Coffee, Dementia and Cognition: Literature Review 2023

Introduction

Our vision at Purity Coffee® is to improve the world’s health through coffee. As we continue our research on coffee and health, an area of study that is of particular interest to us is Alzheimer’s disease (AD) and dementia. This is a disease that is personal to several of our Purity team members, as we have parents and grandparents whom we’ve lost or are currently suffering from this incurable disease.

In studying the literature on coffee and dementia, it has been a goal of ours to create a specific roast that (we imagine) follows the science of preventing dementia diseases in our families or improving the quality of life of our loved ones. As our families and customers drink this coffee, we hope to collect stories that may point to additional research by our science partners.

In essence, we’ve sought to identify the characteristics of coffee that scientists have found to support brain and cognitive functions. Much research on coffee and dementia also includes coffee’s impact on Parkinson’s disease. We’ve decided to separate the two and address Parkinson’s in the future on its own. For this literature review, we wanted to investigate coffee and dementia, with a focus on Alzheimer’s disease. Worldwide, around 50 million people have dementia, with nearly 10 million new cases a year. Alzheimer's disease is the most common form of dementia and may contribute to 60–70% of cases. What solutions or support might be found in coffee?

Of course, caffeine is one obvious answer, but coffee is much more than just caffeine, especially regarding health. Coffee is a complex blend of compounds, the amounts and combinations of which depend on the coffee's quality. Which of these compounds, other than caffeine, might positively impact brain health? And is there anything about which we should be cautious?

Many studies on coffee consumption are observational, associating disease incidence with multiple factors for which scientists record everything: Lifestyle choices, diet, level of exercise, genetics, geography, environment, culture, etc. Observational studies cover large populations, and for them to be published, they must endure a rigorous scientific peer review process that provides an unbiased, independent, and critical assessment of the research. This creates security both for the scientific community and the public. Any study that is finally published in an academic, peer-reviewed medical journal has been vetted by multiple experts in their own specific fields.

Scrutiny over research about coffee intake is known to be performed with high validity and reproducibility, particularly because coffee intake is a long-term habitual behavior, which makes it less prone to misreporting (Watson, 2017). Unfortunately, very few studies explained what “a cup of coffee” is, or they stated that it ranges in type and brew. Quality is determined by the type of coffee (arabica or robusta), cultivar, handling and processing from farm to country of consumption, how it is roasted (degree of roasting, type of roaster used, etc.), when and how it is ground, and finally how it is brewed. A “cup of coffee” to many Westerners might be about 200 ml (about 6.7 fl. oz.) brewed using about 12–13 grams of coffee, a paper filter, and about 4 minutes of steep time… That’s a little strong for some people, but many studies are from other countries where coffee is stronger and may not be filtered with paper. The effects of preparation techniques on the antioxidant capacity of coffee brews are impactful, as studied by Komes and Belščak-Cvitanović in 2014.

Executive Summary: Alzheimer's Disease and Coffee

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Alzheimer's Statistics

Alzheimer’s is the most common cause of dementia, accounting for an estimated 60% to 80% of cases. An estimated 6.7 million Americans live with AD, with about 1 in 9 people (10.8%) age 65 and older having AD. Symptoms often progress in this order: Difficulty remembering recent conversations, names, or events; apathy and depression; communication problems, confusion, poor judgment, and behavioral changes; and difficulty walking, speaking, and swallowing (ALZ.org, 2023) Caring for a person with Alzheimer’s or dementia often involves a team of people, and over 11 million Americans provide unpaid care for a family member or friend with dementia, valued nationally to reach nearly $340 billion.

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Coffee and AD

According to a growing number of studies, coffee may have some benefits for preventing or delaying Alzheimer's disease. A vast amount of research exists specifically on caffeine and Alzheimer's and dementia, which we cannot ignore, but we want to emphasize (again) that coffee is a complex food product with hundreds of compounds, of which caffeine is only one. Overwhelmingly, coffee intake was associated with a decreased risk of cognitive disorders, but more specifically regarding disease prevention.

The keys to coffee’s preventive effects lie in its antioxidant and anti-inflammatory properties and compounds. Oxidative stress and inflammation are the hallmarks of dementia and play a role in cognitive decline with age because of numerous mechanisms, such as epigenetic alterations and genomic instability, that affect intracellular functions and intercellular communication. Also, growing evidence suggests an influence of microbial-derived metabolites on neurological function, highlighting the role of gut microbiota in cognition—the enteric nervous system. Another related issue is recent research on the relationship between sugar intake, insulin, and Alzheimer’s, with some researchers now calling AD “Type 3 Diabetes”. In coffee, chlorogenic acid and other polyphenols (like ferulic acid), diterpenes (cafestol and kahweol), and trigonelline are the primary coffee compounds with anti-diabetic potential.

Once Alzheimer's has taken hold, caffeinated coffee is only recommended to be consumed carefully, noting how the person feels afterward. Since coffee can cause anxiety and sleeplessness in some people, this can compound the effect on those suffering from AD who do not react well to caffeine. Caffeine can amplify typical behavioral changes in people with AD, such as feelings of anxiety, worry, or general agitation. Instead, naturally decaffeinated coffee, such as Swiss Water Process®, would be a better choice.

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Decaf and AD

The benefits of coffee for the brain can be found in decaffeinated coffee, too. Current evidence shows that decaffeinated coffee could be effective against neurodegeneration acting in different neurological pathways and disorders. Non-caffeine compounds in decaffeinated coffee have been shown to play an important role in the prevention and modulation of neurological disorders. Phenolic acids, such as chlorogenic and caffeic acids, exhibit many positive neurological effects. Also, ferulic acid could be considered a promising compound, acting mainly not only as an antioxidant, anti-inflammatory, and neurotrophic agent but also as protection against amyloid toxicity. In addition, many recent studies on quercetin show its great potential both for its antioxidant and anti-inflammatory properties and for its effect against amyloid beta aggregation and toxicity of tau hyperphosphorylation (considered to be the major trigger that causes abnormal tau that is toxic to neurons and leads to dementia) (Colombo and Papetti 2019).

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Conclusion

We need to encourage companies to source, test, and produce coffees that bring out the most antioxidants and have the least amount of contaminants, like heavy metals and mycotoxins. This is important in coffee to support the preventive qualities that coffee has against dementia and AD because contaminants can impact both the brain and the enteric nervous system (the gut), all of which are important for neurological health. When we pay more attention to something we do every day (and multiple times), the easiest choice we can make to make the biggest impact is to drink coffee proven to meet the highest health, nutritional, and food safety standards.

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Dementia, Alzheimer's Disease (AD) and Coffee

Dementia and Alzheimer's Disease Background

Dementia is a syndrome in which cognitive function deteriorates, and it is usually chronic and progressive. It is found worldwide and is one of the major causes of disability and loss of independence among older people. Not only is it debilitating and overwhelming for the people who have it, but also for family, friends and caregivers, impacting everyone involved in physical, psychological, social, and financial ways. In some countries, those with dementia may even risk losing their basic human rights. There is no treatment currently available to cure dementia or to alter its progression, although new treatments are continually being investigated.

As most studies show regarding good health, people can reduce their risk of dementia by exercising regularly, not smoking, avoiding the damaging use of alcohol, and maintaining a healthy weight, blood pressure, cholesterol and blood sugar levels. Of course, this leads us to focus on how coffee might be a healthy option in the anti-dementia arsenal.

Genetic and experimental evidence shows key causes of AD are the accumulation of plaque deposits of the peptide β-amyloid (Aβ) in the brain and the tangles of the microtubule-binding protein tau. Aβ peptides are generated from the cleavage of amyloid precursor protein (APP) by the enzymes β-secretase (BASE1) and γ-secretase. These two enzymes are key to AD development and will play a part in coffee discussions later in this paper.

Preventing secretase production is a logical strategy to inhibit Aβ, although clinical trials in 2018 of secretase inhibitors were unsuccessful at stopping the cognitive decline in patients with mild-to-moderate AD (and inhibiting γ-secretase had several side effects). However, in 2009 Arendash et al. reported that caffeine protected AD mice against cognitive impairment and reduced Aβ production by reducing β- and γ -secretase activities, showing that coffee consumption could be a preventive intervention before the appearance of AD symptoms.

Several epidemiological and preclinical studies supported the protective effect of coffee on Alzheimer's disease (AD) (please see citations at the end of this paper).

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Caffeine (Just one of MANY bioactive compounds in coffee)

Caffeine & Adenosine: A Complex Story

Caffeine is an alkaloid found in the leaves, seeds, and fruits of coffee, cocoa, cola, guarana and tea plants. Within 10 minutes of drinking coffee, the stomach and first part of the intestine absorb the caffeine, reaching maximum concentration in the bloodstream within about an hour. Caffeine has quite a checkered reputation in the world of human consumption and health, causing debate and even emotional responses. This literature review intends to look specifically at what science has discovered about caffeine concerning brain functions, cognition, memory and related diseases.

It is undeniable that many people drink coffee for the effect of caffeine on their alertness. Caffeine is an antagonist of adenosine receptors (it blocks the receptors) in humans, most known for inhibiting neural activity and causing drowsiness. This is just one result of the interaction of caffeine with adenosine, which leads to increased activity of the neurotransmitters dopamine and glutamate (see glossary, p. 3). The story of caffeine, adenosine, and the brain is complex and involves several effects, actions, and counter-effects.

Adenosine is present in all cells, and performs numerous actions in the body, among them: (1) Adenosine plays a role in inflammatory response. It is released to reduce inflammation and prevent tissue damage (Chakraborti 2003). (2) Adenosine receptors are key in opening the blood-brain barrier (BBB), which increases the transport of amyloid plaque antibodies and prodrugs associated with AD. Since inflammation is an essential part of the AD pathogenic pathway and AD includes increased oxidative stress, it is possible that the anti-inflammatory and antioxidant actions of coffee contribute to its pro-cognitive effects.

Administration of adenosine receptor agonists (mainly A1) disrupts learning and memory in rodents, while nonselective adenosine receptor blockade by caffeine/theophylline or selective blockade of A1 and A2A receptors improves the performance of rodents in different behavioral tasks. Caffeine helps support antioxidant activity, and its catabolic products theobromine and xanthine also exhibit antioxidant properties (Azam 2003).

Also, at high doses, caffeine inhibits cAMP (see Glossary page 3), yet a low dose of caffeine regulates cAMP levels through antagonism of the A2A receptor. In certain parts of the body caffeine modulates intracellular levels of cyclic adenosine monophosphate (cAMP), which regulates immune cell functions, plays an important role in metabolism, and promotes the release of insulin from pancreatic beta cells. Upregulation of cAMP inhibits the activation of inflammatory effector cells, such as T cells. In T cells, cAMP downregulates various cellular functions, including cytokine production and cytotoxicity (Setkovsky 1988). In short, the lower doses of caffeine were proinflammatory, which would be difficult to deduce from the observational/epidemiological studies. This is one reason that scientists believe it is the caffeine in conjunction with other compounds in coffee (chlorogenic acid, caffeic acid, ferulic acid, etc.), diterpenes (cafestol, kahweol), and trigonelline, which may exert protective effects (Farah et. al. 2019).

With receptors distributed in all brain cells, any imbalance of such a widespread system is expected to lead to neurological dysfunctions/diseases (Ribero 2010), which means that caffeine, like adenosine, can potentially exert effects on all brain areas. Whenever a person’s internally produced adenosine levels are continuously activating receptors with low neurotransmitter levels, caffeine is shown to do the opposite of adenosine receptor activation. This means caffeine can affect brain activities such as sleep, reasoning, learning, and memory, and modify brain dysfunctions and diseases: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, epilepsy, pain/migraine, depression, and others (Ribero 2010; Zeitlin et. al 2011).

The seemingly paradoxical use of both adenosine receptor agonists and antagonists as neuroprotective agents has been attributed to differences in dosage levels (Rivera-Oliver and Díaz-Rios 2014). There have been hundreds of studies on caffeine and cognitive disorders. In a 2015 meta-analysis, out of 293 articles identified through the search and bibliographies of relevant articles, 20 epidemiological studies from 19 articles, which involved 1,479 participants (8,398 in six cross-sectional studies, 4,601 in five case-control studies, and 19,918 in nine cohort studies), were included in the final analysis: Researchers noted specifically about coffee (not just caffeine) that "Coffee intake was associated with a decreased risk of cognitive disorders in the meta-analysis of all the observational studies, including cross-sectional, case-control, and cohort studies." (Kim et al. 2015).

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Final words on Caffeine … we get it.

In a 2016 study (n = 6,467), caffeine intake was associated with a lower risk of incident dementia and cognitive decline in women over the age of 65 (Driscoll et al. 2016). In a 2016 meta-analysis of 29,155 participants enrolled in 11 prospective studies, no association was found between caffeine intake and dementia or cognitive decline, but high caffeine intake was significantly associated with a decreased risk of incident AD (Liu et al. 2016). In a 2017 meta-analysis of 34,282 individuals enrolled in 9 prospective cohort studies, a J-shaped association was found whereby 1–2 cups of coffee daily intake was associated with a lower risk of cognitive disorders, but the association for 3 cups of coffee or more was not significant (Wu et al. 2017). However, a 2018 dose-response meta-analysis of 8 prospective studies found no significant association between caffeine dosage and the risk of AD or dementia (Larsson and Orsini 2018). Nevertheless, a 2019 study found that, compared to drinking less than two cups of coffee daily, lifetime drinking two or more cups of coffee a day was significantly associated with reduced Aβ plaque burden in 411 cognitively intact older adults (Kim et al. 2019). Putting together all these meta-studies, the overall conclusion is that caffeine intake may be associated with a decreased risk of dementia, cognitive decline, and/or AD.

In AD mouse models, caffeine significantly decreases senile plaques and amyloid beta (Aβ) levels while also protecting against or reversing cognitive impairment. In 2009, Arendash et al. demonstrated that Alzheimer's disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) were protected from the development of certain cognitive impairments and had decreased hippocampal amyloid-β (Aβ) levels due to suppression of both β-secretase and γ-secretase expression. Similarly, in 2009, Cao et al. showed that long-term oral caffeine treatment of aged AD mice provided not only sustained reductions in plasma Aβ but also decreased soluble and deposited Aβ in the hippocampus and cortex.

Breakdown of the blood-brain barrier has been reported in AD and appears to precede Aβ plaque formation in mice, however, caffeine was shown to block disruptions in the blood-brain barrier induced by a high-cholesterol diet in rabbits. Researchers concluded that blood-brain barrier stabilization by caffeine could be a viable mechanism for consideration. A final word on caffeine: The therapeutic benefits of coffee are not due to caffeine alone. One study showed that improvements in cognition and psychomotor behaviors in aged rats were due to coffee, and not caffeine itself. In line with these observations, crude caffeine – a by-product of the coffee decaffeination process – was observed in another study to have a greater therapeutic effect on memory impairment in AD mouse model than pure caffeine (Chu et al. 2012). Specifically, the study reported that administration of crude caffeine, but not pure caffeine, reduced amyloid burden, improved antioxidant activity, and enhanced glucose uptake in AD mouse model.

This glucose connection is important: Researchers have been studying the link between Type 2 diabetes and AD, with large longitudinal studies showing that adults with Type 2 diabetes have a higher risk of developing Alzheimer's. More on this in a bit.

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Mechanisms of Coffee’s Impact on the Brain

Coffee & Amyloid Beta Levels (Aβ)

The literature is abundantly clear that caffeine intake has been associated with a lower incidence of Alzheimer's disease (AD) in humans, but let’s move on to coffee’s other components.

It remains controversial whether a single ingredient in coffee is effective against Aβ pathology or whether a combination of ingredients is effective. In 2019, Kim et al. set out to determine whether coffee is specifically related to reduced brain AD pathologies in humans. They investigated relationships between coffee intake and in vivo AD pathologies, including cerebral beta-amyloid (Aβ) deposition, the neurodegeneration of AD signature regions, and cerebral white matter hyperintensities (WMH). A total of 411 non-demented older adults with various coffee consumption levels underwent comprehensive clinical assessment and multimodal neuroimaging. Lifetime coffee intake of ≥2 cups/day was significantly associated with a lower Aβ positivity than coffee intake of <2 cups/day, even after controlling for potential confounders. In contrast, neither lifetime nor current coffee intake was related to hypometabolism, atrophy of the AD-signature region, or WMH volume. The findings suggest that higher lifetime coffee intake may contribute to lowering the risk of AD or related cognitive decline by reducing pathological cerebral amyloid deposition.

From Kim et al: The present finding of the relationship between higher coffee intake and a decreased rate of pathological Aβ deposition is in line with results from previous studies using animal models, which indicated that higher caffeine, one of the major ingredients of coffee, intake exerts a protective effect via molecular Aβ-related mechanisms16–18,37,38. For example, Arendash et al.18 suggested that caffeine protects AD mice against cognitive impairment and reduces brain Aβ production by deactivating the positive-feedback loop from the γ- to β-secretase cleavages on the Aβ protein precursor. The same group also reported that high caffeine intake improves the cognitive performance of aged AD mice, but not of wild-type mice, with reduced brain Aβ levels, suggesting that a decrease in Aβ concentration mediates the cognitive enhancing effect of caffeine in AD mice (Arendash 2009).

Additionally, in 2009, Cao et al. reported that caffeine suppresses Aβ levels in the plasma and brain of AD mice and also suggested that caffeine and other components in coffee may synergize to protect against cognitive decline in AD mice. Moreover, Li et al. indicated that caffeine suppresses Aβ protein precursor internalization and Aβ generation via adenosine A3 receptor-mediated actions. The present finding also provides a neuropathological explanation for the relationship between higher coffee intake and reduced risk of AD dementia observed in several clinical and epidemiological studies. Those studies reported higher coffee drinkers had a 31–65% decrease in the risk of AD dementia, which is quite comparable to about 65% decrease of Aβ positivity rate in higher coffee drinkers (27.14%) compared to lower coffee drinkers (17.61%). Furthermore, the relationship between higher coffee intake and lower Aβ positivity was more prominent for lifetime coffee intake than for current coffee intake. This suggests that the protective effects of higher coffee intake against Aβ pathology involve the chronic effects associated with prolonged exposure rather than an acute or short-term effect.

It remains controversial whether a single ingredient in coffee is effective against Aβ pathology or whether a combination of ingredients is effective. Published in 2021, data from the 10½ year Australian Imaging, Biomarkers, and Lifestyle Study support the idea that habitual coffee intake may be a protective factor against AD, and evidence suggests the observed benefits are not due to caffeine alone. Increased coffee consumption could contribute to slower cognitive decline potentially by slowing the rate of cerebral Aβ-amyloid accumulation, ameliorating the associated neurotoxicity from Aβ-amyloid-mediated oxidative stress and inflammatory processes. Overall, coffee intake could be incorporated as a modifiable lifestyle factor to delay the onset of AD.

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Chlorogenic Acid (CGA)

Chlorogenic acids (CGA) are a group of phenolic compounds produced by certain plants and are a major component of coffee. CGA has various biological effects, such as antioxidant, anti-inflammatory, anti-cancer and anti-diabetic activities. They may also protect your eyesight by preventing the development of diabetic cataracts. CGA is metabolized in your body into quinic acid and caffeic acid, which may have further health benefits.

Coffee’s high concentration of CGA is why coffee is considered one of the most important contributors to antioxidant intake in many countries since people drink it daily and often multiple times. There is an abundance of literature on coffee's CGA and its antioxidant activity. CGA plays one of the most important roles in coffee’s positive impact on brain health. Maintaining homeostasis and health happens through the uptake of various antioxidants from food, and many plants we eat produce antioxidant polyphenols. The beneficial effects of coffee may be attributed in part to polyphenols and caffeine serving as antioxidants (Farah 2019 V.1, Ch. 9), and the polyphenols in black coffee (without milk products) are readily bioavailable, which is not the case with all foods.

While the mechanism by which CGA impacts the brain isn’t completely understood, “About ⅓ of consumed chlorogenic acids are absorbed in the small intestine, and about ⅔ of consumed chlorogenic acids are absorbed in the large intestine” (Socala 2020). Those that are absorbed in the large intestine will be metabolized by the gut microbiota. Much more is left to learn about how this could impact our microbiota and how this plays an underlying role in the cognitive benefits of CGA based on the connection between our enteric nervous system and the central nervous system.

It is important to mention, though, that the roasting process has a major impact on CGA: The darker the coffee is roasted, the more some of the original nine CGA break down to form CGA lactones (CGL) or quinides during the roasting process. The CGA content can vary among coffees due to general plant nutrition, growing conditions, cultivar, processing, and roasting (Jung et al. 2017). For example, CGA concentrations are higher in light roasts and in the robusta species. This becomes important to note as the CGA concentration may influence a coffee’s ability to impact cognitive processes, as higher cognitive scores have been associated with drinking robusta varieties, though not significantly (Alharbi et al. 2018). Lighter roasted coffees are higher in chlorogenic acids, but also higher in acrylamide, so a balanced approach of a light-medium roast is needed for optimum health-roasted coffee.

It is important to note that CGA in supplement form hasn’t shown the same beneficial impact as when consumed naturally with coffee or decaf. Scientists seek to learn more about why, with the thousands of other compounds in coffee, there is a synergistic effect between other coffee compounds and CGA leading to this mental benefit and unique effect requiring coffee as the source.

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Polyphenols [Chlorogenic Acid (CGA) Ferulic Acid] and Types 2 & 3 Diabetes

Emerging evidence highlights that hyperglycemia and brain insulin resistance represent risk factors for AD development, thus suggesting an additional AD mode, associated with glucose metabolism impairment. Some researchers now refer to this as Type 3 diabetes to highlight insulin resistance and insulin-like growth factor dysfunction in the brain as a possible cause of Alzheimer's disease because they may impair the function and survival of neurons and lead to inflammation and oxidative stress. High blood sugar levels may damage the blood vessels in the brain and reduce blood flow, which may affect cognitive function and increase the risk of strokes.

Also, research suggests a connection between Type 2 diabetes and the production or accumulation of amyloid beta and tau proteins. The prevention of both types 2 and 3 diabetes involves reducing the risk factors for diabetes and applying them to Alzheimer's disease, such as maintaining a healthy weight, limiting alcohol intake, managing cholesterol levels, eating a balanced diet rich in antioxidants and omega-3 fatty acids, and limiting sugar intake. Coffee can help support the reduction of all these risk factors with some of its many compounds.

Specifically, CGA in coffee stimulates the production of glucagon-like peptide 1 (GLP-1). The average coffee drinker may ingest between 500-1000 mg of CGA per day (McCarty 2005). Both human and animal studies suggest GLP-1 protects against diabetes by enhancing beta-cell responsiveness to hyperglycemia. (McCarty 2005, Nieber 2017).

Another risk factor for diabetes is the accumulation of misfolded proinsulin or amylin molecules in the beta cells. Coffee polyphenols, including 5-O-caffeoylquinic acid, pyrocatechol, and melanoidins, may help preserve beta-cell function by disrupting this process (Kolb 2021). Additionally, chlorogenic acid and caffeic acid may counteract some of the damaging effects of a high-fat diet on pancreatic beta cells. In one study, mice fed a high-fat diet experienced reduced body weight and visceral fat when placed on chlorogenic acid supplements (Lee 2019).

Ferulic acid is another notable coffee compound. It is a hydroxycinnamic acid derivative widely distributed in nature, especially in fruits, and known to be endowed with antioxidant, anti-inflammatory and antidiabetic, thus suggesting it could be exploited as a possible neuroprotective strategy. Some studies have shown that ferulic acid can affect glucose metabolism, exhibiting antidiabetic effects in vitro and in vivo models. Ferulic acid forms a substance that scavenges free radicals and reduces oxidative stress. It improves glucose and lipid profiles in diabetic rats by enhancing the activities of antioxidant enzymes, superoxide dismutase and catalase in the pancreatic tissue and improving the uptake of certain diabetic medications (Nankar 2017).

Phenylindanes are coffee compounds formed from hydroxylated cinnamates such as caffeic acid during roasting, and higher concentrations are found in dark roast coffees (Mancini et al.2018). These bitter-tasting compounds have been shown to have strong antioxidant activity. Phenylindanes in coffee were shown to inhibit Aβ and tau aggregation and support neuroprotection in AD pathologies for individuals who consumed coffee (Mancini et al. 2018). Phenylindanes are unique in that they are the only compound investigated in the study that prevents -- or rather, inhibits—both beta-amyloid and tau, two protein fragments common in Alzheimer's and Parkinson's, from clumping (University Health Network 2018).

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Coffee’s Metal Chelating Properties

Exposures to lead, cadmium, and manganese are ubiquitous in our environments and stored in cells around the body. Lead was commonly used in commercial products in the last century, and was only banned in the 1970s. Similarly, cadmium is also found throughout the environment, particularly in cigarette smoke, certain foods (shellfish, grains or plants that may absorb cadmium from soil and water, where it is prevalent. Cadmium’s long half-life in the kidney, as does manganese, which has a similarly long half-life in tissues and especially accumulates in the brain. Older adults carry historic exposure to these metals, and lead, cadmium, and manganese are well-documented neurotoxicants acting through multiple pathways to contribute to AD pathology.

These metals induce oxidative stress, neuroinflammation, and apoptosis (programmed cell death) in neurons. In addition, animal models treated with these metals observe AD-related pathological features in the brain (Aβ and tau tangles). Human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline in adults (Bakulski et al. 2020).

In addition to the organic bases and phenolic compounds (CGA and caffeoyl tryptophan), melanoidins and phenylindanes produce antioxidant activity in coffee. More than 300 heterocyclic compounds (which include many biochemicals essential to the metabolism of all living things) are also found in brewed coffee. These include pyrroles, furans, thiophenes, pyrazines and thiazoles, which exert antioxidant activity, are chelating agents (remove toxic metals from the body), and modulate the activity of several enzyme systems, which protect the body against chemical and physical stressors (Muriel 2012).

Melanoidins, in particular, have been shown to have metal-chelating activity for various metals, such as iron, copper, zinc, calcium, and aluminum. In addition, CGA and two compounds derived from CGA during roasting (p-Coumaroyl-(L)-tryptophan and quinic acid), which can be present in high concentrations in coffee beans, have been suggested to have metal-chelating properties for iron and aluminum. By modulating the bioavailability or toxicity of metals in the body, coffee has shown another way to have AD prevention potential.

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Decaffeinated Coffee

Decaf coffee still contains significant amounts of CGA and many of the other compounds noted in this review. High-CGA decaf coffee is associated with improved mood and attention processes compared to regular-CGA decaf coffee, supporting a dose-response relationship that is not dependent on caffeine (Cropley 2012). In another 2012 study, researchers found that decaffeinated coffee may improve glucose utilization in the brain, reducing the risk for Type 2 diabetes and the brain dysfunction associated with some neurological and neurocognitive disorders. "Impaired energy metabolism in the brain is known to be tightly correlated with cognitive decline during aging and in subjects at high risk for developing neurodegenerative disorders. This is the first evidence showing the potential benefits of decaffeinated coffee preparations for both preventing and treating cognitive decline caused by type 2 diabetes, aging, and/or neurodegenerative disorders" (Mount Sinai 2012).

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Summary

In summary, the overall trend emerging from the literature review of the past 30 years suggests that regular coffee consumption can be a protective factor against the evolution of Alzheimer’s Disease and other dementias. An abundance of research on caffeine, and particularly coffee, has shown it prevents the accumulation of beta-amyloid, a protein that forms plaques in the brain and is commonly associated with Alzheimer's. Other research has shown that coffee …

• Reduces the risk of developing diabetes, which is a risk factor for Alzheimer's. Caffeine, chlorogenic acid and ferulic acid can improve insulin sensitivity and glucose metabolism, lowering blood sugar levels.
• Enhances cognitive function and memory by stimulating the central nervous system and increasing the levels of neurotransmitters such as dopamine, acetylcholine, and norepinephrine.
• Has an antioxidant effect, which can protect the brain cells from oxidative stress and inflammation that can damage the neurons and impair cognition. Coffee also contains phenylindanes, compounds that are produced during the roasting process and have a neuroprotective effect. Phenylindanes can inhibit the clumping of both beta-amyloid and tau, another protein that forms tangles in the brain and is linked to Alzheimer's.

However, it is important to note that these findings are just the beginning of our understanding of the complexity of coffee and its impact on human health. For coffee drinkers, choosing a healthy coffee is one of the most powerful choices you can make for your health.