway of the general progression of the disease ^[20].