Extra-virgin olive oil for potential prevention of Alzheimer disease

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Environmental Neurology

Extra-virgin olive oil for potential prevention of Alzheimer disease G.C. Roma´n a,b,*, R.E. Jackson b,c, J. Reis d, A.N. Roma´n e, J.B. Toledo f, E. Toledo g,h,i a

Methodist Neurological Institute and Research Institute, Houston Methodist Hospital, Houston, TX, USA Weill Cornell Medical College, Cornell University, New York, NY, USA c Department of Internal Medicine and Research Institute, Houston Methodist Hospital, Houston, TX, USA d University of Strasbourg, Strasbourg, France e University of Houston, Houston, TX, USA f Houston Methodist Hospital, Methodist Neurological Institute-Neurology, Houston, TX, USA g Department of Preventive Medicine and Public Health, University of Navarra, School of Medicine, Pamplona, Navarra, Spain h Centro de Investigacio´n Biome´dica en Red Fisiopatologia de la Obesidad y Nutricio´n, Instituto de Salud Carlos III, Madrid, Spain i Navarra Institute for Health Research, IdiSNA, Pamplona, Navarra, Spain b

info article

abstract

Article history:

Observational epidemiological studies provide valuable information regarding naturally

Received 30 June 2019

occurring protective factors observed in populations with very low prevalences of vascular

Received in revised form

disease. Between 1935 and 1965, the Italian-American inhabitants of Roseto (Pennsylvania,

12 July 2019

USA) observed a traditional Italian diet and maintained half the mortality rates from

Accepted 12 July 2019

myocardial infarction compared with neighboring cities. In the Seven Countries Study, during

Available online xxx

40 years (1960–2000) Crete maintained the lowest overall mortality rates and coronary heart

Keywords:

French Three-City Study, a ten-year follow-up (2000–2010) showed that higher consumption

disease fatalities, which was attributed to strict adherence to the Mediterranean diet. In the Alzheimer disease

of olive oil was associated with lower risk of death, as well as protection from cognitive

Cerebrovascular disease

decline and stroke. A large number of population-based studies and intervention trials have

Mediterranean diet

demonstrated that the Mediterranean diet is associated with lower prevalence of vascular

Olive oil

disease, obesity, arthritis, cancer, and age-associated cognitive decline. Many of these effects

Environmental neurology

are the result of consumption of fruits, seeds, legumes and vegetables but olive oil is the chief dietary fat in Mediterranean countries and the main source of monounsaturated fatty acids, as well as an important source of beneficial polyphenols and other antioxidants. Considering the critical role of vascular factors in the pathogenesis of late-onset Alzheimer disease it seems appropriate to focus on disease modification through proven dietary therapy. The authors base their hypothesis on meta-analyses of epidemiological data, numerous experimental studies, and a comprehensive review of the mechanisms of action of extra-virgin olive oil and its components in the prevention of vascular disease. In addition, extra-virgin olive oil

* Corresponding author at: Methodist Neurological Institute, Houston Methodist Hospital, 77030 Houston, TX, USA. E-mail address: [email protected] (G.C. Roma´n). https://doi.org/10.1016/j.neurol.2019.07.017 0035-3787/# 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Roma´n GC, et al. Extra-virgin olive oil for potential prevention of Alzheimer disease. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.017

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has had positive effects on experimental animal models of Alzheimer disease. We therefore propose that extra-virgin olive oil is a promising tool for mitigating the effects of adverse vascular factors and may be utilized for potential prevention of late-onset Alzheimer disease. # 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1.

Introduction

The olive tree belongs to the botanical family Oleaceae of which the genus Olea has forty species. Today’s modern olive oil is produced from the fruit of Olea europaea subsp. europaea var. europaea (to be distinguished from its wild cousin var. sylvestris). According to the International Olive Oil Council (http://www.internationaloliveoil.org/) the first ancient olive trees were cultivated some 6000 years ago in the Middle East. The earliest written references to olives have been found on clay tablets 4400 years old discovered near Ebla, an ancient Syrian city. The Phoenicians appeared to have spread olive cultivation throughout the Mediterranean. The wealth of the Minoan Empire is said to have been based on olive cultivation and wars were fought over olive groves and trading routes. Olive wreaths from the wild olive tree, Kallistefanos olea, were placed on the heads of winners of ancient Olympic games. In the Iliad, Homer refers to olive oil as ‘‘liquid gold.’’ The great historian Pliny wrote, ‘‘Except the vine there is no plant which bears a fruit of as great importance as the olive.’’ Olive oil has been used as a source of nutrition, fuel in lamps, lubricants for athletes and warriors, and in religious rituals (Psalm 23:5 ‘‘Thou anointest my head with oil’’). Olive oil and olive trees are considered sacred by the three great monotheistic religions: Judaism, Christianity and Islam. For thousands of years, the positive impact of olive oil on health has been chronicled throughout history. Most recently we have scientific evidence that validates the wisdom of the ancients. Regular consumption of olive oil improves health. As discussed below, a number of observational epidemiological studies have revealed the natural occurrence of populations with remarkable longevity and very low rates of vascular disease. These examples of natural protection against premature death, coronary heart disease and brain infarction have been largely ignored in the widespread scientific search for a pharmacological magic bullet, a pill that will assure longevity and will avert the diseases of aging, in particular late-onset Alzheimer disease (LOAD). Considering the near total failure of Alzheimer’s medications [1] affecting beta amyloid (Ab) and tau protein (tP), and the importance of vascular factors in the pathogenesis of neurodegenerative diseases, a timely review of physiologically protective vascular factors in LOAD is relevant. We summarize early epidemiological studies of populations with naturally occurring low rates of vascular disease linked to the Mediterranean diet and we review the role of extra-virgin olive oil (EVOO) — the sine qua non component of the Mediterranean diet — in the prevention of vascular disease, stroke and age-associated cognitive loss. Next, we

analyze the experimental effects of EVOO and its components on animal models of Alzheimer disease. Finally, based on epidemiological and experimental data we propose EVOO as a potential tool for prevention of LOAD.

2. Protection against vascular risk in epidemiological studies 2.1.

The Roseto story

In 1964, Stout et al. [2] noted among first-generation ItalianAmericans residing in Roseto (Pennsylvania, USA) that death rates from myocardial infarction were half those of Bangor, an immediately adjacent town, and of three other nearby communities [2,3]. For instance, between 1945 and 1954 the age-adjusted mortality rates (per 1000) for myocardial infarction were as follows: Bangor men, 64.9 vs. Roseto men, 43.0; Bangor women, 27.4 vs. Roseto women, 19.1 [4]. These ‘‘abnormally’’ low mortality rates from myocardial infarction persisted for some 30 years (1935–1965) [4]. With time and adaptation to the local way of living, cardiac death rates in Roseto increased to ‘‘normal’’ values. From 1975 to 1984, the mortality rates were the following: Bangor men, 76.3 vs. Roseto men, 78.5; Bangor women, 34.5 vs. Roseto women, 36.6 [4]. Wolf and Bruhn [5] postulated that low stress explained this phenomenon; the role of the diet was dismissed since, in addition to olive oil, the consumption of saturated animal fats was high. Another factor was the progressive decline in wine making and consumption of wine with meals given that ‘‘nearly half of the households made their own wine in 1963; by 1985 only 10 percent, mainly the elderly, were making wine’’ [5]. It is conceivable that adoption of Western-type diet instead of the Mediterranean diet was a likely cause of the increased vascular risk.

2.2.

The Seven Countries Study

The Seven Countries Study (7CS) was a population-based international survey conceived in 1947 by Ancel Keys [6] at the University of Minnesota in Minneapolis. This ecological study was launched in 1957 and included 12,763 men aged 40– 59 years at the outset. Selection criteria were similar and all participants were studied with analogous methods. The main objective was to compare overall mortality, coronary and cancer death rates in sixteen rural and urban communities in the USA, Japan, Finland, Italy, the Netherlands, YugoslaviaSerbia, and Greece (Corfu and Crete) with the practical goal of discovering predictive risk factors amenable to preventive interventions [6–8].

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2.2.1.

Crete

Consistently over the years of the study, the lowest all-cause mortality, cancer and coronary death rates were found in Crete and Japan [6,7]. For instance, according to Menotti et al. [8], the 25-year follow-up death rates for coronary disease (Fig. 1) were 25% in Crete compared with 268% in Finland. Arterial hypertension and dietary intake of saturated fats appeared to be the main risk factors in The Netherlands, USA, and Finland, the countries with high rates of cardiovascular disease [9]. Likewise, all-cause mortality and coronary death rates were negatively related to consumption of olive oil, fish, wine, vegetables, cereals, and soy [8,9]. It was concluded that dietary—rather than ethnic—factors were important since Japanese living in Japan and consuming larger amounts of fish [10] had less coronary deaths than those living in Hawaii or California, despite the presence of hypertension, smoking and other vascular risk factors in both places. Adherence to the Mediterranean diet [11,12] in 16 cohorts of the 7CS inversely correlated with the 25-year death rates from coronary heart disease in all cohorts (R = 0.72 to 0.84; P = 0.001). The Cretan diet had the strongest protective effect after 40 years of follow-up (1960–2000); this cohort from Crete maintained the lowest age-standardized all-cause and coronary heart disease death rates [12]. These population-based observations linked the Mediterranean-Cretan diet with protection against coronary heart disease [13] and led to an early intervention clinical trial, the Lyon Diet Heart Study, conducted in France.

2.3.

The French Paradox

In 1992, Serge Renaud and Michel de Lorgeril [14] noticed that coronary death rates in France were much lower than in the USA and closer to those of Japan, despite the high intake of saturated fats mainly from consumption of French cheese. They called this phenomenon the ‘‘French paradox’’ and suggested that alcohol drinking in France (20–30 g/d) plus consumption of long chain fatty acids could reduce coronary heart disease risk by at least 40% [14,15]. This was based on the

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observation that the main v-3 fatty acid in the Cretan cohort in the 7CS—a-linolenic acid (C18:3,n-3) had plasma levels three times higher in Crete compared with Zutphen (The Netherlands); the levels of the v-6 fatty acid linoleic acid (C18:2,n-6) were 21% lower in Crete than in The Netherlands [16]. In contrast, total cholesterol levels of elderly men in Crete and Zutphen were similar (5.98 and 5.92 mmol/L, respectively) but Cretans had significantly higher high-density-lipoprotein (HDL)-cholesterol level (1.28 vs. 1.09 mmol/L) [16]. The percentage of smokers and the average body mass index (BMI) did not differ between the Cretan and Zutphen men [16]. Also, de Lorgeril et al. [14,15] pointed out that Crete and Japan, the two populations with the lowest coronary heart disease mortality in the world, have high intake of the v-3 fatty acid a-linolenic acid. The Japanese from fish, algae, canola and soybean oils, and the Cretans from olive oil, fish, seafood, walnuts, flaxseeds, and purslane (Portulaca oleracea L., Sp. verdolaga, Fr. purslane). Based on these observations they launched a secondary prevention dietary trial in patients with myocardial infarction [15].

2.3.1.

The Lyon Diet Heart Study

The Lyon Diet Heart Study was a randomized, multicenter trial on secondary prevention of coronary disease by dietary intervention within 6 months of a first myocardial infarction using Mediterranean diet enriched with a-linolenic acid. The controls (n = 303) continued the ‘‘prudent diet’’ recommended in 1992 by the American Heart Association (AHA): total lipids, 31% energy; saturated fats, 10.5%; polyunsaturated/saturated ratio, 0.78. The experimental group (n = 302) consumed Mediterranean diet with less meat and more fish, bread, cereals, vegetables, legumes, beans, and fruit. Butter and cream were excluded and the experimental group received olive oil and margarine made from canola (rapeseed) oil richer in a-linolenic acid (4.8 vs. 0.6%). Both groups were allowed to consume wine at meals. After 27 months (Fig. 2), there were 16 cardiac deaths and 17 nonfatal myocardial infarcts among controls vs. 3 deaths and 5 infarcts in the Lyon diet group (RR = 0.27; 95% CI: 0.12–0.59, P = 0.001). The overall mortality

Fig. 1 – Comparison of mortality death rates (per thousand) for coronary heart disease in five countries participating in the Seven Countries Study. Notice the difference of one of order of magnitude between Crete (25%) and Japan (36%) in comparison with Finland (268%); USA (160%), Netherlands (169%). Data from Menotti et al. for The Seven Countries Study Research Group [8]. Please cite this article in press as: Roma´n GC, et al. Extra-virgin olive oil for potential prevention of Alzheimer disease. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.017

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Fig. 2 – Results of the Lyon Diet Heart Study after 27 months of the clinical trial. There was a striking difference in the number of cardiac deaths (16 vs. 3) [left columns] and nonfatal myocardial infarctions (17 vs. 5) [right columns] among the Lyon diet group and the control group on the American Hearth Association 1992 diet. Data from de Lorgeril et al. [17].

was 20 fatalities in the control group vs. 8 in the experimental group (RR = 0.30; 95% CI: 0.11–0.82, P = 0.02) [15]. Therefore, the Mediterranean diet enriched with the a-linolenic acid effectively prevented coronary events and death after a first myocardial infarct [15,17]. A protective effect after 4 years of follow-up was demonstrated with 50% to 70% reduction in risk of recurrence of cardiac ischemia [15,16]. According to de Lorgeril and Salen [18], the protective cardiac effect resulted from higher ingestion of alinolenic acid, with contribution from very-long chain v-3 fatty acid derivatives such as eicosapentaenoic acid (C20:5,n3) and docosahexaenoic acid (C22:6,n3). Other than olive oil, sources of long chain v-3 fatty acids are fish and seafood; walnuts, almonds and almond oil; noix de Grenoble oil; rapeseed (canola) oil, flaxseed oil (Linum usitatissimum L.), and chia seeds (Salvia hispanica); as well as eggs from free-range hens fed purslane and other green grasses rich in a-linolenic acid [19].

2.4.

The Three-City Study in France

According to Prof. Annick Alpe´rovitch et al. [20], the ThreeCity Study (3CS) originated from the experience in observational studies with two large population cohorts that determined the incidence and risk factors of Alzheimer disease and other types of dementia in France:  the PAQUID study in Gironde and Dordogne launched in 1988 recruited 3777 participants older than 65 years of age;  the EVA study (‘E´pidemiologie du vieillissement VAsculaire’) involved 1389 participants aged 60 to 70 years from the city of Nantes. These studies provided solid epidemiological data on incidence and vascular risk factors of dementia in France

and led to the larger 3CS involving almost 10,000 participants recruited from the electoral rolls of the cities of Bordeaux, Dijon and Montpellier. All participants underwent clinical examinations at baseline and after two, three, eight and ten years. The 3CS showed that over a period of ten years the risk of death was significantly lower among subjects with the highest consumption of fruit and vegetables, olive oil and fish [21]. Conversely, daily meat eating increased the mortality risk (HR = 1.12; 95% CI: 1.01–1.24, P = 0.03) [21]. The protective effect of olive oil was clearly apparent in women with longer life expectancy than men (HR = 0.72; 95% CI: 0.60–0.85, P = 0.0002) [21]. Moreover, in the 3CS cohort olive oil consumption as part of the Mediterranean diet was associated with slowing of age-associated memory loss, global cognitive decline and dementia [22]. These positive effects were confirmed in a metaanalysis combining the French 3CS cohort plus four USA cohorts (Nurses’ Health Study, Women’s Health Study, Chicago Health and Aging Project and Rush Memory and Aging Project) involving a total of 23,688 white persons older than 65 years, 88% female, followed during four to nine years [23]. Genes associated with Alzheimer disease did not influence the protective effect of fish consumption [23]. Higher consumption of olive oil in the 3CS resulted in a 41% lower risk of stroke (95% CI: 6%–63%, P = 0.03) after a follow-up of over five years [24]. Subjects with maximum use of olive oil confirmed by the highest levels of plasma oleic acid had a 73% reduction of stroke risk (95% CI: 10%–92%, P = 0.03) [24]. About 5% of these 3CS elderly participants had Ideal Cardiovascular Health (ICVH) manifested by a 29% decreased risk of allcause mortality and 67% risk reduction for stroke and coronary disease [25].

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3. Evidence-based vascular effects of the Mediterranean diet All international studies [26–32] have consistently reported a direct association between adherence to the Mediterranean diet and increased longevity together with lower incidence of atherosclerosis and cardiovascular diseases. These benefits have been partially attributed to the dietary use of EVOO along with consumption of fruits, grains, and vegetables [33] as well as other nutrients such as polyphenols found in sesame seeds, flaxseed and cashew nuts [34].

3.1.

Mediterranean diet

Mediterranean diet is the generic name of the typical diet of people living in areas of the Mediterranean basin where olive trees (Olea europaea L.) are cultivated [26,27]. Consequently, olive oil is a basic ingredient of this diet and the principal source of dietary fat providing more calories than any other individual food. Other important components of plant origin in this diet include generous amounts of fruits and vegetables, legumes, grains, and nuts. Whole-grain cereals frequently cooked with spices are characteristic for this type of diet. Other distinguishing elements of this diet are wine, fish, and modest amounts of saturated fats, meat and poultry [35]. There are variations of the Mediterranean diet within the same country; for example, the typical Spanish cuisines of Andalusia, Valencia and Catalonia. Varieties range from the strict Cretan diet [36], to the elaborate Lebanese [37] and Moroccan cuisine, or the cooking from the French Provence. Southern Italian cuisine uses preponderantly Mozzarella cheese, olive oil, dried pasta and abundant tomatoes. Table 1 lists the most important components of the Mediterranean diet [27].

3.2. PREDIMED: extra-virgin olive oil in cardiovascular prevention The ‘Prevencio´n con Dieta Mediterra´nea’, Prevention with the Mediterranean Diet (PREDIMED) [38–41] is a multicenter clinical trial conducted between 2003 and 2010 in Spain (ISRCTN35739639) [39]. It was designed as a large controlled intervention study (n = 7447) in subjects with high-risk of

Table 1 – General Characteristics of the Mediterranean dietsa. 1. Abundant plant foods (fruits, vegetables, breads, other forms of cereals – especially whole-grain cereals –, beans, nuts, and seeds) 2. Minimally processed, seasonally fresh, and locally grown foods 3. Fresh fruits as the typical daily dessert; sweets based on nuts, olive oil, and concentrated sugars or honey consumed during festive days 4. Olive oil is the principal source of dietary fat 5. Dairy products (mainly cheese and yogurt) consumed in low to moderate amounts 6. Red meat consumed in low frequency and amounts. Fish consumption changes according to the regions 7. Wine consumed in low to moderate amounts, generally with meals a

Data from Serra-Majem et al. [27].

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cardiovascular disease ranging from ages 55 to 80 years. The aim was to assess whether or not the Mediterranean diet enriched with EVOO or mixed nuts (walnuts, almonds, and hazelnuts) prevents cardiovascular diseases, compared with a control group that received advice on a low-fat diet. Secondary outcomes included assessment of diet effects on all-cause mortality and on incidence of heart failure, diabetes, cancer, cognitive decline and neurodegenerative disorders, among others. Lower incidence of major cardiovascular events, the main endpoint of the PREDIMED trial, was demonstrated among those assigned to a Mediterranean diet compared with the reduced-fat diet both for the Mediterranean diet with EVOO (HR = 0.69; 95% CI: 0.53–0.91) and for the Mediterranean diet with mixed nuts (HR = 0.72; 95% CI: 0.54–0.95) [40]. The EVOO supplemented Mediterranean diet was associated also with a number of beneficial effects on cardiovascular risk factors including decreases in plasma glucose levels, 24-hour systolic blood pressure, and better ratio total-cholesterol to HDLcholesterol (T-C/HDL-C) [41]. In addition, the dietary intervention reduced inflammatory biomarkers related to atherosclerosis including C-reactive protein (CRP) levels by 0.54 mg/L (95%CI 1.04–0.03 mg/L) compared with the low-fat diet [42]. Other important findings include lower incidence of the metabolic syndrome and type 2 diabetes [43], improved quality of life [44], and most importantly, the Mediterranean diet supplemented with EVOO was associated with a 62% reduction in incidence of invasive breast cancer among postmenopausal women [45] compared with those on the control diet. A summary of recent studies of EVOO can be found in the proceedings of the 2018 International Conference organized by the International Olive Oil Council [26].

4.

Olive oil

Olive oil is probably responsible for a substantial part of the health effects of the Mediterranean diet [46,47]. Olive oil was first produced in Greece around 1500 years BC in Bronze Age Minoan Crete [48]. Not unexpectedly, Greeks have the highest intake of olive oil in the world at 20 kg per capita per year [49]. Greece, Italy and Spain are the main producers and they consume 69% of the world’s olive oil [49]. World olive oil production decreased 20% for the 2016/17 and 2017/18 harvests. Consumption in the USA has increased since 1995 but current olive oil utilization is about 6% of the total California and Texas production [49]. Olive oil has inherent nutritional value and adds to the additional benefits of the foods that are typically prepared with olive oil (vegetables, fish).

4.1.

Virgin olive oil

Olive oil is a natural juice unlike seed oils from sunflower, soybean and rapeseed (canola) that must be refined changing thereby their original composition. By definition of the International Olive Oil Council [49], Virgin olive oil is obtained from the fruit of the olive tree by mechanical or other means under thermal conditions (usually cold pressed) that do not lead to alterations. Olives undergo no other treatment than washing, decantation, centrifugation, and filtration.

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There are several categories of virgin olive oil including extra virgin olive oil (EVOO) that has perfect flavor and aroma (sensory score > 6.5) with a maximum acidity of 1% from oleic acid (1 g/100 g); fine virgin olive oil and semi-fine or ordinary virgin olive oil have decreasing sensory scores and increasing acidity from oleic acid content (2% and 3.3%, respectively) [49]. In addition to its high organoleptic properties, EVOO has a remarkable antioxidant capacity (total radical-trapping antioxidative potential: 668 nM/mL) [50] due to maximum content of antioxidant compounds. Olive oil has hundreds of micronutrients [35]; the most important ones are summarized next.

4.2.

Fatty acids in olive oil

EVOO is a rich source of dietary monounsaturated fatty acids (MUFA) including oleic acid (C18:1) and palmitoleic acid (C16:1) [49]. Olive oil must have a free acidity, expressed as oleic acid, of not more than 0.8 grams per 100 grams, according to the standards of the International Olive Oil Council (http://www. internationaloliveoil.org/estaticos/view/222-standards). The main polyunsaturated fatty acids (PUFA) in olive oil include linoleic acid (C18:2,n-6) (8.3%–8.49%) and low levels of a-linolenic acid (C18:3,n-3) (Fig. 3) ranging from 0.51% to 0.78% [39]. Linoleic acid is considered the most potent dietary fatty acid to reduce total cholesterol and LDL cholesterol. In 2019, Marklund et al. [51] reported a pooled analysis of 30 prospective studies involving 68,659 participants with follow-up ranging from 2.5 to 31.9 years documenting 15,198 incident cardiovascular events. Higher levels of linoleic acid were significantly associated with lower risk of total incident cardiovascular disease (HR = 0.93; 95% CI: 0.88–0.99), lower cardiovascular mortality (HR = 0.78; 95% CI: 0.70–0.85) and ischemic stroke (HR = 0.88; 95% CI: 0.79–0.98), as well as lower coronary disease risk (HR = 0.94; 95% CI: 0.88–1.00). The saturated fatty acids present in EVOO are palmitic acid (C16:0) (9.2%–12.47%) and in lesser amounts stearic (C18:0) (1.39%–3.5%) and myristic (C14:0) (0.05%) acids. Longer-chain saturated fatty acids ( C20) may occur in trace amounts [39].

4.2.1.

trans fatty acids

It is important to note that MUFAs such as oleic acid and PUFAs in olive oil have an all-cis double bond configuration; i.e., the hydrogen atoms are on the same side of the double bond (Fig. 3). Heating vegetable oils causes trans isomerization whereby the hydrogen atoms turn to opposite sides of the bond forming the trans configuration which straightens the fatty acid chain, changing its consistency from liquid to solid

(as in partially hydrogenated vegetable shortening). Olive oil is remarkably resistant to formation of trans fatty acids with heating. Prolonged frying at 200 8C increases the content of trans fatty acids of corn oil or sunflower oil over 12%; in contrast, when frying with olive oil the trans fats content remains below 5.5%, even after seven hours of heating [52]. The resistance of olive oil to trans isomerization of fatty acids with heating increases its advantages for human health, in comparison with other vegetable oils. Human consumption of trans fatty acids has serious health effects that led to public heath regulations banning trans fats from industrial and commercial foods. There is substantial increase in risk of coronary disease with trans fats consumption in low amounts (1%–3% of total energy intake). Mozaffarian et al. [53] performed a meta-analysis of prospective studies involving about 140,000 subjects and demonstrated that a 2% increase in energy intake from trans fatty acids increased the incidence of ischemic coronary disease 23% (RR = 1.23; 95% CI: 1.11–1.37; P < 0.001). Similar results were obtained in pooled retrospective and prospective studies. Adverse effects of trans fatty acids include increased risk of dementia in the elderly [54] mediated by reduction of HDL cholesterol and LDL particle size, along with increases of LDL cholesterol, T-C/HDL-C ratio, triglycerides, and lipoprotein(a)Lp(a). In addition, trans fats promote atherosclerosis by increasing inflammation, tumor necrosis factor-alpha (TNFa), TNF receptors, Iinterleukin-6 (IL-6), C-reactive protein (CRP) and monocyte chemoattractant protein. Endothelial dysfunction is accelerated with elevation of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular-cell adhesion molecule 1 (sVCAM-1), and E-selectin [55]. In 2017, the AHA [56] banned trans-fats advising that ‘‘strongly lowering intake of saturated fat and replacing it with unsaturated fats, especially polyunsaturated fats, will lower the incidence of cardiovascular disease. This recommended shift from saturated to unsaturated fats should occur simultaneously in an overall healthful dietary pattern such as Dietary Approaches to Stop Hypertension (DASH) or the Mediterranean diet as emphasized by the 2013 American Heart Association/American College of Cardiology lifestyle guidelines and the 2015 to 2020 Dietary Guidelines for Americans.’’

4.2.2. Beneficial effects of monounsaturated and polyunsaturated fatty acids For the past several decades the major emphasis in prevention of vascular risk has been to reduce dietary saturated fat and

Fig. 3 – Fatty acids are non-branched hydrocarbon chains ranging from 4 carbons (butyric acid, C4:0) to 22 carbon atoms (docosahexaenoic acid C22:6) or more. By convention, the number of carbons and double bonds in a fatty acid are abbreviated; in the illustration above for a-linolenic acid the symbol is C18:3. The number and position of the double bonds is identified by the number of carbons from the methyl end (CH3) of the chain called the omega (v) or ‘‘n’’ carbon. Omega-3 (v-3) or n-3 indicates that the first double bond is between the 3rd and 4th carbons from the methyl end. Please cite this article in press as: Roma´n GC, et al. Extra-virgin olive oil for potential prevention of Alzheimer disease. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.017

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cholesterol to decrease total serum cholesterol and LDL levels. The Women’s Health Initiative Dietary Modification Trial (WHI-DMT) [57] used this diet but after 8 years showed no significant effects on incidence of coronary heart disease (HR = 0.97; 95% CI: 0.90–1.06) or stroke (HR = 1.02; 95% CI: 0.90– 1.15). These results emphasized the benefits of increasing the dietary intake of polyunsaturated and monounsaturated fatty acids. As summarized by Visioli et al. [26] ‘‘available evidence does not support a benefit from reducing the percentage of energy from total fat in the diet, and the recommendations focusing on decreasing total fat are misleading. More important is the type of dietary fat, which should emphasize unsaturated fats from natural plant sources.’’ In fact, lower cardiovascular disease risk, reduced total cholesterol, and lower LDL serum levels can be achieved with dietary intake of PUFA including both the n-6 and the n-3 (v-3) fatty acids. EVOO is a healthy source of both MUFA and PUFA including linoleic acid. High MUFA content in the diet increases HDL-cholesterol levels and lowers triglycerides compared with low fat-high carbohydrate diet. Furthermore, EVOO improves postprandial lipemia by inducing lower triacylglycerol postprandial levels, when compared with the response to intake of saturated fat. These effects appear to be of particular benefit to patients with type 2 diabetes [58,59]. Of additional interest is the observation that the Mediterranean diet protects against environmental air pollution resulting from exposure to fine particulate matter that increases the risk of cardiovascular disease and stroke, as well as from the increased cardiovascular risk resulting from exposure to nitrogen dioxide at the residential level [60].

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Weinbrenner et al. [65] provide the following percentages of individual phenolics compounds present in EVOO: hydroxytyrosol (6.5%), tyrosol (5.5%), oleuropein aglycones (40%), ligstroside aglycones (26%), lutein (12%), and apigenin (3%). Of these, the phenolics best absorbed after olive oil ingestion are tyrosol and hydroxytyrosol [66], resulting in postprandial increase of total phenolic compounds in LDL [67]; the degree of LDL oxidation decreases as the phenolic content of the olive oil increases.

4.6.

Phospholipids

Olive oil contains phosphatidylcholine (lecithin), phosphatidylethanolamine and phosphatidylinositol, important components of cell membranes. Recently, Razquin et al. [68] demonstrated in the PREDIMED trial that polyunsaturated phosphatidylcholines and polyunsaturated cholesterol esters appear to confer protection against stroke, while phosphatidylethanolamines are probably associated with higher risk of stroke. The cohort plasma lipidome was not substantially affected by the Mediterranean diet.

5. Vascular factors in the pathogenesis of Alzheimer disease

Squalene (C30) is an intermediate in the synthesis of cholesterol present in olive oil in large concentrations (EVOO, 424  21 mg/kg) [61]; these values are superior to those found in shark liver oil.

The proposal to utilize EVOO for the prevention and treatment of Alzheimer disease originates from the evidence accumulated in the past three decades corroborating the critical role of vascular factors in the pathogenesis and clinical expression of LOAD [69–73]. These data led to the conclusion that as many as one-third of all new cases of LOAD could be prevented by early and adequate control of vascular risk factors such as hypertension, hyperlipidemia, smoking, diabetes, obesity, sedentarism, and sleep apnea [74–76]. Cohorts such as the Framingham Heart Study [77] have documented that better control of vascular risk factors resulted in recent decrease in the incidence of dementia.

4.4.

5.1.

4.3.

Hydrocarbons

Sterols

The main sterols in olive oil are b-sitosterols and campesterols [62] structurally related to cholesterol, containing smaller amounts of D-7 stigmasterol, brassicasterol, and cholesterol.

4.5.

Polyphenols

Olive oil contains about 200 mg/kg total phenolics all of which are potent antioxidants [63]; values are significantly higher for EVOO (232  15 mg/kg, P < 0.0001) as well as for simple phenols (hydroxytyrosol and tyrosol). Hydroxytyrosol is a principal bioactive compound of EVOO [64]. The major linked phenols are secoiridoids and lignans, in particular pinoresinol and 1-acetoxypinoresinol [34]. Antioxidant polyphenols in EVOO [61–64] include other tocopherols—such as a-tocopherol or vitamin E—tocotrienols, the triterpenoid derivative compounds ursolic acid, uvaol, and oleanolic acid; o-diphenols; and flavonoid polyphenols such as quercetin, luteolin, and rutin; and pigments such as carotenoids including vitamin A.

Mediterranean diet and cognition

Hardman et al. [78] performed a systematic review of longitudinal and prospective trials demonstrating that higher adherence to a Mediterranean diet is associated with slower cognitive decline, reduced conversion from mild cognitive impairment (MCI) to Alzheimer disease, and improved cognition. However, not all studies are in agreement with these conclusions [79]. More recently, Gardener et al. [80–82] evaluated adherence to an Australian-style Mediterranean diet in an elderly cohort using a food frequency questionnaire. It was found that subjects with MCI and LOAD had statistically significant lower adherence to the Mediterranean diet. Higher adherence to a western diet was associated with greater cognitive decline [81]. Moreover, better adherence to the Mediterranean diet was associated with less deposition of Ab amyloid in the brain from baseline to 36 months of follow-up suggesting a dietary effect in reducing cerebral AD pathology [82]. Likewise, Karstens et al. [83] found that higher Mediterranean diet adherence in an elderly group (n = 121) studied at the

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University of Illinois at Chicago, USA, was associated with better learning and memory performance but not with information processing or executive function. Also, dietary adherence was associated with larger dentate gyri but not with less white matter hyperintensities.

5.2.

Extra-virgin olive oil and cognition

Regarding EVOO consumption, Berr et al. [84] followed 6947 subjects in the 3CS cohort and demonstrated that intensive use of EVOO slowed cognitive decline during the 4-year followup; compared with those that never used EVOO, subjects with moderate or intensive use showed better visual memory (OR = 0.83; 95% CI: 0.69–0.99) and verbal fluency (OR = 0.85; 95% CI: 0.70–1.03). In the same 3CS cohort, Lefe`vre-Arbogast et al. [85] demonstrated in 1329 older subjects that high consumption of EVOO and other polyphenols of plant origin including flavonoids, stilbenes, lignans, and other subclasses reduced by 50% the risk of dementia (95% CI: 20%–68%, P for trend < 0.01) in multivariate models. Valls-Pedret et al. [86] in a group of 334 elderly subjects (mean age, 66.9 years) from Barcelona, Spain, enrolled in PREDIMED, demonstrated that after 4 years of a Mediterranean diet supplemented with EVOO, memory scores, frontal cognition and global cognitive scores declined significantly less than in subjects on other diets. In the controls all cognitive composite scores decreased significantly from baseline (P < 0.05). It was concluded that in this older population, a Mediterranean diet supplemented with EVOO was associated with improved composite measures of cognitive function. In 2013, the PREDIMED-NAVARRA randomized trial [87,88] involved 522 participants at high vascular risk in a nutritional intervention that compared a Mediterranean diet supplemented with either EVOO or mixed nuts versus a low-fat control diet. After 6.5 years of nutritional intervention participants that received EVOO showed higher cognitive scores and improved cognition compared with the control group. Participants on the Mediterranean diet supplemented with EVOO had less cases of MCI than the low-fat diet controls. In summary, dietary EVOO have been shown in epidemiological observational studies and controlled clinical trials to enhance cardiovascular health and cognition in the elderly. We postulate that the multiple therapeutic mechanisms of action of EVOO may modify favorably the progression of Alzheimer disease, considered until now a purely neurodegenerative age-associated condition.

5.3.

Cerebrovascular disease in Alzheimer disease

There has been slow acceptance of the fact that cerebrovascular disease is an important component of LOAD [69–76]. This is paradoxical given that until the early XXth century ‘‘atherosclerotic dementia’’ was the main cause of ageassociated cognitive decline [89]. In 1962, Jean Delay and Serge Brion [90] described ‘‘de´mence se´nile mixte’’ combining Alzheimer disease lesions and strokes. In 1968, Tomlinson, Blessed and Roth [91,92] quantified the volume of ischemic brain lesions in demented vs. non-demented elderly and documented mixed AD with vascular pathology. In 2007, the neuropathology group at La Salpeˆtrie`re Hospital in Paris

confirmed the pathological features of mixed dementia [93]. However, according to Helena Chui and Liliana Ramı´rez Go´mez [94], the acceptance of mixed forms of Alzheimer + vascular dementia by the scientific community required extensive correlation of clinical and neuropathological data from population-based prospective, longitudinal, clinic-toautopsy cohort studies, such as The Nun Study [95], the Religious Orders Study and Rush Memory and Aging Project [96,97], the Baltimore Longitudinal Aging Study [98,99], the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) [100], the Cambridge City Over-75s Cohort [101], the Hisayama (Japan) study [102], and the Honolulu Asia Aging Study [103,104], among others. The above studies totaled almost 4000 brain autopsies. Also remarkable is the data from the USA National Alzheimer’s Coordinating Centre [105] demonstrating the presence of vascular pathology in 80% of 4629 brains from patients with Alzheimer disease confirmed by neuropathology and studied clinically at NIH-sponsored Alzheimer’s centers. According to Jon Toledo et al. [105], vascular lesions included large-vessel disease with atherosclerosis of the Circle of Willis and its branches resulting in large territorial infarcts, smallvessel disease with arteriolosclerosis and small infarcts mainly lacunes and multiple microinfarcts, ischemic periventricular leukoencephalopathy and brain hemorrhages. Cerebral amyloid angiopathy was present in 41% of the brains. Currently there is universal acceptance that cerebrovascular lesions affect the brains of most patients with LOAD contributing to the clinical manifestations [106], onset and progression of the symptoms and to the pathophysiology of the disease [107,108]. Vascular lesions in Alzheimer disease patients can be demonstrated by brain imaging [109] as well as neuropathologically [110,111]. The combination of Alzheimer plus cerebrovascular pathology is the predominant manifestation of patients in Alzheimer’s clinics, as well as in autopsyconfirmed cases of dementia in the elderly.

5.3.1.

Cholesterol in Alzheimer disease

Elevated total serum cholesterol is a well-known risk factor for vascular disease. Likewise, hypercholesterolemia in midlife has been associated with cognitive decline in the elderly [112,113]; however, the role of cholesterol in LOAD remains unsettled [114]. The e4 allele of the apolipoprotein E gene (APOE), a protein involved in cholesterol transport, is a well-defined risk for LOAD [115]. ApoE binds cholesterol acting as a ligand for cell-surface-lipoprotein receptors, such as low-density lipoprotein (LDL)-receptor-related proteins (LRP). Other genes such as clusterin or apolipoprotein J (APOJ) and sterol O-acyltransferase (SOAT1, sterol acyl-CoA cholesterol acyl transferase 1) involved in cholesterol pathways have also been studied in AD [116]. Other than cholesterol, low serum levels of docosahexaenoic acid have been associated with higher brain amyloid deposition and decreased entorhinal and hippocampal volumes [117]; it has been proposed that v-3 supplementation may slow memory decline in APOE e4 carriers [118]. Brain cholesterol, predominantly nonesterified, represents 20% of the total body cholesterol [119]; the blood-brain barrier (BBB) prevents serum cholesterol from penetrating in the CNS. In the brain, excess cholesterol is metabolized by cholesterol 24-hydroxylase into 24S-hydroxycholesterol

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(24S-HC) via the neuron-specific enzyme CYP46A1 [119] and then eliminated into the circulation across the BBB. Plasma and cerebrospinal fluid (CSF) concentrations of oxysterols have been studied in neurological diseases and elevated CSF levels of total 24S-HC are found in patients with early Alzheimer disease, along with low CYP46A1 [120–125]. In late stages, 24S-HC content at brain autopsy decreases from loss of neurons [126–128]. Alterations of CNS cholesterol metabolism have also been reported in patients with amyotrophic lateral sclerosis (ALS) [120]. ˚ ke Gustafsson’s group [129–133] has extensively Prof. Jan-A studied liver X receptors (LXRa and LXRb), natural agonists of oxysterol 24S-HC, particularly the b-isoform (LXRb) found in the brain. Adult knockout LXRb / mouse [129–131] develop motor neuron pathology along with increased spinal cord cholesterol levels, accumulation of cholesterol in ventral horn neurons, gliosis, and inflammation preceding motor neuron loss and clinical disease onset. Other LXR ligands include side-chain hydroxycholesterols such as 22R-HC, 25-HC and 26HC [134]. LXRs from brain pericytes in vitro express the ABCA1 (ATPbinding cassette, subfamily A, member 1) gene and respond to 24S-CH by reversing cholesterol transfer to ApoE, ApoA-1 and to high density lipoprotein (HDL) particles [133]. LXRs affect not only cholesterol metabolism but also buildup of brain deposits of Ab peptides, particularly Ab1-40 and Ab1-42. Transgenic mouse models of AD treated with synthetic LXR agonists that modulate brain ABCA1 gene expression show improved memory and decreased amyloid burden [134–137], including the experimental mouse model of Alzheimer disease induced by high-fat diet [138]. Therefore, brain pericytes appear to contribute via LXRb to Ab peptide clearance from the brain [133,139,140]. As described below, pericytes are critical cells for control of autoregulation of cerebral blood flow (CBF) and for the integrity of the blood-brain barrier (BBB).

5.4. Vascular factors in experimental models of Alzheimer disease Extensive clinical and experimental research has clarified the pathophysiological mechanisms involved in the association of vascular disease and Alzheimer disease [141]. It is now clear that in the presence of vascular risk factors, such as hypertension [142], patients with MCI and prodromal Alzheimer disease accumulate a higher cerebral burden of Ab and tP tangles resulting in cerebrovascular dysfunction and more severe cognitive decline [143–147]. The normal mechanism of CBF autoregulation responsible for the neurovascular coupling – the process whereby activation of a brain region evokes a local increase in blood flow – is blunted with age resulting in overall decrease of brain perfusion in the elderly [148,149]. Moreover, breakdown of the BBB [150,151] occurs due to alterations of the neurovascular unit, involving in particular the pericyte [152]. Early BBB alterations have been demonstrated in AD using imaging biomarkers [153–156]. Other early vascular alterations include brain microbleeds [157–161], abnormal cerebrovascular reactivity [162,163], reduced resting CBF [164–170], and increased cerebrovascular resistance [171–177]. Autoregulation of CBF is severely impaired in transgenic mouse models of Alzheimer disease that produce Ab peptide

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b1–42 [178]; these changes are due to cerebral endothelial and pericyte dysfunction that occur at a young age, before Ab deposition in the brain parenchyma [179]. Therefore, neurovascular unit dysfunction is a biomarker of age-associated cognitive decline and a very early event in experimental models of Alzheimer disease [178–180].

6. Extra-virgin olive oil in cognition and Alzheimer disease Three international conferences on the health effects of virgin olive oil held in Jae´n and Cordoba, Spain [181,182], and Davis, California, USA [26], concluded that EVOO improves a substantial number of vascular risk factors such as lipoprotein profile, blood pressure, obesity and glucose metabolism both in healthy subjects and in patients with type 2 diabetes. EVOO improves endothelial function [183] by modulating release of nitric oxide (NO), eicosanoids (prostaglandins and leukotrienes) and adhesion molecules, mainly by activation of NFkB by reactive oxygen species. Olive oil prevents prothrombotic conditions [184] by modifying coagulation components and platelet aggregation; by improving endothelial resistance, NOmediated vasodilatation, and antioxidative capacity. EVOO improves insulin resistance, metabolic syndrome, and diabetes. It has effects on inflammation by modulating biomarkers such as CRP involved in development of atherosclerosis, and oxidative stress [42]. In 2018, Dinu et al. [185] published a systematic review of meta-analyses on the effects of the Mediterranean diet including observational studies and randomized trials in a total population of over 12,800,000 subjects. This umbrella review concluded that EVOO appears to exert a beneficial effect in decreasing overall mortality, cardiovascular diseases, coronary artery disease, myocardial infarction, overall cancer incidence, diabetes, and neurodegenerative diseases.

6.1. Mediterranean diet and extra-virgin olive oil in Alzheimer disease In 2006, Scarmeas et al. [186,187] performed an observational study in a multi-ethnic community in Northern Manhattan, New York City, showing that higher adherence to the Mediterranean diet was associated with significantly lower risk for development of AD. Subjects with high adherence to the diet had 39% to 40% less risk for development of AD. The authors postulated that the antioxidant properties of complex phenols in the Mediterranean diet could reduce the oxidative stress and inflammation occurring in Alzheimer’s patients [188], particularly when associated with defective insulin signaling and adiposity [189–191]. In the ATTICA epidemiological study [192], high-compliance participants had lower CRP, interleukin-6, homocysteine, and fibrinogen serum levels. However, in the New York study, Gu et al. [193] showed that the Mediterranean diet did not influence CRP, insulin, and adiponectin. Nevertheless, clinical trials and cohort studies in other countries support the beneficial vascular effects of the Mediterranean diet [87,88,194–196]. Singh et al. [197] performed a systematic review and meta-analysis of the effects of Mediterranean diet on MCI and Alzheimer disease; the study

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showed that higher adherence to the diet reduced the risk of both MCI (HR = 0.73; 95% CI: 0.56–0.96, P = 0.02) and Alzheimer disease (HR = 0.64; 95% CI: 0.46–0.89, P = 0.007). The neuroprotective effects of the olive oil phenols have been extensively studied [198–201]. The phenols synthesized by the olive tree (Olea europaea L.) are found mainly in the leaves and drupes as defense against microbial or fungal invasion and insects [200]. Phenolic compounds are the main antioxidants found in EVOO and include secoiridoids, such as oleuropein (3,4-dihydroxy-phenyl-elenolic acid) and oleocanthal; simple phenols [61] such as hydroxytyrosol (3,4-dihydroxyphenol-ethanol) and tyrosol (4-hydroxy-phenyl-ethanol); and, lignans [34]. Secoiridoids hydrolyze easily during oil production and aging, increasing hydroxytyrosol and tyrosol that give a bitter taste to olive oils [67].

brain via up-regulation of P-glycoprotein (P-gp) and LDLreceptor-related protein-1 (LRP 1) across the BBB and decreases Ab toxicity in neural cells. Oleocanthal has positive effects against tP by inhibiting tau fibrillization [214–216]. Other effects mitigating microglia-mediated neuroinflammation have also been reported [217–219]. Two other phenolic components of EVOO, hydroxytyrosol [219–221] and tyrosol [222] have also been studied in Alzheimer disease. Tyrosol has neuroprotective effects in brain ischemia [222] but both have strong antioxidant capacity probably mediated by activation of the Keap1-Nrf2 pathway that regulates the antioxidant system.

6.2. Effects of extra-virgin olive oil in animal models of Alzheimer disease

The decreased incidence of breast cancer associated with dietary EVOO in a controlled clinical trial [45] confirmed the solid epidemiological evidence obtained by large populationbased studies (n = 2,130,753 subjects) demonstrating that higher adherence to the Mediterranean diet is associated with reduced cancer incidence and mortality [223,224]. These data are highly suggestive that EVOO or its components might have anti-oncogenic effects in breast cancer [45], colorectal cancer [225], gastric cancer, liver cancer, head and neck cancer, and prostate cancer [223–226]. In the USA, Ornish et al. [227,228] demonstrated in patients with biopsy-proven prostate cancer that dietary changes (similar to those of the Mediterranean diet) induced within 3 months detectable changes in gene expression resulting in 48 up-regulated genes and 453 down-regulated transcripts affecting pathways that modulate tumorigenesis, including protein metabolism, intracellular protein traffic, and protein phosphorylation [227]. After 5 years, relative telomere length increased in the intervention group compared with the control group [228]. Short telomere length is a marker of poor outcome in cancer and other conditions. Intensive research has recently begun to elucidate the importance of epigenetic factors in the pathogenesis of Alzheimer disease. In particular, epigenome-wide association studies (EWAS) have revealed changes in the pattern of methylation and expression of genes involved in the vascular pathology and deposition of Ab and tP in LOAD. We recently reviewed [229–231] the critical role of methylenetetrahydrofolate reductase (MTHFR) and cystathionine-gamma-lyase (CTH) gene polymorphisms, and the transsulfuration pathway responsible for plasma elevation of total homocysteine, as well as the importance of nutritional factors including the Bvitamins folate, vitamin B12, and vitamin B6 in aging and LOAD pathology. Elevation of homocysteine – an independent vascular risk factor – is important in oxidative stress contributing to the decrease of S-adenosyl-L-methionine (SAM) levels, which induce demethylation of DNA resulting in over-expression of genes involved in LOAD pathology. Changes affecting oncogene expression induced by EVOO have not been described but other anti-oncogenic mechanisms have been postulated, including the following. Flavonoids and lignans are very good agonists of estrogen receptor beta (ERb) [232], a receptor involved in dampening the immune system (including microglia) [233], inducing genes

EVOO contains phenolic compounds with strong antioxidant properties in brain tissue potentially useful for prevention and treatment of neurodegenerative diseases [201]. Oleuropein and hydroxytyrosol are direct free radical scavengers; oleocanthal has Ibuprofen-like activity [202] and is a strong inhibitor of cyclooxygenases, like hydroxytyrosol; oleuropein blocks LDL oxidation [203]. Oleuropein aglycone fed to an Ab mouse model induced autophagy via the Ca2+-calmodulindependent kinase b-AMPK proceeding through mTOR inhibition [203]. Oleuropein has protective effects against Ab deposition in TgCRND8 mice [204] and protects against pyroglutamylated-3 amyloid-b toxicity [205]. Pitozzi et al. [206,207] demonstrated that chronic feeding of EVOO to ageing rats and mice improved brain biochemical parameters, memory and motor coordination to levels similar to those of young animals by controlling oxidative stress, activating glutathione reductase, reducing glutathione, and enhancing superoxide dismutase. Dietary EVOO fed to the senile mouse model SAMP8, improved learning and memory [208]. Qosa et al. [209,210] fed EVOO to transgenic SwDI mice expressing human amyloid b precursor protein (APP) under control of Thy 1.2 neuronal promoter harboring double Swedish mutations and the amyloid angiopathy Dutch and Iowa vasculotropic Ab mutations. These mice begin to accumulate Ab in the brain at age 2 to 3 months and amyloid deposits are extensive at 12 months of age. Mice fed EVOOenriched diet before onset of Ab accumulation showed reduced total brain Ab and tP brain levels and EVOO also improved mouse cognition. Feeding mice with EVOO-enriched diet for 3 months after onset of Ab accumulation resulted in reduced Ab but tP brain levels and cognition were unaffected. EVOO likely reduced brain Ab by enhancing Ab clearance across the BBB and by lowering Ab production via modulation of APP processing. Oleocanthal from EVOO appears to have similar effects [211]. Qosa et al. [210] show reduction of amyloid load in the hippocampal parenchyma and microvessels. Oleocanthal treatment in cultured mice brain endothelial cells and in the C57BL/6 wild-type mice model of Alzheimer disease [212,213] confirmed that oleocanthal enhances Ab clearance from the

6.3. Relevant anti-oncogenic effects of olive oil in lateonset Alzheimer disease

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involved in preventing oxidative stress [234], increasing vasodilation, reducing blood pressure [235], regulating endothelium [236], inhibiting the activity of mTORC1 by disruption of ERb-raptor-mTOR complex assembly [237], inhibiting expression of NFkB [238], as well as the expression of oncogenic genes such as cyclin D1, increasing expression of cyclin-dependent kinase inhibitors (p21, p27, and p57) [239], as well as the tumor suppressor gene, PTEN [240]. Some lignans, including pinoresinol and syringaresinol luteolin, and flavonoids, including apigenin and luteolin, have powerful anti-inflammatory activity acting via ERb by inhibiting 5-lipoxygenase (5-LOX) [240]. ERb agonists decrease expression of the protein 5-lipoxygenase associated protein, which is required for leukotriene synthesis [241]. Overexpression of LOX-5 worsens memory and tau pathology in mice [242]. Oleic acid could have an antiproliferative effect by affecting the expression of human oncogenes; in particular it specifically represses the transcriptional activity of the Her-2/neu gene [243], analogous to the effect of Herceptin, a novel breast cancer treatment. The hydrocarbon squalene protects mammary epithelial cells against intracellular oxidative stress and DNA oxidative damage [244]. In vitro studies of EVOO polyphenols suggest a potential role in breast cancer prevention [245]. Oleocanthal inhibits in vitro and in vivo tumor growth and proliferation, migration, and invasiveness of breast cancer cells [246]. Oleuropein has been associated with increased apoptosis of cultured breast cancer cells [247,248]. Hydroxytyrosol protects against oxidative DNA damage reducing intracellular reactive oxygen species in human breast epithelial cells [249]. Dietary consumption of lignans [34] has been associated with a lower risk of breast cancer in postmenopausal women [250].

7.

Conclusion

We have reviewed the extensive literature on the nutritional and health effects of EVOO, emphasizing the demonstrated cardiovascular and cerebrovascular benefits that could positively affect the vascular component of LOAD. Moreover, EVOO and some of its phenolic components appear to have numerous therapeutic effects in vitro and in animal models of Alzheimer disease. Given the proven efficacy of EVOO against vascular disease, its palatability, nutritional value and easy acceptance we conclude that EVOO should be tested in a controlled clinical trial for the prevention of LOAD.

Disclosure of interest The authors declare that they have no competing interest.

Acknowledgments The authors gratefully acknowledge the careful review and valuable comments from Prof. Margaret Warner and Prof. Jan˚ ke Gustafsson at the University of Houston. Prof. Roma´n’s A

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research is funded by the Wareing Family Fund and the Scurlock Foundation, Houston, Texas, USA.

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Please cite this article in press as: Roma´n GC, et al. Extra-virgin olive oil for potential prevention of Alzheimer disease. Revue neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.017