The topic of this extended essay deals with the degree to which it is possible to establish whether the phenolic compound oleocanthal in extra-virgin olive oil, a dominant ingredient of the Mediterranean diet, affects the decline of cognitive function and thus diminishes the risk of developing -or slows down the degradation of- Alzheimer's disease.
Before being able to delve into the affect of oleocanthal on Alzheimer's it is necessary to identify the cause of this neurological disease. Hence I will determine the way in which this phenol averts this cause, thus protecting neurons in the brain from being damaged. The role of oleocanthal as an anti-inflammatory may be the explanation for its beneficial effects in the brain. I attempt to show that it is the presence of oleocanthal in extra-virgin olive oil which distinguished it from other oils and qualities of olive oil. Additionally I shall highlight the difficulties which arise from research studies of this nature, but also shed light on research which has successfully demonstrated the cognition enhancing effect of oleocanthal. I will undertake an investigation concerning the possible correlation between extra- virgin olive oil consumption and the number of full health years lost due to Alzheimer's in different countries around the world.
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Through the subsequent evaluation of research of this nature, I conclude that it is extremely difficult to demonstrate the affect of oleocanthal on Alzheimer's disease with complete certainty. The main challenges that arose were the multi-factorial nature of this neurodegenerative disease; the different criteria of diagnosis, as well as various other evaluative points. Finally, it has become evident to me that supplementary evidence is required, if we are to ever be able to demonstrate the effect of oleocanthal on Alzheimer's with certainty.
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Alzheimer's, a neurological disease, has been the centre of interest within the medical and other scientific societies, due to its cumulative nature. While it was hardly heard of in the 1960's, it rapidly became recognized as the "disease of the century" by Newsweek magazine in the 1980's.  Today, research into one of the world's most menacing public health threats is still increasing exponentially. 
The findings of research done on the dietary implications of Alzheimer's disease, strike me most. Anti-oxidants, such as vitamins C and D  may be responsible for a positive effect on the brain, although further evidence is required in order to be certain of the function of these supplements. Also, numerous studies have been conducted with the aim of establishing a relationship between lipid composition in one's diet and the reduced risk of cognitive impairment. I have narrowed my topic of investigation down to oils in the diet, as they are so culture and location specific, yet consumed by generally everyone. Next, the increasing consumption of olive oil around the world  intrigued me to examine the underlying reason for this augmentation and to explore which constituent of extra-virgin olive oil has an effect, if at all, on the brain of Alzheimer's patients. This led me to further investigate the role that extra-virgin olive oil might play in the decreased deterioration of neurons.
I shall attempt to indicate a correlation between extra-virgin olive oil intake and the occurrence of Alzheimer's disease in human populations. However, the multi-factorial nature of this disease invites me to critically examine the research studies I intend to use, and to demonstrate the problems with research of this kind. I aim to incorporate research studies which have gained reliability throughout the scientific community and those which have attempted to control as many variables as possible in order to increase the validity of their results. In addition to the vast amount of factors which may contribute to the development of Alzheimer's and the difficulty to control all these variables, there are differing criteria for diagnosing Alzheimer's around the world, making it problematic to compare the prevalence of the disease in different countries. Furthermore, another problem we face is that no one exactly knows the cause of this illness and therefore we might overlook something that may be crucial to the rise of this disease. Therefore, I predict, that to prove the effect of a dietary component on such a disease is extremely challenging. All research findings need to be carefully evaluated, even if the study is conducted by professionals in the field.
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Taking all the above mentioned reasons for the development of my topic into consideration, I finally derived at the following research question: To what extent is it possible to demonstrate that the phenol oleocanthal in extra-virgin olive oil affects the decline of cognitive function and thus reduces the risk of developing Alzheimer's disease?
2.0 Neurons in the brain
It is essential to know how the brain works and is constructed in order to understand the changes which occur in the brain of an Alzheimer's patient. In addition, this knowledge is crucial when determining which compounds may slow down cognitive decline. The brain is unquestionably the most exigent organ in the body, carrying out the complex tasks of our senses, as well as movement, control of body physiology, eating habits, sleeping patterns, memory and many more challenging tasks.  Its complex organisation includes 100 billion  nerve cells known as neurons, which all interact with each other chemically. This is achieved by neurotransmitter molecules moving across the synaptic cleft from the pre-synaptic membrane of one neuron to the postsynaptic membrane of another.  One specific neurotransmitter is received at the postsynaptic membrane by the corresponding receptor molecule.  There are thousands of these synapses forming connections between neurons in our brains. New linkages are formed everyday of our lives, even while sleeping; however, they can also be lost or disrupted- resulting in brain disorders such as Alzheimer's.  This changing nature of the brain, as we are exposed to innovative experiences and information, is extraordinary.
During the gestation period prior to birth, genes control the formation of the basic organisation of the brain. It is then further developed, shaped and altered throughout childhood and remains to do so during the later stages of life.  Nearly every gene in the human genome, during gestation, is used for brain construction.  The brain provides us with the ability to learn, store and recall data. Due to aging, the architecture of brain can break down. Changes in the brain come less readily due to loss of synapses and changes in brain chemistry. 
3.0 Delving into Alzheimer's disease: Areas affected and brief background
Alzheimer's disease is a neurodegenerative form of dementia meaning that it affects the nervous system by the destruction of nerve cells.  As a result, neurons are no longer capable of communicating effectively with each other, meaning that they aren't able to send and receive information both chemically and electronically.  Secondly, their metabolism starts to falter: the neurons stop synthesizing their own energy for the formation of proteins and other compounds useful to the cell.  Lastly, nerve cells experience difficulties with excretion and cease to function how they are meant to.  This syndrome is also associated with the shrinking and loss of function of the muscle and brain cells in the hippocampus, an area of the brain which is responsible for learning, short-term and long-term memory.  Another area of the brain dominantly affected by atrophy is the limbic system which controls one's emotions  and damage to the frontal lobe leads to a lack of reticence  . An Alzheimer patient suffers from loss of logical thinking, memory and their personality becomes noticeably altered. 
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German physician, Dr. Alois Alzheimer (1864-1915) first diagnosed this multi-factorial syndrome while carrying out an autopsy of the brain on a deceased 51 year old patient in 1907.  He discovered some atypical features, including: deposits of "amyloid plaques" in the cerebral cortex - the outer layer of the cerebrum (which itself was noticeably thinner than normal) - and many more "neurofibrillary tangles" than in a normally ageing human being.  It has been found that the severity of this form of dementia is positively correlated with the number of plaques  .
4.0 Extra-virgin olive oil in the Mediterranean diet
The Mediterranean diet is known to exemplify a limited consumption of dairy products and meat, a high intake of vegetables, fruits, cereals and fish in addition to the usage of considerable quantities of unsaturated fatty acids present in extra-virgin olive oil.  Numerous empirical studies have been conducted concerning the effects which most of the above ingredients have on cognitive decline and dementia. However, the usefulness of various constituents of olive oil has only recently been investigated more abundantly.  The purpose of my next step of research is to focus on the affect which extra-virgin olive oil (the least processed form of olive oil  ) has on this most prevailing form of dementia (60 %).  The concentration of the compound Oleocanthal in the oil is significantly dependant on the ripeness of the olives being harvested. The concentration is at its peak just before the fruit starts to ripen, which is when its abundance commences to diminish. 
It seems that "particular compounds present in extra-virgin olive oil might protect against Alzheimer's disease", stated Jean-Michel Gibert, from the Biology Faculty of the University of Geneva.  Various research studies agree that a specific phenolic compound epitomizes anti-inflammatory and thus, cognition enhancing effects.
4.1 Amyloid plaques
During the development of Alzheimer's, amyloid plaques are said to activate the brain's immune cells (microglia) resulting in the production of more amyloid plaques  which are deposited in the brain and cumulate on the surface of neurons, forming clusters amongst them.  This cycle is believed to pursue, explaining the increase of amyloid plaques  over time and hence, brain deterioration. On the other hand, some researchers have found inflammation to be the body's way of trying to eliminate these threatening plaques. 
Amyloid plaques consist of beta-amyloid proteins which are initially part of the larger amyloid precursor protein, before being broken down by the enzyme secretase.  These plaques are most abundantly found in the areas of the brain discussed previously. The reason why these amyloid precursor proteins appear in the first place is still unknown, however it is thought that they play a role in the growth and survival of neurons. 
Another concern is whether beta-amyloid plaques really do contribute to the cause of Alzheimer's, or are merely a by-product of the disease.  Taking that they do act as harmful neurotoxins, "stimulation of the immune system"  or "inhibition of secretase"  may have potential for Alzheimer's disease therapeutics. However, in July 2009, researchers of the University of California suggested that Alzheimer's is caused due to the immune system mistaking the identity of these amyloid fibrils for structures synthesized by a certain bacteria in the gut.  The bacteria E. coli and salmonella were introduced into the immune system of mice, resulting in the generation of "curli fibrils": "fiber-like structures consisting of curli proteins that allow bacteria to stick to host tissue and to each other, forming colonies."  Baumler enlightens that the morphological similarities of these two proteins cause the immune system to respond in the same manner when introduced to the cells in our body.  This might explain the reason for the inflammation response associated with beta-amyloid proteins in Alzheimer's disease. It is suspected that a certain phenol in extra-virgin olive oil is responsible for ameliorating and reducing inflammation in the brain, which I will now explore further.
4.2 Oleocanthal's anti-inflammatory properties
The aim of the "Three City Study" -published October 30, 2009- was to examine the relationship between olive oil consumption and cognitive decline in a large elderly population.  6,947 participants completed a questionnaire concerning their diet and underwent several cognitive tests.  Through the use of questionnaires, 22.7% of the subjects were found to use no olive oil in their diet; 39.9% used it for either dressing or cooking, which was considered a moderate dosage; and a large intake -corresponding to 37.4% of the participants- corresponded to using olive oil for both dressing as well as cooking.  The researchers of this study made sure to take into account numerous variables which may have had effects on their results. These included: "socio-economic factors, health behaviours, health measures and other dietary intakes."  Those who never used olive oil showed more severe cases of cognitive impairment when it came to visual recall tests and verbal fluency.  In the 4-year follow-up of this study, it was found that abundant use resulted solely in elevated visual memory abilities. 
These data offer merely an indication of the significance of olive oil consumption even though the researchers have attempted to control several variables including: age, sex, BMI (body mass index) and educational level of the participants; as well as their financial and marital status; in addition to their location, whether or not they smoke, have cardiovascular disease, diabetes or hypercholesterolemia; show signs of hypertension or depression.  Indeed, populations consuming olive oil may differ by many other factors from other populations, for example by: genetic background, quality and quantity of other food components in their diet, temperature of their surroundings, daily sunlight and more factors which were not all accounted for. Thus, the inversely proportional correlation indicated by the "Three City Study" needs to be looked at critically. Questionnaires are prone to participant bias, which leads us to question the validity of the methodology used. In addition, it is perilous to claim that the single phenol in the oil is responsible for the amelioration of this disease, especially because it is only present in such minute concentrations.  Further evidence is required in order to be able to establish an answer to the effects of this abundant fat supplement in Mediterranean diet on the reduced risk of developing Alzheimer's disease.
Paul Breslin and his team at the 'Monell Chemical Senses Center' in Philadelphia, discovered that Ibuprofen has the same stinging effect at the back of the throat as the compound oleocanthal, found in olive oil.  As a result, it has been discovered that it has a similar pharmacological response to the anti-inflammatory drug ibuprofen, regardless of their different molecular structures. Their similarity lies in the fact that they both act as cyclooxygenase enzymes (Cox-1 and Cox-2) inhibitors.  These biological catalysts play a role in the prostaglandin biosynthesis pathway, which leads to inflammation.  The side effect of cyclooxygenase inhibitors is that when taken in high doses they are prone to cause damage to the mucus lining in our stomachs, possibly resulting in ulcers and intestinal bleeding.  A study was carried out to support that oleocanthal is the ingredient in extra-virgin olive oil which is responsible for this stinging sensation. The phenol was extracted from the oil and it was found that its concentration ingested was proportional to the irritation experienced in the throat. To verify that it was not a minor component or a different mixture of molecules found in olive oil which was responsible for the effect, the same experiment was carried out using synthetically manufactured oleocanthal. Again, the results showed that it truly is this compound which results in such a similar sensation to that of ibuprofen.  The daily consumption of 50g of extra virgin olive oil containing an oleocanthal concentration of 200g/cmÂ³ is equivalent to approximately 10% (9mg) of the ibuprofen dosage taken by adults against pain relief.  This relatively small dose of anti-inflammatory taken daily has been suggested to have significant health benefits, such as slowing down cognitive ability deterioration in Alzheimer's patients.
In a mouse model of Alzheimer's it was found that Ibuprofen decreases the secretion of amyloid-42 peptide (which is catalyzed by cyclooxygenase enzymes).  The table below shows the percentage which the enantiomer (-)-oleocanthal (the natural anti-inflammatory form of oleocanthal found in extra-virgin olive oil) as well as Ibuprofen inhibit both types of cyclooxygenase enzymes (Cox-1 and Cox-2), at various concentrations (ÂµM).
Figure 1.  Table showing the affect of changing (-)-oleocanthal and Ibuprofen concentrations on the percentage inhibition of the enzymes cyclooxygenase-2 and cyclooxygenase-2.
Concentration of (-)-oleocanthal (ÂµM)
Cox- 1 (% inhibited)
Cox-2 (% inhibited)
83.5 Â± 3.5
70.9 Â± 8.6
56.1 Â± 3.2
56.6 Â± 9.5
24.6 Â± 7.3
14.5 Â± 2.3
Concentration of Ibuprofen (ÂµM)
Cox- 1 (% inhibited)
Cox-2 (% inhibited)
17.8 Â± 2.3
12.7 Â± 3.6
These data provide us with an indication of the anti-inflammatory effect of oleocanthal and Ibuprofen on the inhibition of these two enzymes. It appears that the greater the concentration of either substance, the higher the percentage of enzyme inhibition. Furthermore, it is clear that (-)-oleocanthal acts as a much more powerful Cox-1 and Cox-2 inhibitor than Ibuprofen. This enlightens us about the beneficial effect this phenol may have on the formation of amyloid plaques and hence, the prevention of inflammation in the brain of an Alzheimer's patient.
Now that I have attempted to show that it is most likely the phenol (-) oleocanthal which inhibits the production of the cyclo-oxygenase enzymes (thus reducing the secretion of beta-amyloid plaques), I will try to find a correlation between the consumption of extra-virgin olive oil (a source of (-)-oleocanthal) in different countries and the corresponding prevalence of Alzheimer's in each country.
5.0 Possible correlation between extra-virgin olive oil consumption and incidents of Alzheimer's in different parts of the world
For my investigation, concerning the relationship between extra-virgin olive oil and the prevalence of Alzheimer's in 2004, I will select countries which will provide me with a range of oil consumption values. Greece being the greatest consumer (26.6 kg per person), all the way down to Lithuania- which has an average of only 0.06 kg consumed per person in 2004. Unfortunately I will have to carry out my research using values of olive oil consumption in general, instead of only extra-virgin olive oil, which gives rise to concerns I will later address in the evaluation of my research. By using countries which had: high, moderate and very low levels of olive oil consumption in the years 2004/2005, I will hopefully be able to observe a correlation between the amount of oil consumed and the number of healthy life years a population has lost due to suffering from Alzheimer's disease.
The burden of the disease is measured in a unit called Age-Standardized DALY's. This is a unit defined by the WHO as "One DALY represents the loss of the equivalent of one year of full health."  This unit of measurement takes into account two major factors that mortality rates don't. Firstly, the age of someone relative to their life-expectancy is considered (most likely measured relative to the average life-expectancy of each country). So assuming that in a country with a life expectancy of 60 years for males, a 10 year old died of a disease that causes sudden death then his death would correspond to 50 DALY's but if someone aged 40 died under similar conditions in the same country it would only correspond to 20 DALY's. Secondly, values measured in DALY's take into account pre-death suffering. This is extremely relevant to Alzheimer's and other dementias, seeing as death is not the major concern but instead, theÂ debilitatingÂ symptoms are. This means that if someone contracts a disease that makes them lose what is deemed the equivalent of 1/2 a year of full health for every year they're alive. Over a period of 10 years even if they don't pass away, that still counts as 5 DALY units. This is extremely significant for Alzheimer's because it reflects intensity and duration of symptoms and not just mortality rates. The units are expressed in terms of 'per 100,000' meaning that for each 100,000 people in a country, Alzheimer's took the equivalent of the stated amount of years of life in full health, as displayed in my table below. Thus, DALY's enlighten us about the total burden of Alzheimer's disease borne by individuals in different countries. 
From looking at the "Three City Study"  earlier -which showed me the possible affect, that extra-virgin olive oil has on cognition- it would be reasonable to hypothesise that in countries where olive oil consumption is high, the occurrence of Alzheimer is slightly less profound. Yet taking into account the numerous problems that arise from this investigation, there is a likely chance that I will not obtain a precise correlation.
Figure 2. Table showing the relationship between the average quantity of olive-oil consumed per person (kg) and the total years lost of full health as a result of Alzheimer's disease and other dementias per 100,000 (Age standardized DALY's) in 2004.
Average olive oil consumption in 2004/2 005 (Kg)
Total midyear population in 2004.
Average olive oil consumption per person in 2004 (Kg)
Total years of full health as a result of Alzheimer's disease and other dementias per 100,000 in 2004.( Age standardized DALY's)
Below I have depicted my results in a graph in order for the relationship between consumption and prevalence to become more apparent.
Figure 3. Graph showing the relationship between the quantity of olive-oil consumed per person (Kg) and the total years of full health lost as a result of Alzheimer's disease and other dementias per 100,000 (Age standardized DALY's) in 2004.
I included a trend line on my graph in order to be able to observe a correlation. It is apparent that as the kilograms of olive oil consumption per person increases, there is a slight increase in the number of full health years lost by a population of my chosen countries. The values however can be seen to fluctuate greatly from above the line of best fit to far below it. This shows how difficult it is to predict the effect of a constituent in the diet. There is no constant or clear correlation, from my results, indicating that countries, whose population on average consumes more olive oil, have a greater number of health years lost from suffering from Alzheimer's disease. This means that, according to my data, there is no certain relationship between the amount of olive oil consumption and the decreased risk of developing Alzheimer's disease. I will now go on to highlighting several reasons for the outcome of my investigation and means by which I could have improved my methodology.
There are diverse reasons as to why it is so extremely challenging to prove the effect of oleocanthal on the decline of Alzheimer's disease. I acknowledge the fact that professional research studies dealing with this matter, control as many variable as they can, which I have not been able to do. The first evaluation point of my study, that I would like to stress is that I used consumption values of all types of olive oils, therefore not taking into account the quality of the olive oil. Only extra-virgin olive oil contains the phenol oleocanthal, meaning that even though the average olive oil intake per person in a certain country may be more than in another, it doesn't mean that the oleocanthal consumption of that country is higher, as the oils consumed there may primarily be more processed forms of olive oil  , thus not containing this phenolic compound.
Furthermore, the dependant variable includes not only age standardized Alzheimer's disease values, but also the number of full health years lost due to all the other forms of dementia. Even though Alzheimer's accounts for 60%  of the world's dementia prevalence, these values do not portray the correct number of full health years lost due to only Alzheimer's disease. This makes all the values higher which probably means that I would have obtained the same trend were I to have used age standardized values of only the population affected by Alzheimer's. However, of course not in every country Alzheimer's disease accounts for 60%  of the cases of dementia. In countries where for example, cardiovascular disease is common, vascular dementia may be more prevalent than Alzheimer's.
In addition, a problem with using DALY's is that it may be that there are more years of full health lost from Alzheimer's in certain parts of the world, because people live up to an older age. In countries in Western Europe for example, the life expectancy is greater, and since age is a major risk factor of Alzheimer's, it might explain the reason for the greater amount of life years lost per 100,000 in Greece -where more olive oil is consumed- than in Brazil. Next, there are different severities of Alzheimer's disease. It could be that in one country people don't have the disease as severely as in another. This is important because DALY's inform us about the burden that Alzheimer's puts on people suffering from it, but not the severity of the burden, which affects the patient as well as his/ her relatives greatly.
The criteria for diagnosing Alzheimer's disease, in most countries, are dissimilar. This affects not only my results, but all other studies conducted in this field will need to take into account the fact that there are different guidelines in the diagnosis of the disease. It is hardly possible for Alzheimer's statistics to be compared and contrasted, if the criteria for diagnosing the disease are different in each country.  If this remains a problem than one should at least identify the inconsistencies of the criteria.  Only when this is done, can we be more confident that the results are not due to the appliance of different "diagnostic criteria". 
Several factors contribute to whether an individual is prone to developing Alzheimer's disease. Those who have suffered from a stroke, rigorous head injuries, are smokers, or are subject to high blood pressure and/or increased levels of cholesterol, are more vulnerable  . Educational stimulus does not so much diminish the risk of developing this clinical syndrome as delay the symptoms. In addition, lack of physical exercise, certain environmental factors and poor general health contribute as well. Age can be said to be the most fundamental risk factor.  For example, research conducted by the UK's Alzheimer's Society demonstrates that 1/6th of the UK citizens above the age of 80; 1/12th of the population above 65; and approximately 16 thousand people under 65 endure the illness at present.  If one has a family member with the disease, this leads to a slightly increased chance of developing Alzheimer's disease.  However, carriers of the ApoE4 gene variant are more at threat of being affected by genetic inheritance.  It has been shown that 10-15 percent of the persons recognized with Mild Cognitive Impairment go on to show symptoms of Alzheimer's during later years.  Furthermore, due to the different chromosomal make up of those suffering from Down's syndrome (who live into their 50's and 60's), they are more liable as well.  It can be clearly seen that this disease stems from numerous causes, which leads to difficulties concerning the control of variables in research studies, as done in cases of laboratory experiments. In order for all variables to be controlled, all participants would have to portray identical characteristics and the same levels of the factors mentioned above, which is nearly impossible.
After having gained a better understanding of the functions and architecture of the brain, I shed light on how the brain of an Alzheimer's patient deteriorates in structure and utility. This cognitive declination is partly due to the appearance of amyloid plaques, which many believe trigger inflammation, hence producing more amyloid plaques resulting in the destruction of neurons.  The phenol oleocanthal, present in limited amounts in extra-virgin olive oil  , has been shown to avert inflammation, much like the anti-inflammatory drug Ibuprofen  . After attempting to demonstrate the phenol's anti-inflammatory properties, I compiled 'average olive oil consumption (kg)' figures in addition to values of 'the total years of full health lost as a result of Alzheimer's disease and other dementias per 100,000 (age standardized DALY's)'. Even though the results represent a trend showing a slight decrease in the burden of Alzheimer's disease in a population, as olive oil consumption increases, the original curve includes irregular values, far above and below the line of best fit. Critical examination of my research (of which several points are relevant to the evaluation of other research studies conducted about Alzheimer's) was necessary. I conclude that the most exigent issues of concern of my research are: the multi-factorial nature of the disease; the lack of only extra-virgin olive oil consumption values; the fact that the health years lost due to other forms of dementia were included, the divers average life expectancy in each country and lastly the differences in the criteria for diagnosing the disease  . Many of these concepts need to be considered when trying to illustrate the effect of a dietary component on Alzheimer's.
Looking back at my research question, "To what extent is it possible to demonstrate that the phenol oleocanthal in extra-virgin olive oil affects the decline of cognitive function and thus reduces the risk of developing Alzheimer's disease?" I conclude that we are not able to show the effect of this phenol with complete confidence due to all the factors illustrated above. The uncertainty of the cause of Alzheimer's, in addition to the numerous other factors I evaluated previously, require research of this nature to be examined critically and judged on the extent of the validity of its results. Lastly, further extensive investigation into this phenomenon is necessary are we to be more sure of the role of oleocanthal on Alzheimer's disease.