Olive leaves from the olive tree, Olea europaea L., are one of the major Mediterranean diet symbols. For the last decades and especially nowadays the scientists are studying this natural product for its potent source of antioxidants and its positive effect on human immune system. The foresaid antioxidants work to reduce the risk of many illnesses by fighting the cell damage along with other health benefits including the association of this natural product with lower rate of chronic diseases such as cancer, heart disease and Alzheimer’s¹.

The antioxidants of olive leaf extract are mainly polyphenols with a coexistence of different antioxidant nature substances like vitamins. The phenolic compounds particularly abundant in unprocessed olive fruit and leaves, exist in concentrations up to 140 mg/g^2,3.

Olive leaf also contains two uniquely powerful polyphenols called Oleuropein (Ole) and Hydroxy-Tyrosol (HydT). These two and especially Ole present in the olive oil after the hydrolysis process which is happening during the mechanical extraction of the oil. Endogenous β-glucosidases, which naturally exist in olive fruit, are accountable for this activity, forming oleuropein aglycone (OleA), the chief phenolic substance of extra virgin olive oil (EVOO) and responsible for the bitter and pungent taste of EVOO^4,5.

Recently, both oleuropein isoforms and hydroxy-tyrosol, have attracted scientific attention for their health benefits, including antioxidant, anti-inflammatory, cardio, neuro-protective and anti-cancer effects. These pharmacological activities are mainly due to their putative radical scavenging features. Mechanistic studies indicate that these compounds are also able to act at different sites, interfering with protein function and gene expression, or modifying cellular pathways relevant to many different diseases^{6, 7}.

In conclusion, several in vitro and in vivo studies have demonstrated the ability of olive leaves (and their phenolic compounds) to counteract oxidative stress and inflammation, to modulate the autophagy pathway, as well as to interfere in the amyloid aggregation process, suggesting its use, not only in the prevention, but also as a complementary therapy of some neurodegenerative diseases. The effective daily dose of phenols to be administered in humans to achieve a therapeutic effect is known to be at 5mg/20g of oil content, and the clinical and experimental evidence suggest that regular intake of these compounds can be long term effective, representing a continuous cellular defense^1,4,5.

Olive leaf complex & brain function

Alzheimer’s disease (AD) is a progressive, fatal, and currently incurable neurodegenerative disease. It is clinically characterized by a gradual loss of cognitive function, including slow deterioration of memory, reasoning, abstraction, language, and emotional stability. As a consequence, in the final stages of the disease, the patient is unable to perform any daily task without adequate assistance from family members or social services. ⁷AD is the most common cause of dementia worldwide. Research shows that, at the age of 65, nearly 5% of older people suffer from AD and, by the age of 85, it is more than 40%. The aging population presents the highest risk of the disease, especially in developed countries, therefore the number of affected people is expected to increase dramatically up to 115 million in 2050 ².

Since AD cannot be cured yet, considerable efforts are being made to at least delay this cognitive decline among elderly in order to maintain and prolong the quality of their life. This is done, for example, by non-pharmacological approaches such as performing physical activities, cognitive training, or adhering to a Mediterranean Diet (MedDiet) ^9-14.

Alzheimer’s disease is a multifactorial pathology in which both genetic, psychological and environmental factors are involved, highlighting among the latter certain aspects of lifestyle. The Mediterranean diet (MD) has already demonstrated on multiple occasions its beneficial effects in preventing age- specific defects, including attenuating and preventing AD and cognitive impairment ^15-17.

This neuroprotective effect has been associated with several foods found in MD, including wine and extra virgin olive oil (EVOO) standing out, the latter being one of the most internationally recognized due to its multiple beneficial properties. Among them, it is worth mentioning its role as a mental health promoter as it is connected with lower mitochondrial oxidative stress, which might counteract with age-related cognitive decline ^18-20.

Similar beneficial effect has been observed in both in vitro and in vivo studies where supplementation with EVOO is able to reduce the advance of Tau and Aβ pathology and cognitive deterioration ^21-23. In the same line, several studies in animal models have shown that this beneficial action is due to a series of substances known as polyphenols 24 ²⁴, including oleuropein aglycone (Ole) and Hydroxy-Tyrosol present in EVOO ²⁵.

A large number of in vitro and in vivo studies have shown the pleiotropic effect of the different phenol compounds. The positive properties of oleuropein and Hydroxy-Tyrosol include antioxidant, antidiabetic, antimicrobial, antiviral, antitumor, hepatoprotective, cardioprotective, anti-aging, anti-inflammatory, and also neuroprotective effects ²⁶. An overview of the most significant effects of these compounds is provided in Table below.

Published scientific papers for oleuropein complex

1. Abaza L, Taamalli A, Nsir H, Zarrouk M. Olive Tree (Olea europeae L.) Leaves: Importance and Advances in the Analysis of Phenolic Compounds. Antioxidants (Basel). 2015 Nov 3;4(4):682-98. doi: 10.3390/antiox4040682.
2. Amiot, M.J.; Fleuriet, A.; Macheix, J.J. (1986). Importance and evolution of phenolic compounds in olive during growth and maturation. J. Agric. Food Chem.34, 823–826. [CrossRef]
3. Le Tutour, B.; Guedon, D. (1992). Antioxidative activities of Olea europaea leaves and related phenolic compounds. Phytochemistry. 31, 1173–1178. [CrossRef]
4. Nediani, C., Ruzzolini, J., Romani, A., & Calorini, L. (2019). Oleuropein, a bioactive compound from olea europaea l., as a potential preventive and therapeutic agent in non-communicable diseases. In Antioxidants (Vol. 8, Issue 12). MDPI AG. https://doi.org/10.3390/antiox8120578
5. Xu, F., Li, Y., Zheng, M., Xi, X., Zhang, X., & Han, C. (2018). Structure properties, acquisition protocols, and biological activities of oleuropein aglycone. In Frontiers in Chemistry (Vol. 6, Issue AUG). Frontiers Media S.A. https://doi.org/10.3389/fchem.2018.00239
6. Piroddi, M.; Albini, A.; Fabiani, R.; Giovannelli, L.; Luceri, C.; Natella, F.; Rosignoli, P.; Rossi, T.; Taticchi, A.; Servili, M.; et al. (2017). Nutrigenomics of extra-virgin olive oil: A review: Nutrigenomics of extra-virgin olive oil. BioFactors. 43, 17–41. [CrossRef] [PubMed]
7. Menendez, J.A.; Joven, J.; Aragonès, G.; Barrajón-Catalán, E.; Beltrán-Debón, R.; Borrás-Linares, I.; Camps, J.; Corominas-Faja, B.; Cufí, S.; Fernández-Arroyo, S.; et al. (2013). Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: A new family of gerosuppressant agents. Cell Cycle. 12, 555–578. [CrossRef].

Published scientific papers for olive leaf complex & brain function

1. K. Blennow and H. Hampel, (2003). “CSF markers for incipient Alzheimer’s disease,” The Lancet Neurology, vol. 2, no. 10, pp. 605–613.
2. A. Wimo, L. Jönsson, J. Bond, M. Prince, B. Winblad, and Alzheimer Disease International, (2013). “The worldwide economic impact of dementia 2010,” Alzheimers Dement, vol. 9, no. 1, pp. 1–11.e3.
3. Klimova B, Valis M, Kuca K. (2017). Cognitive decline in normal aging and its prevention: A review on non-pharmacological lifestyle strategies. Clin Interv Aging. 2017;12:903–910. doi:10.2147/CIA.S132963
4. Alzheimer ́s Association (2014). 2014 Alzheimer’s disease facts and figures. Alzheimers Dement. 10(2):e47–e92.
5. Klimova B, Maresova P, Kuca K. (2016). Non-pharmacological approaches to the prevention and treatment of Alzheimer ́s disease with respect to the rising treatment costs. Curr Alzheimer Res;13(11):1249–1258.
6. Klimova B, Maresova P, Valis M, Hort J, Kuca K. (2015). Alzheimer ́s disease and language impairments: social intervention and medical treatment. Clin Interv Aging. 10:1401–1408. doi:10.2147/CIA.S89714
7. Hardman RJ, Kennedy G, Macpherson H, Scholey AB, Pipingas A. (2015). A randomised controlled trial investigating the effects of mediterra- nean diet and aerobic exercise on cognition in cognitively healthy older people living independently within aged care facilities: the Lifestyle Intervention in Independent Living Aged Care (LIILAC) study protocol [ACTRN12614001133628]. Nutr J. 14:53.
8. Ngandu T, Lehtisalo J, Solomon A, et al. (2015). A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 385(9984):2255–2263. doi:10.1016/S0140-6736(15) 60461-5
9. C. Dussaillant, G. Echeverría, I. Urquiaga, N. Velasco, and A. Rigotti, (2016). “Evidencia actual sobre los beneficios de la dieta mediterránea en salud,” Revista Médica de Chile, vol. 144, no. 8, pp. 1990–1997.
10. C.Feart,C.Samieri,andP.Barberger-Gateau, (2010). “Mediterranean diet and cognitive function in older adults,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 13, no. 1, pp. 14–18.
11. N. Scarmeas, Y. Stern, M. X. Tang, R. Mayeux, and J. A. Luchsinger, (2006). “Mediterranean diet and risk for Alzheimer’s dis- ease,” Annals of Neurology, vol. 59, no. 6, pp. 912–921.
12. Valls-Pedret C, Lamuela-Raventós RM, Medina-Remón A, et al. (2012). Polyphenol-rich foods in the mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk. J Alzheimers Dis. 29(4):773–782. doi:10.3233/JAD-2012- 111799
13. Quiles JL, Barja G, Battino M, Mataix J, Solfrizzi V. (2006). Role of olive oil and monounsaturated fatty acids in mitochondrial oxidative stress and aging. Nutr Rev. 64(s4):31–39. doi:10.1111/j.1753-4887.2006. tb00170.x
14. St-Laurent-Thibault C, Arseneault M, Longpré F, Ramassamy C. (2011). Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-β-induced toxicity. Involvement of the NF-κB signaling. Curr Alzheimer Res. 8(5):543–551.
15. A. H. Abuznait, H. Qosa, B. A. Busnena, K. A. el Sayed, and A. Kaddoumi, (2013). “Olive-oil-derived oleocanthal enhances β-amyloid clearance as a potential neuroprotective mecha- nism against Alzheimer’s disease: in vitro and in vivo studies,” ACS Chemical Neuroscience, vol. 4, no. 6, pp. 973– 982.
16. S. A. Farr, T. O. Price, L. J. Dominguez et al., (2012). “Extra virgin olive oil improves learning and memory in SAMP8 mice,” Journal of Alzheimer’s Disease, vol. 28, no. 1, pp. 81–92.
17. H. Qosa, L. A. Mohamed, Y. S. Batarseh et al., (2015). “Extra-virgin olive oil attenuates amyloid-β and tau pathologies in the brains of TgSwDI mice,” The Journal of Nutritional Biochemistry, vol. 26, no. 12, pp. 1479–1490.
18. C. Valls-Pedret, R. M. Lamuela-Raventós, A. Medina-Remón et al., (2012). “Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk,” Journal of Alzheimer’s Disease, vol. 29, no. 4, pp. 773–782.
19. V.Pitozzi,M.Jacomelli,M.Zaidetal.,(2010). “Effectsofdietaryextra- virgin olive oil on behaviour and brain biochemical parameters in ageing rats,” British Journal of Nutrition, vol. 103, no. 11, pp. 1674–1683.
20. Cordero JG, García-Escudero R, Avila J, Gargini R, García-Escudero V. (2018). Benefit of oleuropein aglycone for Alzheimer’s disease by promot- ing autophagy. Oxid Med Cell Longev. 2018:5010741. doi:10.1155/2018/5010741

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