Relación entre aluminio y la enfermedad de Alzheimer: Revisión

Background

Research on AD began when Dr. Alois Alzheimer discovered histological alterations in the brain of a 51-year-old woman in the late 1880s. In 1906, Dr. Alzheimer, during a lecture in Tubingen (Germany), presented his first observations on the symptoms and pathology of this disease (Hippius and Neundörfer, 2003; Lopera, 2004). In 1907, Dr. Alzheimer formally established the existence of a new disease, which was initially considered a strange form of presenile dementia characterized by behavioral disorders, depression, psychotic symptoms, and cognitive impairment. At the time, these symptoms were considered strange because the main origin of dementia was believed to be the "hardening of the arteries". In 1910, Emil Kraepelin assigned the name .Alzheimer’s disease"to this pathology, a disease which was a significant burden for patients, their caregivers, and the community at large (Hippius & Neundörfer, 2003). Subsequent advances in neuropathology allowed AD to be considered a type of presenile dementia distinct from senile dementia. This hypothesis prevailed until the 1960s, and for the next 20 years, AD remained the dominant and prototypical form of dementia, centered on prominent memory disturbances. However, the term dementia has gradually fallen out of use when referring to major neurocognitive disorder and the heterogeneity of the syndrome at the phenotypic and molecular levels has once again been recognized (Assal, 2019).

Diagnosis of Alzheimer’s disease

A definitive diagnosis of AD should include multiple types of progressive cognitive impairments leading to dementia with post-mortem neuropathologic confirmation, as well as a clinical history of memory impairment. Recently, the importance of the use of biomarkers that aid in the in vivo diagnosis of AD has been accepted. Among these markers, one can find the main cerebrospinal fluid (CSF) biomarkers of AD, namely are amyloid-beta (Aβ42), which shows the cortical deposition of amyloid, total tau (t-tau), which reflects the intensity of neurodegeneration, and phosphorylated tau (p-tau), which correlates with pathological neurofibrillary changes. Magnetic resonance imaging (MRI) and fluorodeoxyglucose (FDG) positrón emission tomography (PET) techniques have also been implemented to discard intracranial causes (meningioma, subdural hematoma) and have been complemented by the notion that the demonstration of regional atrophy in the medial temporal region can provide positive diagnostic information (Scheltens et al., 2016).

MRI remains the modality of choice for the assessment of cerebral vascular changes, such as white matter hyperintensities, lacunae, and microbleeds, which have gained increasing attention because these are frequent secondary effects in antiamyloid trials. Meanwhile, FDG PET estimates the density and distribution of aggregated tau neurofibrillary tangles in cognitively impaired adults being evaluated for AD. Precise interpretation of FDG with PET in patients with dementia is not based on the presence or absence of a single region of hypometabolism, but should take into account the pattern of hypometabolism throughout the cortex (Scheltens et al., 2016; Barthel, 2020). However, further standardization is required to have universal clinical use of biomarkers (McKhann et al., 2011; Barthel, 2020). Likewise, although age is one of the primary factors associated with AD, there is a wealth of research which currently points to neurodegeneration, inflammation, atrophy, and other elements of concern as chronic circumstances that may favor the manifestation of dementia as well as the development of lesions in the structures of the medial temporal lobe, hippocampus, and entorhinal cortex. These lesions are characteristic of the anatomopathological alterations typical of AD due to Aβ protein plaques outside neurons and Tau protein neurofibrillary tangles inside neurons, physiological characteristics of a patient which usher the progression of the disease (Stephan et al., 2012).

General information on aluminum

Aluminum is the third most abundant chemical element in the earth’s crust, making up 7.5%of its composition. Despite its prevalence, it has no biological function in human or animal organisms. However, its low density and ability to self-passivate cause it to be widely used in industries (Stephan et al., 2012; Stahl et al., 2017).

According to the European Aluminum Foil Association, aluminum has been used commercially for more than a century.

Due to its abundant availability and characteristics, since the late 19th century, it has increasingly shaped the modern lifestyle and has become necessary for space exploration, electricity transmission, the construction of modern buildings, and the manufacturing of aircrafts, automobiles, vessels, and currently, high-quality packaging of various types for the food industry, to which it is especially suited given its low cost and high levels of conductivity which enable effective temperature regulation (Casaburi et al., 2019).

Therefore, the production of primary aluminum has increased significantly in recent years, reaching a worldwide production level of 68,461 thousand metric tons in 2022, with China being the largest producer at 40,430 thousand metric tons (International-Aluminum, 2023). However, alloying additives and recycled aluminum, which are excluded from the processing of primary aluminum, are used in the production of secondary aluminum, a process which can be repeated almost indefinitely, which cuts costs and multiplies environmental benefits. Aluminum figures are thus expected to increase considerably due to advances in aluminum alloy metallurgy (Brough & Jouhara, 2020).

Sources and behavior of aluminum in food

The migration of aluminum into food impacts the health of consumers, bringing as consequences neurological diseases involving inflammatory neural degeneration, behavioral deterioration, and cognitive impairment (Barthel, 2020). In addition, its accumulation in the central nervous system (CNS) over time can lead to irreversible brain cell damage and functional decline resulting in cognitive, memory, and behavioral deficits. Consequently, researchers have analyzed the aluminum content of the temporal lobe neocortex, finding a range of 1.9 16.8 ug aluminum/gm tissue in autopsies performed on patients whose cause of death was AD (McLachlan et al., 2018).

One of the causes of aluminum accumulation in the human body is the consumption of foods which contain this element, either from primary or secondary sources. Primary aluminum in food is generated by the natural migration of aluminum from the earth’s crust (where this element is present) to food. This phenomenon occurs primarily in plants. Plants absorb nutrients from the soil that are used for nutrition, development, and growth. Aluminum can be found in fresh vegetables, with values between 2 and 10 mg/kg, depending on the type of soil (alkaline or acidic) where it is harvested, the concentration of aluminum present in the soil, the water used for irrigation, and the type of vegetable, leafy vegetables having the highest values, followed by bulb, stem, flower, pod, root, and tuber vegetables. In fruits, on the other hand, concentrations are lower (mean value of aluminum 1.3 mg/kg) (Liang et al., 2019; Daouk et al., 2020).

Estimates suggest that 40-50% of cultivable soils worldwide are acidic (pH <5.0). Here, aluminum is present in a cationic form (being highly soluble) which allows plants to easily obtain a higher concentration (Rahman et al., 2018). However, cereal plants are among the plants with the lowest aluminum accumulation. Levels of aluminum in cereal plants are also highly variable between countries or even regions of the same country, as shown in Table 2, which outlines the presence of this metal not only in grains but also in other parts of plants (leaves and shoots) and cereal-based products.

Table 2: Aluminum concentration (mg/kg) in some grains, parts of plants, or cereal products

Soil geochemistry not only affects plants and plant products through aluminum migration but also alters water quality. This contamination causes water quality to decrease to levels prejudicial to biota in waterways affected by the easy discharge of aluminum due to the high solubility of this contaminant in more acidic conditions such as those in acidic soil and rain (acid rain) (Hu et al., 2017; Toivonen et al., 2020). Therefore, the above-mentioned phenomena may be factors in the increased levels of aluminum in some plants, as is the case of tea plants (Camellia sinensis) which are produced in acid soils with a pH range of 3.5 5.6 (De Silva et al., 2016; Hu et al., 2017). Research has reported aluminum concentrations in tea leaves between 1836.77 and 487.57 mg/kg (Peng et al., 2018; de Silva et al., 2016; Li et al., 2015), which has generated research to address the management and control of aluminum levels in soils and crops. Reducing these levels could help counteract the concentrations present in water systems. Besides coming from areas with acidic rocks and soils, this metal can also be found in nature, in lake water, either as untreated water or as water treated with Al salts or with electrocoagulation/ electroflotation. The latter is a recognized decontamination method for water treatment in which aluminum electrodes can be used wherever the release of aluminum metal molecules may occur to decontaminate the water containing dyes (Garcia et al., 2016). Moreover, these electrodes are used to remove heavy metals such as chromium present in water (VillabonaOrtíz et al., 2021). Salts are also inappropriately used as coagulants in drinking water treatment to reduce organic matter, color, turbidity, and microorganism levels. In this way, aluminum is transported via the liquid until it reaches residences where it is sometimes consumed directly from the tap. This water could contain a higher aluminum content after purification with aluminum salts since this compound increases the percentage of dissolved polyaluminum species (Al Zubaidy et al., 2011; D’Haese et al., 2019).

This can cause a risk to human health, especially when aluminum is present in high concentrations (≥ 0.1 mg/L aluminum) as it becomes a catalyst for AD and dementia (FAO/WHO, 2007; Matías-Cervantes et al., 2018). Similarly, water treatment affects the aquatic ecosystem by generating contamination with non-essential oligoelements, mainly aluminum, which is transferred through the trophic chain to crustaceans and especially fish. The latter has been held to be amongst the most susceptible aquatic organisms to the accumulation of metals. Consequently, these marine species become vectors of metal contamination for humans which can cause health risks when levels of toxic elements are very high (Trevizani et al., 2019; Dos Santos et al., 2023). Therefore, research has focused on finding natural alternatives to reduce the use of aluminum salts as flocculants in drinking water purification (Ekong et al., 2017; Chao et al., 2020).

Another way in which humans can be exposed to aluminum is through the ingestion of aluminum through food contaminated during processing, packaging, and/or storage. This is secondary source of aluminum associated with the lixiviation of this element from kitchen equipment and utensils (pots, cutlery, trays, knives, frying pans, grills, etc.) that are manufactured with the material. Aluminum is widely used in the industry for the production of these utensils mainly because it is an easily obtainable material with good malleability, thermal conductivity, ease of clean up, and durability (Odularu et al., 2013; Stahl et al., 2018). Despite these industrial benefits, aluminum can easily leach into food due to factors such as the type of aluminum utensils used, exposure time, cooking temperature, salinity, pH, fat content, and food composition in general (Al Zubaidy et al., 2011; Bassioni et al., 2012). Another secondary factor of aluminum exposure is the use of aluminum foil in food preparation and culinary practices. Aluminum foil has been widely used to wrap heat-sensitive foods (mainly seafood and meat products) before cooking, which can generate a high concentration of aluminum in the producto after heating.

Table 3 shows studies that have evaluated the leaching of aluminum from aluminum foil into various foods. It shows that the amount of leaching can increase depending on the characteristics of the food, pH, whether it is marinated (wines, citric acid, tomato juice, apple cider vinegar), acidity, or whether it contains spices or additives. Here, acidic solutions and spices, along with increased temperature and cooking time, contributed to increased leaching of the aluminum exposure area. Weidenhamer et al. (2016) studied the release of aluminum from cookware materials in 10 developing countries (Bangladesh, Guatemala, India, Indonesia, Ivory Coast, Kenya, Nepal, Philippines, Tanzania, and Vietnam), finding that there was an average aluminum exposure for all cookware studied of 125 mg per serving, six times higher than the provisional tolerable weekly intake for a 70-kg adult (20 mg/day). These authors made preliminary evaluations of three possible methods to reduce metal leaching in the cookware tested (boiling or near-boiling water, addition of curcumin, and fluoropolymer coating), where the fluoropolymer coating reduced up to 98% of the aluminum level in the final extraction.

Table 3: Leaching of aluminum from food through food preparation and storage.

Likewise, trays or containers can be found in the market, which are made of aluminum sheets with thicknesses greater than those used to make paper; these are mainly designed for solid and/or semi-solid products. Therefore, this material has attracted much interest in the industry as it is an excellent barrier against gases, light, moisture, odors, flavors, and microorganisms and has properties of impermeability, resistance to freezing, inertness, especially perfect dead fold characteristics, and recyclability (Sarkar & Aparna, 2020). However, it can pose risks to human health due to the migration that occurs when the material comes into contact with food and is exposed to heat. This can lead to corrosion and erosion of the container, allowing aluminum to leach into the food and then follow the digestive and circulatory tract, and finally, it is stored in the tissues, including the brain; similar process happens with aluminum containers, traces of this metal are extracted from the walls of the container, it passes to the liquid phase and followed by the product, presenting itself in low pH sauces and fruit juices (Bejarano & Suárez, 2015; Deng et al., 2021).

Aluminum can also be found as a secondary source of food additives. These are substances that are intentionally added to food for a technological purpose in the manufacture, preparation, processing, treatment, packaging, wrapping, transport, or preservation of the food, so the use of Al-containing additives can affect the total concentration in the final product (Yokel, 2016; FAO/WHO, 2021). In the additives market, aluminum can be found as an ingredient in several of these compounds, such as sodium aluminum sulfate (sodium aluminum dúplex sulfate, E521, INS 521), potassium aluminum sulfate (potassium alum, E522, INS 522), ammonium aluminum sulfate (ammonium alum, E523, INS 523), potassium aluminum sulfate (potassium alum, E522, INS 522), ammonium aluminum sulfate (ammonium alum, E523, INS 523), sodium aluminum phosphate (aluminum salt and phosphoric acid salt, E541i, INS 541i), sodium aluminosilicate (sodium aluminum silicate, E554, INS 554), calcium aluminum silicate (E556, INS 556), and aluminum silicate (E559, INS 559). These additives are technically used in processed products and water as synthetic stabilizers, coagulants, and leavening agents to control the rate of CO2 gas generation, emulsifiers, and acidity regulators (Ogimoto et al., 2016; FAO/WHO, 2021). Among the above-mentioned additives are included fermenting agents, demolding agents, anti-caking agents, and protectants such as aluminum and sodium silicate in cake mixes and dry products, gelatins, wheat flour, and wheat-based foods (including fried dough sticks, fried dough cakes, steamed bread, noodles, cakes, and pastries, etc.). These are the foods with the highest levels of aluminum and potassium dodecahydrate due to the use of aluminum and potassium sulfate dodecahydrate, fried dough cakes, steamed bread, noodles, cakes, and pastries, etc.) are the foods with the highest levels of aluminum due to the use of aluminum potassium sulfate dodecahydrate (alum) in the preparation of these types of products (Ning et al., 2016; Wang et al., 2022). Due to the health risks posed by aluminum, some countries, such as China, have conducted several studies (Guo et al., 2015; Chen et al., 2017; Ding et al., 2021) on the use of additives containing this metal to provide scientific information to the government so that it can better control the limits of aluminum residues in food additives.

In the food industry, aluminum is also used as a colorant (E173), known as Çl pigment metal", which presents a silver-gray hue or tiny sheets used to decorate bakery and confectionery products (Silva et al., 2022). It is also used in the extraction process of some colorants such as carmine (carminic acid E120), which is obtained naturally from cochineal when it is subjected to a heat treatment and pH 5 in combination with aluminum, citric acid, and calcium salts (Gebhardt et al., 2020). This colorant is commonly used in the production of meat products (smoked fish, crustacean paste, fish paste, pre-cooked crustaceans), dairy products (yogurts, ice creams, fresh flavored cheeses, cured cheeses, edible cheese rinds), among others (candies, sweets, candies, chewing gum, desserts, cakes, pastries, candies, jams, vitamins, pharmaceutical tablets, and medicinal capsules), due to the tonality (purple to red) that it imparts in the product mainly used (Silva et al., 2021). Another colorant extensively used to improve the appearance of soft drinks, dairy products, candies, and confectionery, are anthocyanins (E163) which can be obtained from vegetables and edible fruits, such as blueberries, strawberries, raspberries, blackberries, currants, and grapes. In this colorant can be found aluminum particles product of the extraction of this compound (Gebhardt et al., 2020; Silva et al., 2022). Also, aluminum in the form of aluminum oxide is used to improve the technological properties of titanium dioxide or ”CI white pigment 6", a colorant that is used in confectionery products, decorations, dairy products and analogs, surimi and similar products, salmon substitutes, seasonings, condiments, mustard, sauces, broths, soups, among others (Ropers et al., 2017; Silva et al., 2022).

In general, the use of aluminum-containing additives is gaining increasing significance due to the technological benefits they offer in terms of their visual impact on food. Sometimes these additives enhance the food’s color, making it much more attractive than its natural hue. Additionally, some additives like sodium aluminum silicate, calcium aluminum silicate, and aluminum silicate, serve as anti-caking agents in dry powdered products and generate greater solubility at the time of preparation (FAO/WHO, 2021). Sodium aluminum phosphate is also used to emulsify and improve product quality, melt cheese, thicken juices and sauces, and for pickling vegetables, and is found in fruit confectionery, meat binders, dough reinforcers, stabilizers, buffers, neutralizers, texturizers, and curing agents (Ogimoto et al., 2016). Likewise, the additives aluminum sodium sulfate, aluminum potassium sulfate, and aluminum ammonium sulfate are used to regulate acidity in order to reduce the growth of organisms both in water and in foods, mainly of vegetable origin, resulting in them being used as preservatives. Therefore, these additives function in ways that both appeal to consumers and, at the same time, lead to better results for the industry due to the profitability of these foods on the market. Thus, in some countries, attempts to ban the use of additives which contain aluminum have not been successful, which has led to the regulation of the use of each additive based on the concentration of aluminum it contains. This includes stipulations that products must be labeled with the type of additive used according to the specifications established by the Codex alimentarium

(Ropers et al., 2017; FAO/WHO, 2021).

Adverse effects of aluminum on human health

According to WHO, the tolerable daily intake (TDI) of aluminum for humans should be 1 mg/kg body weight/day (FAO/WHO, 2007). Exposure at these levels is not a problem since the human body can excrete small amounts of this metal very efficiently. Unfortunately, a large part of the population is exposed to and ingests more than their bodies can excrete. As a result, the effects that this metal can produce on tissue function can be significant, starting with the reduction of human brain cell growth, proportional to the amount of concentrated aluminum (Diamond, 2008; Bassioni et al., 2012). The above has spurred a surge in research on the relationship between the accumulation of aluminum in the human body and the risk of multiple neurological pathologies. Some studies, cited in Table 4, were carried out to determine the levels of aluminum present in patients diagnosed with neurological pathologies such as autism spectrum disorder, the precise origins of which are unknown. Mold et al. (2018) performed the first study which examined the aluminum content in the brain tissue of people diagnosed with autism. The results showed a high presence of aluminum in the extracellular and intracellular tissue, suggesting that aluminum may be related to the etiology of this disorder. Likewise, aluminum has been associated with breast cancer due to the accumulation of traces from the use of cosmetic products such as deodorants that may contain aluminum salts. In the cases studied, women and the elderly were found to be the most susceptible to the accumulation of metals in their bodies as a result of the use of some medications, environmental exposure, water intake, and foods with high concentrations of additives such as those mentioned in this study. Therefore, it is important to give consumers the information necessary to make informed decisions about the type of products consumed and the type of utensils used for their preparation. This is especially important for pregnant women, since this metal may from an early age, and research has even established that aluminum may be related to congenital malformations of the central nervous system (Troisi et al., 2019).

Table 4: Research on the relationship between aluminum and human health risks

Also in the studies mentioned in Table 4, AD is one of the most studied pathologies because of the relationship aluminum has with the neurotoxin associated with the disorder. The research indicates that the abnormal aluminum concentrations found in elderly patients, as well as in young patients with AD, can cause an excess of inflammatory activity in the brain, which is a factor that accelerates the rate of brain aging, in turn inevitably increasing the incidence of age-related neurological diseases (Bondy, 2016).

According to Exley (2017), AD is considered an acute response to chronic aluminum intoxication, with aluminum acting as a catalyst in the early onset of the disease because of the way the brain responds to this aluminum load. This metal is accumulated in the body in the frontal cortex and hippocampal regions of the brain, generating neurotoxic activities in the central nervous system which lead to decreased enzymatic activities, increased oxidative stress, and aggregation of proteins such as beta-amyloid (Aβ), all of which contribute to the generation of senile plaques where a series of processes can lead to neurodegeneration and cell death (Kabir et al., 2020).

Research on aluminum from cookware and aluminum foil

One of the sources of aluminum contamination in food is cooking equipment such as pots and pans, among others, which, when subjected to high temperatures (>100 ºC), undergo a leaching process, causing the food to absorb traces of aluminum which are subsequently ingested by the consumer. In 2010, Luján studied the aluminum ingestion that occurs when boiling water and cooking food in pots made with aluminum. The results found that aluminum was present in the water and food (vegetable soup) after 30 minutes of heating at concentrations of 220 µg/L for the water and 400 µg/L for the soup. In another study, Cisneros et al. (2019) found a range between 2.33 and 5.12 mg/kg of aluminum in rice cooked in 6 containers from different brands, which exceeds the limits set out in European regulations of 1 mg/kg.

Another source of contamination by this element is aluminum foil, which is widely used to wrap food for cooking or reheating, either in the oven or using pots or pans. To address this concern, Ertl and Goessler (2018) evaluated the aluminum content in foods that were coated with aluminum foil and baked at 5 min at 180 °C. Notably, the results revealed a 12-fold increase of aluminum in cow (from 0.021 to 0.27 mg/kg), a 5-fold increase in onion (from 0.088 to 0.51 mg/kg), and a 4-fold increase in pork (from 0.055 to 0.28 mg/kg), after the baking process. These findings provide clear evidence of the metal leaching into the food after being subjected to a thermal process. In this same research, it was found that high temperatures are not the only cause of aluminum leaching into foods. After 3 days of refrigeration at 7 ºC, foods such as salmon, ham, lemon, and orange increased their aluminum content 16 times (from 0.13 to 2.2 mg/kg), 32 times (from 0.11 to 3.6 mg/kg), 163 times (from 0.032 to 5.2 mg/kg), and 200 times (from 0.034 to 6.9 mg/kg) respectively.

Likewise, Ejovwokoghenea and Philipa (2020) investigated the risk of aluminum consumption through the ingestion of barbecued catfish that was wrapped in aluminum foil for protection during cooking. These researchers found that the fish went from 0.039 mg/kg (raw) to 0.047 mg/kg after the cooking process, which indicated the rate of leaching of 18.65 % aluminum into the fish. However, consuming this food in small quantities, prepared as described here, does not pose a danger, as the aluminum content remains below the amount allowed by the norms (1 mg/kg).

On the other hand, the presence of aluminum can also be caused by migration from the food packaging. Iscuissati et al. (2021) evaluated the migration of aluminum to coffee prepared by a high-pressure machine with metal seals (Nespresso® Essenza Mini machine). It was found that using the machines to prepare the beverages contributes to increase the aluminum content by approximately 13 % (459 µg/L) compared to a conventional filtration coffee preparation process (408 µg/L). Concerns are also expressed about the reuse of ground coffee, since the increase in aluminum content is approximately 3.5 times higher in this after its preparation, and therefore this recycling strategy should be discarded.

For this reason, Stahl et al. (2018) investigated human exposure to aluminum and food contact materials. The study found regional differences that led to variations in the global consumption of aluminum. For the adult population, the average exposure to this metal was between 0.2 and 1.5 mg/kg body weight/week. On the other hand, children and adolescents, who have a lower body weight, were found to have a higher aluminum concentration (between 0.7 and 2.3 mg/kg body weight/week). These results show values between 14 and 105 mg of aluminum/week for an adult weighing 70 kg while the values for a child weighing 30 kg were 21 to 69 mg aluminum/week. These values indicate that a portion of the human population can consume enough aluminum through their usual diet to reach the tolerable weekly intake.

Between 2015 and 2016, Takanashi et al. (2018) conducted a survey in Japan on the aluminum content in flour-based products and confectionery with baking powder. Aluminum was found in 33.33 % of the evaluated products (corresponding to 41 out of 123 samples), at levels between 0.01 (limit of quantification) and 0.40 mg/g. The presence of this metal in confectionery products was reduced compared to previous studies. However, the presence of aluminum was high in Japanese confectionery and flour-based foods. Consuming one serving of 4 of the 41 samples analyzed would result in an aluminum intake that exceeds the recommended levels for young children, whose average weight was 16 kg.

To study the toxic risk of aluminum intake, Hardisson et al. (2017) collected and compared data on the concentrations of this metal across various types of foods, aiming to estimate the total dietary intake. The most predominant analytical techniques for aluminum determination were inductively coupled plasma atomic mass spectrometry and atomic emission spectroscopy (ICP-OES and ICP-AES). The highest aluminum levels were found in vegetables (16.8 mg/kg), fish and shellfish (11.9 mg/kg), and roots and tubers (9.60 mg/kg). Among the foods that contributed most to the tolerable weekly intake of this metal were fruits (18.2 % for adults and 29.4 % for children) and vegetables (32.5 % for adults and children). As a result, it could be concluded that the dietary intake of aluminum may pose a health risk due to the accumulation of this metal in the brain caused by long-term intake.

Plant extracts to fight Alzheimer’s disease

Considering the need of reducing the effects generated by aluminum on the nervous system, researchers have been driven to explore the potential of the Moringa oleifera plant. Ekong et al. (2017) studied the neuroprotective effects of moringa leaf extract on aluminum-induced temporal cortical degeneration in rats and concluded that it protects against aluminum-induced neurotoxicity of the temporal cortex of rats.

Previous research has confirmed that yerba mate (Ilex paraguariensis) has an antioxidant potential that could help reduce the risk of developing neurodegenerative diseases, such as AD; antioxidants can mitigate the oxidative stress that causes and/or contributes to the development or progression of AD. Bortoli et al. (2018) evaluated the potential of I. paraguariensis in the etiology of AD using Caenorhabditis elegans strains. The study explored the concentration of aluminum and antioxidants in the plant’s leaf extract. It was determined that the metal content impacts the Acetylcholinesterase (AChE) activity. Consequently, acute and chronic exposure to both the element and leaf extract of I. paraguariensis demonstrated notable similarity to wildtype worms. In addition, it was observed that the results in both transgenic strains exposed long-term to leaf extract and aluminum concentrations showed an increase in AChE activity.

Similarly, Elufioye et al. (2019) found that extracts from the leaves of Macrosphyra longistyla have high antioxidant and anticholinesterase activities. According to the results found, extracts from this plant can potentially be used in the treatment of neurodegenerative diseases such as AD. Similarly, Oboh et al. (2021) found that extracts from the leaves of Heinsia crinita and Pterocarpus soyauxii, owing to their anticholinesterase, antioxidant and metal chelating properties, can reduce the presence of aluminum in the body. Researches have shown that the use of extracts from natural sources (mainly plants like the aforementioned) can be an alternative against AD, due to the multiple benefits they offer.