Extra-virgin olive oil for potential prevention of Alzheimer disease

Extra-virgin olive oil for potential prevention of Alzheimer disease

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx Available online at ScienceDirect www.sciencedirect.com Environmental Neurology ...

1MB Sizes 1 Downloads 289 Views

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

Available online at

ScienceDirect www.sciencedirect.com

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

NEUROL-2116; No. of Pages 19

2

revue neurologique xxx (2019) xxx–xxx

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].

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

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

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

3

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

NEUROL-2116; No. of Pages 19

4

revue neurologique xxx (2019) xxx–xxx

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].

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

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

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].

5

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.

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

NEUROL-2116; No. of Pages 19

6

revue neurologique xxx (2019) xxx–xxx

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

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

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].

7

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

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

NEUROL-2116; No. of Pages 19

8

revue neurologique xxx (2019) xxx–xxx

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

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

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

(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

9

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

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

NEUROL-2116; No. of Pages 19

10

revue neurologique xxx (2019) xxx–xxx

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

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

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

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

11

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

references

[1] Terry M. A long line of Alzheimer’s failures: Roche drops two drug trials; 2019, https://www.Biospace.com [Published Jan 30, 2019]. [2] Stout C, Marrow J, Brandt Jr EN, Wolf S. Unusually low incidence of death from myocardial infarction. Study of an Italian-American community in Pennsylvania. JAMA 1964;188:845–9. [3] Wolf S. Mortality from myocardial infarction in Roseto. JAMA 1966;195:142. [4] Egolf B, Lasker J, Wolf S, Potvin L. The Roseto effect: a 50year comparison of mortality rates. Am J Public Health 1992;82:1089–92. [5] Wolf S, Bruhn JG. The power of clan. The influence of human relationships on heart disease. New Brunswick: Transactions Publishers; 1993. [6] Keys A. Seven countries: a multivariate analysis of death and coronary heart disease. Cambridge: Harvard University Press; 1980. [7] Keys A, Menotti A, Karvonen MJ, Aravanis C, Blackburn H, Buzina R, et al. The diet and 15-year death rate in the Seven Countries study. Am J Epidemiol 1986;124:903–15. [8] Menotti A, Kromhout D, Blackburn H, Fidanza F, Buzina R, Nissinen A, et al. Food intake patterns and 25-year mortality from coronary heart disease: cross-cultural correlations in the Seven Countries Study. Eur J Epidemiol 1999;15:507–15. [9] Keys A, Grande F. Role of dietary fat in human nutrition. Diet and the epidemiology of coronary heart disease. Am J Public Health 1957;47:1520–30. [10] Kagawa Y, Nishizawa M, Suzuki M, Miyatake T, Hamamoto T, Goto K, et al. Eicosapolyenoic acids of serum lipids of Japanese islanders with low incidence of cardiovascular diseases. J Nutr Sci Vitaminol (Tokyo) 1982;28:441–53. [11] Fidanza F, Alberti A, Lanti M, Menotti A. Mediterranean adequacy index: correlation with 25-year mortality from coronary heart disease in the Seven Countries Study. Nutr Metab Cardiovasc Dis 2004;14:254–8. [12] Moschandreas J, Kafatos A, Aravanis C, Dontas A, Menotti A, Kromhou D. Long-term predictors of survival for the Seven Countries Study cohort from Crete: from 1960 to 2000. Int J Cardiol 2005;100:85–91. [13] Menotti A, Puddu PE. How the seven countries study contributed to the definition and development of the Mediterranean diet concept: a 50-year journey. Nutr Metabol Cardiovasc Dis 2015;25:245e52. [14] Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary artery disease. Lancet 1992;339:1523–6. [15] de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, et al. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet 1994;343:1454–9. [16] Sandker GW, Kromhout D, Aravanis C, Bloemberg BP, Mensink RP, Karalias N, et al. Serum cholesteryl ester fatty acids and their relation with serum lipids in elderly men in Crete and The Netherlands. Eur J Clin Nutr 1993;47:201–8. [17] de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after

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

NEUROL-2116; No. of Pages 19

12

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

revue neurologique xxx (2019) xxx–xxx

myocardial infarction: final report of the Lyon Diet Heart Study. Circulation 1999;99:779–85. de Lorgeril M, Salen P. The Mediterranean diet in secondary prevention of coronary heart disease. Clin Invest Med 2006;29:154–8. Bourre JM, Galea F. An important source of omega-3 fatty acids, vitamins D and E, carotenoids, iodine and selenium: a new natural multi-enriched egg. J Nutr Health Aging 2006;10(5):371–6. Alpe´rovitch A, Amouyel P, Dartigues J-F, Ducimetie´re P, Mazoyer B, Ritchie K, et al. Les e´tudes e´pide´miologiques sur le vieillissement en France : de l’e´tude Paquid a` l’e´tude des Trois Cite´s. C R Biologies 2002;325:665–72. Letois F, Mura T, Scali J, Gutierrez L-A, Fe´ art C, Berr C. Nutrition and mortality in the elderly over 10 years of follow-up: the Three-City study. Br J Nutr 2016;116:882–9. Fe´art C, Samieri C, Rondeau V, Amieva H, Portet F, Dartigues JF, et al. Adherence to a Mediterranean diet, cognitive decline, and risk of dementia. JAMA 2009;302(6):638–48. Samieri C, Morris MC, Bennett DA, Berr C, Amouyel P, Dartigues JF, et al. Fish intake, genetic predisposition to Alzheimer disease, and decline in global cognition and memory in 5 cohorts of older persons. Am J Epidemiol 2018;187(5):933–40. http://dx.doi.org/10.1093/aje/kwx330. Samieri C, Fe´art C, Proust-Lima C, Peuchant E, Tzourio C, Stapf C, et al. Olive oil consumption, plasma oleic acid, and stroke incidence: the Three-City Study. Neurology 2011;77(5):418–25. http://dx.doi.org/10.1212/ WNL.0b013e318220abeb. Gaye B, Canonico M, Perier MC, Samieri C, Berr C, Dartigues JF, et al. Ideal cardiovascular health, mortality, and vascular events in elderly subjects: the Three-City Study. J Am Coll Cardiol 2017;69(25):3015–26. http:// dx.doi.org/10.1016/j.jacc.2017.05.011. Visioli F, Franco M, Toledo E, Luchsinger J, Willett WC, Hu FB, et al. Olive oil and prevention of chronic diseases: summary of an International conference. Nutr Metab Cardiovasc Dis 2018;28(7):649–56. http://dx.doi.org/ 10.1016/j.numecd.2018.04.004. Serra-Majem L, Roma´n B, Estruch R. Scientific evidence of interventions using the Mediterranean diet: a systematic review. Nutr Rev 2006;64(2 Pt 2):S27–47. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003;348(26):2599–608. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. Am J Clin Nutr 2010;92:1189–96. ´ , Hershey MS, Zazpe I, Martı´nez-Gonza´lez MA Trichopoulou A. Transferability of the Mediterranean diet to non-Mediterranean countries: what is and what is not the Mediterranean diet. Nutrients 2017;9(11):E1226. Tierney AC, Zabetakis I. Changing the Irish dietary guidelines to incorporate the principles of the Mediterranean diet: proposing the MedE´ire diet. Public Health Nutr 2018;22(2):375–81. http://dx.doi.org/10.1017/ S136898001800246X. Guasch-Ferre´ M, Hu FB, Martı´nez-Gonza´lez MA, Fito´ M, Bullo´ M, Estruch R, et al. Olive oil intake and risk of cardiovascular disease and mortality in the PREDIMED Study. BMC Med 2014;12:78. http://dx.doi.org/10.1186/ 1741-7015-12-78. Toledo E, Martı´nez-Gonza´lez MA. Fruits, vegetables, and legumes: sound prevention tools. Lancet 2017;390(10107):2017–8. http://dx.doi.org/10.1016/S01406736(17)32251-1.

[34] Rodrı´guez-Garcı´a C, Sa´nchez-Quesada C, Toledo E, Delgado-Rodrı´guez M, Gaforio JJ. Naturally lignan-rich foods: a dietary tool for health promotion? Molecules 2019;24:917. http://dx.doi.org/10.3390/molecules24050917. [35] Matalas A-L, Zampelas A, Stavrinos V, Wolinsky I, editors. The Mediterranean diet: constituents and health promotion. The CRC Press modern nutrition series. Boca Raton: CRC Press; 2001. [36] Psilakis M, Psilakis N. La cuisine Cre´toise. Heraklion (Crete) Greece: Karmanor; 2000. [37] Anthony D, Anthony E, Anthony S. Lebanese cookbook. Secaucus, NJ: Chartwell Books; 1978. [38] Estruch R, Martı´nez-Gonza´lez MA, Corella D, SalasSalvado J, Ruiz-Gutie´rrez V, Covas MI, et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 2006;145:1–11. [39] Martı´nez-Gonza´lez MA, Corella D, Salas-Salvado´ J, for the PREDIMED Study Investigators. et al. Cohort profile: design and methods of the PREDIMED study. Int J Epidemiol 2012;41(2):377–85. [40] Estruch R, Ros E, Salas-Salvado´ J, Covas M-I, Corella D, Aro´s F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med 2018;378(25):e34. http:// dx.doi.org/10.1056/NEJMoa1800389. [41] Dome´nech M, Roma´n P, Lapetra J, Garcı´a de la Corte FJ, Sala-Vila A, de la Torre R, et al. Mediterranean diet reduces 24-hour ambulatory blood pressure, blood glucose, and lipids: one-year randomized clinical trial. Hypertension 2014;64(1):69–76. http://dx.doi.org/10.1161/ HYPERTENSIONAHA.113.03353. [42] Medina-Remo´n A, Casas R, Tressserra-Rimbau A, Ros E, Martı´nez-Gonza´lez MA, Fito´ M, et al. Polyphenol intake from a Mediterranean diet decreases inflammatory biomarkers related to atherosclerosis: a sub-study of the PREDIMED trial. Br J Clin Pharmacol 2017;83:114–28. [43] Wang DD, Zheng Y, Toledo E, Razquin C, Ruiz-Canela M, Guasch-Ferre´ M, et al. Lipid metabolic networks, Mediterranean diet and cardiovascular disease in the PREDIMED trial. Int J Epidemiol 2018;47(6):1830–45. http:// dx.doi.org/10.1093/ije/dyy198. [44] Galilea-Zabalza I, Buil-Cosiales P, Salas-Salvado´ J, Toledo E, Ortega-Azorı´n C, Dı´ez-Espino J, et al. Mediterranean diet and quality of life: baseline cross-sectional analysis of the PREDIMED-PLUS trial. PLoS One 2018;13(6):e0198974. http://dx.doi.org/10.1371/journal.pone.0198974. [45] Toledo E, Salas-Salvado´ J, Donat-Vargas C, Buil-Cosiales P, Estruch R, Ros E, et al. Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: a randomized clinical trial. JAMA Intern Med 2015;175(11):1752–60. http://dx.doi.org/ 10.1001/jamainternmed.2015.4838. [46] Serra-Majem L, Ngo de la Cruz J, Ribas J, Salleras L. Mediterranean diet and health: is all the secret in olive oil? Pathophysiol Haemost Thromb 2003/2004;33:461–5. [47] Foscolou A, Critselis E, Panagiotakos D. Olive oil consumption and human health: a narrative review. Maturitas 2018;118:60–6. [48] Riley FR. Olive oil production on Bronze Age Crete: nutritional properties, processing methods, and storage life of Minoan olive oil. Oxford J Archaeol 2002;21:63–75. [49] International Olive Oil Council. International trade standard applying to olive oil and olive pomace oil. https:// www.oliveoiltimes.com/library/ ioc-november-2017-newsletter.pdf. [50] Gorinstein S, Martin-Belloso O, Katrich E, Lojek A, Ciz M, Gligelmo-Miguel N, et al. Comparison of the contents of the main biochemical compounds and the antioxidant activity of some Spanish olive oils as determined by four

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

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

different radical scavenging tests. J Nutr Biochem 2003;14:154–9. Marklund M, Wu JHY, Imamura F, Del Gobbo LC, Fretts A, de Goede J, et al. Biomarkers of dietary omega-6 fatty acids and incident cardiovascular disease and mortality: an individual-level pooled analysis of 30 cohort studies. Circulation 2019. http://dx.doi.org/10.1161/ CIRCULATIONAHA.118.03890. Kiritsakis A, Aspris P, Markakis P. Trans isomerization of certain vegetable oils during frying. In: Charambous G, editor. Flavors and off flavors, Proceedings of the 6th International Flavor Conference. Amsterdam: Elsevier; 1989. p. 883–96. Mozaffarian D, Katan MB, Ascherio A, Stampfer MJ, Willett WC. Trans fatty acids and cardiovascular disease. N Engl J Med 2006;354:1601–13. Barnard ND, Bunner AE, Agarwal U. Saturated and trans fats and dementia: a systematic review. Neurobiol Aging 2014;35(Suppl. 2):S65–73. http://dx.doi.org/10.1016/ j.neurobiolaging.2014.02.030. Ganguly R, Pierce GN. The toxicity of dietary trans fats. Food Chem Toxicol 2015;78:170–6. http://dx.doi.org/ 10.1016/j.fct.2015.02.004. Sacks FM, Lichtenstein AH, Wu JHY, Appel LJ, Creager MA, Kris-Etherton PM, et al. Dietary fats and cardiovascular disease: a presidential advisory from the American Heart Association. Circulation 2017;136(3):e1–23. http:// dx.doi.org/10.1161/CIR.0000000000000510. Howard BV, Van Horn L, Hsia J, Manson JE, Stefanick ML, Wassertheil-Smoller S, et al. Low-fat dietary pattern and risk of cardiovascular disease. The Women’s Health Initiative randomized controlled dietary trial. JAMA 2006;295:655–66. Thomsen C, Storm H, Holst JJ, Hermansen H. Differential effects of saturated and monounsaturated fats on postprandial lipemia and glucagon-like peptide 1 responses in patients with type 2 diabetes. Am J Clin Nutr 2003;77:605–11. Ros E. Dietary cis-monounsaturated fatty acids and metabolic control in type 2 diabetes. Am J Clin Nut 2003;78(Suppl.):617S–25S. Lim CC, Hayes RB, Ahn J, Shao Y, Silverman DT, Jones RR, et al. Mediterranean diet and the association between air pollution and cardiovascular disease mortality risk. Circulation 2019;139:1766–75. http://dx.doi.org/10.1161/ CIRCULATIONAHA.118.035742. Owen RW, Mier W, Giacosa A, Hule WE, Spiegelhalder B, Bartsch H. Phenolic compounds and squalene in olive oils: the concentration and antioxidant potential of total phenols, simple phenols, secoiroids, lignans and squalene. Food Chem Toxicol 2000;38:647–59. Ulbricht CE. An evidence-based systematic review of betasitosterol, sitosterol (22,23-dihydrostigmasterol, 24ethylcholesterol) by the Natural Standard Research Collaboration. J Diet Suppl 2016;13(1):35–92. Andrikopoulos NK, Kaliora AC, Assimopoulou AN, Papageorgiou VP. Inhibitory activity of minor polyphenolic and nonpolyphenolic constituents of olive oil against in vitro low-density lipoprotein oxidation. J Med Food 2002;5:1–7. Wani TA, Masoodi FA, Gani A, Baba WN, Rahmanian N, Akhter R, et al. Olive oil and its principal bioactive compound: hydroxytyrosol – A review of the recent literature. Trends Food Sci Technol 2018;77:77–90. Weinbrenner T, Fito M, de la Torre R, Saez GT, Rijken P, Tormos C, et al. Olive oils high in phenolic compounds modulate oxidative/antioxidative status in men. J Nutr 2004;134:2314–21.

13

[66] Covas MI, de la Torre K, Farre-Albaladejo M, Kaikkonen J, Fito M, Lopez-Sabater C, et al. Postprandial LDL phenolic content and LDL oxidation are modulated by olive oil phenolic compounds in humans. Free Radic Biol Med 2006;40:608–16. [67] Sun Y, Dayong Zhou D, Shahidia F. Antioxidant properties of tyrosol and hydroxytyrosol saturated fatty acid esters. Food Chem 2018;245:1262–8. [68] Razquin C, Liang L, Toledo E, Clish CB, Ruiz-Canela M, Zheng Y, et al. Plasma lipidome patterns associated with cardiovascular risk in the PREDIMED trial: a case-cohort study. Int J Cardiol 2018;253:126–32. http://dx.doi.org/ 10.1016/j.ijcard.2017.10.026. [69] Gorelick PB, Scuteri A, Black SE, DeCarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke 2011;42(9):2672–713. http://dx.doi.org/10.1161/STR.0b013e3182299496. [70] Roma´n GC. Alzheimer’s disease research: have we forgotten the cerebrovascular circulation? Alzheimer Dis Assoc Disord 2008;22(1):1–3. [71] Roma´n GC, Nash DT, Fillit H. Translating current knowledge into dementia prevention. Alzheimer Dis Assoc Disord 2012;26(4):295–9. http://dx.doi.org/10.1097/ WAD.0b013e31825cbc4b. [72] Roma´n GC, Boller F. Vascular factors in neurodegenerative diseases: a path towards treatment and prevention. Funct Neurol 2014;29(2):85–6. [73] Leshner AI, Landis S, Stroud C, Downey A. Preventing cognitive decline and dementia: a way forward. Washington, DC: National Academy of Sciences; 2017. [74] Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol 2011;10:819–28. [75] Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol 2014;13(8):788–94. http://dx.doi.org/10.1016/S14744422(14)70136-X. [76] Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, et al. Vascular dysfunction – The disregarded partner of Alzheimer’s disease. Alzheimers Dement 2019;15(1):158–67. http://dx.doi.org/10.1016/j.jalz.2018.07.222. [77] Satizabal CL, Beiser AS, Chouraki V, Cheˆne G, Dufouil C, Seshadri S. Incidence of dementia over three decades in the Framingham Heart Study. N Engl J Med 2016;374(6):523–32. http://dx.doi.org/10.1056/ NEJMoa1504327. [78] Hardman RJ, Kennedy G, Macpherson H, Scholey AB, Pipingas A. Adherence to a Mediterranean-style diet and effects on cognition in adults: a qualitative evaluation and systematic review of longitudinal and prospective trials. Front Nutr 2016;3:22. http://dx.doi.org/10.3389/ fnut.2016.00022. [79] Brouwer-Brolsma EM, Benati A, van de Wiel A, van Lee L, de Vries JHM, Feskens EJM, et al. Higher Mediterranean Diet scores are not cross-sectionally associated with better cognitive scores in 20- to 70-year-old Dutch adults: the NQplus study. Nutr Res 2018;59:80–9. http://dx.doi.org/ 10.1016/j.nutres.2018.07.013. [80] Gardener S, Gu Y, Rainey-Smith SR, Keogh JB, Clifton PM, Mathieson SL, et al. Adherence to a Mediterranean diet and Alzheimer’s disease risk in an Australian population. Transl Psychiatry 2012;2:e164. http://dx.doi.org/10.1038/ tp.2012.91. [81] Gardener SL, Rainey-Smith SR, Barnes MB, Sohrabi HR, Weinborn M, Lim YY, et al. Dietary patterns and cognitive

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

NEUROL-2116; No. of Pages 19

14

[82]

[83]

[84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92] [93] [94]

[95]

[96]

[97]

revue neurologique xxx (2019) xxx–xxx

decline in an Australian study of ageing. Mol Psychiatry 2015;20(7):860–6. http://dx.doi.org/10.1038/mp.2014.79. Rainey-Smith SR, Gu Y, Gardener SL, Doecke JD, Villemagne VL, Brown BM, et al. Mediterranean diet adherence and rate of cerebral Ab-amyloid accumulation: data from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing. Transl Psychiatry 2018;8(1):238. http://dx.doi.org/10.1038/s41398-018-0293-5. Karstens AJ, Tussing-Humphreys L, Zhan L, Rajendran N, Cohen J, Dion C, et al. Associations of the Mediterranean diet with cognitive and neuroimaging phenotypes of dementia in healthy older adults. Am J Clin Nutr 2019;109(2):361–8. http://dx.doi.org/10.1093/ajcn/nqy275. Berr C, Portet F, Carriere I, Akbaraly TN, Feart C, Gourlet V, et al. Olive oil and cognition: results from the Three-City study. Dement Geriatr Cogn Disord 2009;28(4):357–64. http://dx.doi.org/10.1159/000253483. Lefe`vre-Arbogast S, Gaudout D, Bensalem J, Letenneur L, Dartigues J-F, Hejblum BP, et al. Pattern of polyphenol intake and the long-term risk of dementia in older persons. Neurology 2018;90:e1979–88. http://dx.doi.org/ 10.1212/WNL.0000000000005607. Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R, Martı´nez-Gonza´lez MA, et al. Mediterranean diet and age-related cognitive decline: a randomized clinical trial. JAMA Intern Med 2015;175(7):1094–103. http:// dx.doi.org/10.1001/jamainternmed.2015.166. Martı´nez-Lapiscina EH, Clavero P, Toledo E, Estruch R, Salas-Salvado´ J, San Julia´n B, et al. Mediterranean diet improves cognition: the PREDIMED-NAVARRA randomised trial. J Neurol Neurosurg Psych 2013;84(12):1318–25. http:// dx.doi.org/10.1136/jnnp-2012-304792. Martı´nez-Lapiscina EH, Clavero P, Toledo E, San Julia´n B, Sanchez-Tainta A, Corella D, et al. Virgin olive oil supplementation and long-term cognition: the PREDIMEDNAVARRA randomized trial. J Nutr Health Aging 2013;17(6):544–52. http://dx.doi.org/10.1007/s12603-0130027-6. Roma´n GC. Historical evolution of the concept of dementia: a systematic review from 2000 BC to AD 2000. In: Qizilbash N, Schneider LS, Chui H, Tariot P, Brodaty H, Kay J, Erkinjuntti T, editors. Evidence-based dementia practice. Oxford: Blackwell Science; 2002. p. 199–227 [Chapter III.1]. Delay J, Brion S. De´mence se´nile mixte. In: Delay J, Brion S, editors. Les de´mences tardives. Paris: Masson; 1962. p. 195–201. Tomlinson BE, Blessed G, Roth M. Observations on the brains of nondemented old people. J Neurol Sci 1968;7:331–56. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970;11:205–42. Zekry D, Duyckaerts C, Hauw JJ. De´mences vasculaires et de´mences mixtes. Presse Med 2007;36(10 Pt. 2):1469–76. Chui HC, Ramirez Gomez L. Clinical and imaging features of mixed Alzheimer and vascular pathologies. Alzheimers Res Ther 2015;7(1):21. http://dx.doi.org/10.1186/s13195015-0104-7. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease: the Nun Study. JAMA 1997;277:813–7. Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA. The neuropathology of older persons with and without dementia from community versus clinic cohorts. J Alzheimers Dis 2009;18:691–701. Bennett DA, Wilson RS, Arvanitakis Z, Boyle PA, de ToledoMorrell L, Schneider JA. Selected findings from the

[98]

[99]

[100]

[101]

[102]

[103]

[104]

[105]

[106]

[107]

[108]

[109]

[110]

[111]

[112] [113]

Religious Orders Study and Rush Memory and Aging Project. J Alzheimers Dis 2013;33:S397–403. Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O’Brien RJ. Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol 2008;64:168–76. Dolan H, Crain B, Troncoso J, Resnick SM, Zonderman AB, Obrien RJ. Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of Aging cohort. Ann Neurol 2010;68:231–40. Richardson K, Stephan BC, Ince PG, Brayne C, Matthews FE, Esiri MM. The neuropathology of vascular disease in the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Curr Alzheimer Res 2012;9:687– 96. Brayne C, Richardson K, Matthews FE, Fleming J, Hunter S, Xuereb JH, et al. Neuropathological correlates of dementia in over-80-year-old brain donors from the populationbased Cambridge City Over-75s Cohort (CC75C) study. J Alzheimers Dis 2009;18:645–58. Matsui Y, Tanizaki Y, Arima H, Yonemoto K, Doi Y, Ninomiya T, et al. Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama study. J Neurol Neurosurg Psychiatry 2009;80:366–70. White L. Brain lesions at autopsy in older JapaneseAmerican men as related to cognitive impairment and dementia in the final years of life: a summary report from the Honolulu-Asia aging study. J Alzheimers Dis 2009;18:713–25. Launer LJ, Hughes TM, White LR. Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia Aging Study Autopsy Study. Ann Neurol 2011;70:774–80. Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain 2013;136(9):2697–706. http://dx.doi.org/10.1093/ brain/awt188. Sachdev P, Kalaria R, O’Brien J, Skoog I, Alladi S, Black SE, et al. Diagnostic criteria for vascular cognitive disorders. A VASCOG statement. Alzheimer Dis Assoc Disord 2014;28(3):206–18. http://dx.doi.org/10.1097/ WAD.0000000000000034. Roma´n GC, Kalaria RN. Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. Neurobiol Aging 2006;27:1769–85. Chui HC, Ramirez Gomez L. Vascular contributions to cognitive impairment in late life. Neurol Clin 2017;35:295– 323. http://dx.doi.org/10.1016/j.ncl.2017.01.007. Mimenza-Alvarado A, Aguilar-Navarro SG, Yeverino´ vila-Funes JA, Roma´n GC. Castro S, Mendoza-Franco C, A Neuroimaging characteristics of small-vessel disease in older adults with normal cognition, mild cognitive impairment, and Alzheimer disease. Dement Geriatr Cogn Dis Extra 2018;8(2):199–206. http://dx.doi.org/10.1159/ 000488705. Kalaria RN. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease. Acta Neuropathol 2016;131:659–85. Wallin A, Roma´n GC, Esiri M, Kettunen P, Svensson J, Paraskevas GP, et al. Update on vascular cognitive impairment associated with subcortical small-vessel disease. J Alzheimers Dis 2018;62:1417–41. Shobab LA, Hsiung G-YR, Feldman HH. Cholesterol in Alzheimer’s disease. Lancet Neurol 2005;4:841–52. Anstey KJ, Lipnicki DM, Low LF. Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of

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

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

[114]

[115]

[116]

[117]

[118]

[119]

[120]

[121]

[122]

[123]

[124]

[125] [126]

[127]

[128]

[129]

prospective studies with meta-analysis. Am J Geriatr Psychiatry 2008;16:343–54. Mathew A, Yoshida Y, Maekawa T, Sakthy Kumar D. Alzheimer’s disease: cholesterol a menace? Brain Res Bull 2011;86:1–12. Loera-Valencia R, Goikolea J, Parrado-Fernandez C, Merino-Serrais P, Maioli S. Alterations in cholesterol metabolism as a risk factor for developing Alzheimer’s disease: potential novel targets for treatment. J Steroid Biochem Mol Biol 2019;190:104–14. http://dx.doi.org/ 10.1016/j.jsbmb.2019.03.003. Loera-Valencia R, Piras A, Ismail MAM, Manchanda S, Eyjolfsdottir H, Saido TC, et al. Targeting Alzheimer’s disease with gene and cell therapies. J Intern Med 2018;284(1):2–36. Yassine HN, Feng Q, Azizkhanian I, Rawat V, Castor K, Fonteh AN, et al. Association of serum docosahexaenoic acid with cerebral amyloidosis. JAMA Neurol 2017;73:1208–16. Yassine HN, Braskie MN, Mack WJ, Castor KJ, Fonteh AN, Schneider LS, et al. Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E e4 carriers: a review. JAMA Neurol 2017;74(3):339–47. http://dx.doi.org/10.1001/ jamaneurol.2016.4899. Russell DW, Halford RW, Ramirez DMO, Shah R, Kotti T. Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain. Annu Rev Biochem 2009;78:1017–40. http://dx.doi.org/10.1146/ annurev.biochem.78.072407.103859. ˚ , Warner Abdel-Khalik J, Yutuc E, Crick PC, Gustafsson J-A M, Roma´n G, et al. Defective cholesterol metabolism in amyotrophic lateral sclerosis. J Lipid Res 2017;58:267–78. http://dx.doi.org/10.1194/jlr.P071639. Bjo¨rkhem I. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med 2006;260(6):493–508. Bretillon L, Siden A, Wahlund O, Lutjohann D, Minthon L, Crisby M, et al. Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases. Neurosci Lett 2000;293:87–90. Leoni V, Masterman T, Mousavi FS, Wretlind B, Wahlund LO, Diczfalusy U, et al. Diagnostic use of cerebral and extracerebral oxysterols. Clin Chem Lab Med 2004;42:186–91. Bjo¨rkhem I, Heverin M, Leoni V, Meaney S, Diczfalusy U. Oxysterols and Alzheimer disease. Acta Neurol Scand Suppl 2006;185:43–9. Bjo¨rkhem I. Five decades with oxysterols. Biochimie 2013;95:448–54. Wang HL, Wang YY, Liu XG, Kuo SH, Liu N, Song QY, et al. Cholesterol, 24-hydroxycholesterol, and 27hydroxycholesterol as surrogate biomarkers in cerebrospinal fluid in mild cognitive impairment and Alzheimer’s disease: a meta-analysis. J Alzheimers Dis 2016;51(1):45–55. http://dx.doi.org/10.3233/JAD-150734. Testa G, Staurenghi E, Zerbinati C, Gargiulo S, Iuliano L, Giaccone G, et al. Changes in brain oxysterols at different stages of Alzheimer’s disease: their involvement in neuroinflammation. Redox Biol 2016;10:24–33. Bogdanovic N, Bretillon L, Lund EG, Diczfalusy U, Lannfelt L, Winblad B, et al. On the turnover of brain cholesterol in patients with Alzheimer’s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett 2001;314:45–8. ˚. Andersson S, Gustafsson N, Warner M, Gustafsson J-A Inactivation of liver X receptor beta leads to adult-onset motor neuron degeneration in male mice. Proc Natl Acad Sci U S A 2005;102:3857–62.

15

[130] Kim HJ, Fan X, Gabbi C, Yakimchuk K, Parini P, Warner M, et al. Liver X receptor beta (LXRb): a link between beta-sitosterol and amyotrophic lateral sclerosisParkinson’s dementia. Proc Natl Acad Sci U S A 2008;105:2094–9. [131] Bigini P, Steffensen KR, Ferrario A, Diomede L, Ferrara G, Barbera S, et al. Neuropathologic and biochemical changes during disease progression in liver X receptor b / mice, a model of adult neuron disease. J Neuropathol Exp Neurol 2010;69(6):593–605. [132] Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JA, Holtzman DM, et al. Critical role of astroglial apolipoprotein E and LXRa expression for microglial Ab phagocytosis. J Neurosci 2011;31:7049–59. [133] Saint-Pol J, Vandenhaute E, Boucau MC, Candela P, Dehouck L, Cecchelli R, et al. Brain pericytes ABCA1 expression mediates cholesterol efflux but not cellular amyloid-b peptide accumulation. J Alzheimer Dis 2014;30:489–503. [134] Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, et al. The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer’s disease. J Biol Chem 2005;280:4079–88. [135] Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK, et al. The LXR agonist TO901317 selectively lowers hippocampal Ab42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease. Mol Cell Neurosci 2007;34:621–8. [136] Burns MP, Vardanian L, Pajoohesh-Ganji A, Wang L, Cooper M, Harris DC, et al. The effects of ABCA1 on cholesterol efflux and Ab levels in vitro and in vivo. J Neurochem 2006;98:792–800. [137] Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, et al. ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/ presenilin 1 mice. J Biol Chem 2010;285:34144–5. [138] Fitz NF, Cronican A, Pham T, Fogg A, Fauq AH, Chapman R, et al. Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by highfat diet in APP23 mice. J Neurosci 2010;30:6862–72. [139] Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al. Human ApoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 2011;3:57–67. [140] Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, et al. ApoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest 2008;118:4002–13. [141] Iadecola C, Gottesman RF. Cerebrovascular alterations in Alzheimer’s disease. Incidental or pathogenic? Circ Res 2018;123:406–8. http://dx.doi.org/10.1161/ CIRCRESAHA.118.313400. [142] Langbaum JBS, Chen K, Launer LJ, Fleisher AS, Lee W, Liu X, et al. Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons. Neurobiol Aging 2012;33. 827.e11–827.e19. [143] Bangen KJ, Nation DA, Delano-Wood L, Weissberger GH, Hansen LA, Galasko DR, et al. Aggregate effects of vascular risk factors on cerebrovascular changes in autopsyconfirmed Alzheimer’s disease. Alzheimers Dement 2015;11. 394–403.e1. [144] Gottesman RF, Schneider ALC, Zhou Y, Coresh J, Green E, Gupta N, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 2017;317:1443–50.

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

NEUROL-2116; No. of Pages 19

16

revue neurologique xxx (2019) xxx–xxx

[145] Vemuri P, Lesnick TG, Przybelski SA, Knopman DS, Lowe VJ, Graff-Radford J, et al. Age, vascular health, and Alzheimer disease biomarkers in an elderly sample. Ann Neurol 2017;82:706–18. [146] Rabin JS, Schultz AP, Hedden T, Viswanathan A, Marshall GA, Kilpatrick E, et al. Interactive associations of vascular risk and b-amyloid burden with cognitive decline in clinically normal elderly individuals findings from the Harvard Aging Brain Study. JAMA Neurol 2018;75:1124–31. [147] Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-Pe´rez JM, Evans AC, for the Alzheimer’s Disease Neuroimaging Initiative. Early role of vascular dysregulation on lateonset Alzheimer’s based on multifactorial data-driven analysis. Nat Commun 2016;7:11934. http://dx.doi.org/ 10.1038/ncomms11934. [148] Iadecola C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 2017;96:17–42. http://dx.doi.org/10.1016/ j.neuron.2017.07.030. [149] Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 2018;21(10):1318–31. http:// dx.doi.org/10.1038/s41593-018-0234-x. [150] Bowman GL, Dayon L, Kirkland R, Wojcik J, Peyratout G, Severin IC, et al. Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults. Alzheimers Dement 2018;14(12):1640–50. [151] Nation DA, Sweeney MD, Montagne A, Sagare AP, D’Orazio LM, Pachicano M, et al. Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med 2019;25(2):270–6. http://dx.doi.org/10.1038/s41591018-0297-y. [152] Winkler EA, Sagare AP, Zlokovic BV. The pericyte: a forgotten cell type with important implications for Alzheimer’s disease? Brain Pathol 2014;24(4):371–86. http://dx.doi.org/10.1111/bpa.12152. [153] van de Haar HJ, Burgmans S, Jansen JFA, van Osch MJP, van Buchem MA, Muller M, et al. Blood-brain barrier leakage in patients with early Alzheimer disease. Radiology 2016;281:527–35. [154] van de Haar HJ, Jansen JFA, van Osch MJP, van Buchem MA, Muller M, Wong SM, et al. Neurovascular unit impairment in early Alzheimer’s disease measured with magnetic resonance imaging. Neurobiol Aging 2016;45:190–6. [155] van de Haar HJ, Jansen JFA, Jeukens CRLPN, Burgmans S, van Buchem MA, Muller M, et al. Subtle blood-brain barrier leakage rate and spatial extent: considerations for dynamic contrast enhanced MRI. Med Phys 2017;44:4112–25. [156] Montagne A, Nation DA, Pa J, Sweeney MD, Toga AW, Zlokovic BV. Brain imaging of neurovascular dysfunction in Alzheimer’s disease. Acta Neuropathol 2016;131:687–707. [157] Poliakova T, Levin O, Arablinskiy A, Vasenina E, Zerr I. Cerebral microbleeds in early Alzheimer’s disease. J Neurol 2016;263:1961–8. [158] Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology 2008;70:1208–14. [159] Heringa SM, Reijmer YD, Leemans A, Koek HL, Kappelle LJ, Biessels GJ, et al. Multiple microbleeds are related to cerebral network disruptions in patients with early Alzheimer’s disease. J Alzheimers Dis 2014;38:211–21. [160] Shams S, Martola J, Granberg T, Li X, Shams M, Fereshtehnejad SM, et al. Cerebral microbleeds: different prevalence, topography, and risk factors depending on

[161]

[162]

[163]

[164]

[165]

[166]

[167]

[168]

[169]

[170]

[171]

[172]

[173]

[174]

[175]

dementia diagnosis—The Karolinska Imaging Dementia Study. AJNR Am J Neuroradiol 2015;36:661–6. Shams S, Wahlund L-O. Cerebral microbleeds as a biomarker in Alzheimer’s disease? A review in the field. Biomark Med 2016;10:9–18. Suri S, Mackay CE, Kelly ME, Germuska M, Tunbridge EM, Frisoni GB, et al. Reduced cerebrovascular reactivity in young adults carrying the APOE e4 allele. Alzheimers Dement 2015;11. 648–657.e1. Hajjar I, Sorond F, Lipsitz LA. Apolipoprotein E, carbon dioxide vasoreactivity, and cognition in older adults: effect of hypertension. J Am Geriatr Soc 2015;63:276–81. Thambisetty M, Beason-Held L, An Y, Kraut MA, Resnick SM. APOE epsilon4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol 2010;67:93–8. Hirao K, Ohnishi T, Matsuda H, Nemoto K, Hirata Y, Yamashita F, et al. Functional interactions between entorhinal cortex and posterior cingulate cortex at the very early stage of Alzheimer’s disease using brain perfusion single-photon emission computed tomography. Nucl Med Commun 2006;27:151–6. Kogure D, Matsuda H, Ohnishi T, Asada T, Uno M, Kunihiro T, et al. Longitudinal evaluation of early Alzheimer’s disease using brain perfusion SPECT. J Nucl Med 2000;41:1155–62. Matsuda H, Kitayama N, Ohnishi T, Asada T, Nakano S, Sakamoto S, et al. Longitudinal evaluation of both morphologic and functional changes in the same individuals with Alzheimer’s disease. J Nucl Med 2002;43:304–11. Alexopoulos P, Sorg C, Forschler A, Grimmer T, Skokou M, Wohlschla¨ger A, et al. Perfusion abnormalities in mild cognitive impairment and mild dementia in Alzheimer’s disease measured by pulsed arterial spin labeling MRI. Eur Arch Psychiatry Clin Neurosci 2012;262:69–77. Dai W, Lopez OL, Carmichael OT, Becker JT, Kuller LH, Gach HM. Mild cognitive impairment and Alzheimer disease: patterns of altered cerebral blood flow at MR imaging. Radiology 2009;250:856–66. Hirao K, Ohnishi T, Hirata Y, Yamashita F, Mori T, Moriguchi Y, et al. The prediction of rapid conversion to Alzheimer’s disease in mild cognitive impairment using regional cerebral blood flow SPECT. NeuroImage 2005;28:1014–21. Nation DA, Wierenga CE, Clark LR, Dev SI, Stricker NH, Jak AJ, et al. Cortical and subcortical cerebrovascular resistance index in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 2013;36:689–98. Michels L, Warnock G, Buck A, Macauda G, Leh SE, Kaelin AM, et al. Arterial spin labeling imaging reveals widespread and Ab-independent reductions in cerebral blood flow in elderly apolipoprotein epsilon-4 carriers. J Cereb Blood Flow Metab 2016;36:581–95. Wirth M, Pichet Binette A, Brunecker P, Kobe T, Witte AV, Flel A. Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients. J Cereb Blood Flow Metab 2017;37:814–24. de Eulate RG, Gori I, Galiano A, Vidorreta M, Recio M, Riverol M, et al. Reduced cerebral blood flow in mild cognitive impairment assessed using phase-contrast MRI. J Alzheimers Dis 2017;58:585–95. Leijenaar JF, van Maurik IS, Kuijer JPA, van der Flier WM, Scheltens P, Barkhof F, et al. Lower cerebral blood flow in subjects with Alzheimer’s dementia, mild cognitive impairment, and subjective cognitive decline using twodimensional phase-contrast magnetic resonance imaging. Alzheimers Dement (Amsterdam) 2017;9:76–83.

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

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

[176] Alsop DC, Detre JA, Grossman M. Assessment of cerebral blood flow in Alzheimer’s disease by spin-labeled magnetic resonance imaging. Ann Neurol 2000;47:93–100. [177] Yew B, Nation DA, for the Alzheimer’s Disease Neuroimaging Initiative. Cerebrovascular resistance: effects on cognitive decline, cortical atrophy, and progression to dementia. Brain 2017;140(7):1987–2001. http://dx.doi.org/10.1093/brain/awx112. [178] Iadecola C, Zhang F, Niwa K, Eckman C, Turner SK, Fischer E, et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci 1999;2:157–61. [179] Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 2004;5:347– 60. [180] Claassen JAHR, Zhang R. Cerebral autoregulation in Alzheimer’s disease. J Cereb Blood Flow Metab 2011;31(7):1572–7. http://dx.doi.org/10.1038/jcbfm.2011.69. [181] Pe´rez-Jime´nez F, Alvarez de Cienfuegos G, Badimon L, Barja G, Battino M, Blanco A, et al. International conference on the healthy effect of virgin olive oil. Eur J Clin Invest 2005;35:421–4. [182] Lo´pez-Miranda J, Pe´rez-Jime´nez F, Ros E, De Caterina R, Badimon L, Covas MI, et al. Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaen and Cordoba (Spain) 2008. Nutr Metab Cardiovasc Dis 2010;20(4):284–94. http://dx.doi.org/ 10.1016/j.numecd.2009.12.007. [183] Perona JS, Cabello-Moruno R, Ruiz-Gutierrez V. The role of virgin olive oil components in the modulation of endothelial function. J Nutr Biochem 2006;17:429–45. [184] Delgado-Lista J, Garcia-Rios A, Perez-Martinez P, LopezMiranda J, Perez-Jimenez F. Olive oil and haemostasis: platelet function, thrombogenesis and fibrinolysis. Curr Pharm Des 2011;17(8):778–85. [185] Dinu M, Pagliai G, Casini A, Sofi F. Mediterranean diet and multiple health outcomes: an umbrella review of metaanalyses of observational studies and randomised trials. Eur J Clin Nutr 2018;72(1):30–43. http://dx.doi.org/10.1038/ ejcn.2017.58. [186] Scarmeas N, Stern Y, Mayeux R, Luchsinger JA. Mediterranean diet, Alzheimer disease, and vascular mediation. Arch Neurol 2006;63(12):1709–17. http:// dx.doi.org/10.1001/archneur.63.12.noc60109. [187] Scarmeas N, Stern Y, Tang M-X, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol 2006;59:912–21. [188] Huang W-J, Zhang XIA, Chen WW. Role of oxidative stress in Alzheimer’s disease. Biomed Rep 2016;4(5):519–22. [189] Ferreira ST, Clarke JR, Bomfim TR, De Felice FG. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimers Dement 2014;10(1):S76–83. [190] Misiak B, Leszek J, Kiejna A. Metabolic syndrome, mild cognitive impairment and Alzheimer’s disease – The emerging role of systemic low-grade inflammation and adiposity. Brain Res Bull 2012;89(3–4):144–9. [191] Platt TL, Beckett TL, Kohler K, Niedowicz DM, Murphy MP. Obesity, diabetes, and leptin resistance promote tau pathology in a mouse model of disease. Neuroscience 2016;315:162–74. [192] Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C. Adherence to the Mediterranean diet attenuates inflammation and coagulation process in healthy adults: the ATTICA Study. J Am Coll Cardiol 2004;44:152–8. [193] Gu Y, Luchsinger JA, Stern Y, Scarmeas N. Mediterranean diet, inflammatory and metabolic markers and risk of

[194]

[195]

[196]

[197]

[198]

[199]

[200] [201]

[202]

[203]

[204]

[205]

[206]

[207]

[208]

[209]

17

Alzheimer’s disease. J Alzheimers Dis 2010;22(2):483–92. http://dx.doi.org/10.3233/JAD-2010-100897. Psaltopoulou T, Naska A, Orfanos P, Trichopoulos D, Mountokalakis T, Trichopoulou A. Olive oil, the Mediterranean diet, and arterial blood pressure: the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study. Am J Clin Nutr 2004;80:1012–8. Knoops KT, de Groot LC, Kromhout D, Perrin AE, MoreirasVarela O, Menotti A, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA 2004;292:1433–9. Ros E, Martı´nez-Gonza´lez MA, Estruch R, Salas-Salvado´ J, Fito´ M, Martı´nez JA, et al. Mediterranean diet and cardiovascular health: teachings of the PREDIMED Study. Adv Nutr 2014;5:330S–6S. http://dx.doi.org/10.3945/ an.113.005389. Singh B, Parsaik AK, Mielke MM, Erwin PJ, Knopman DS, Petersen RC, et al. Association of Mediterranean diet with Mild Cognitive Impairment and Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis 2014;39(2):271–82. Angeloni C, Malaguti M, Barbalace MC, Hrelia S. Bioactivity of olive oil phenols in neuroprotection. Int J Mol Sci 2017;18:2230. http://dx.doi.org/10.3390/ijms18112230. Rigacci S. Olive oil phenols as promising multi-targeting agents against Alzheimer’s disease. In: Vassallo N, editor. Natural compounds as therapeutic agents for amyloidogenic diseases. Springer International Publishing: Switzerland. Adv Exp Med Biol 2015;863:1–20. http://dx.doi.org/10.1007/978-3-319-18365-7_1. Khalatbary AR. Olive oil phenols and neuroprotection. Nutr Neurosci 2013;16(6):243–9. Rodrı´guez-Morato´ J, Xicota L, Fito´ M, Farre´ M, Dierssen M, De la Torre R. Potential role of olive oil phenolic compounds in the prevention of neurodegenerative diseases. Molecules 2015;20:4655–80. Beauchamp GK, Keast RS, Morel D, Lin J, Pika J, Han Q, et al. Phytochemistry: ibuprofen-like activity in extravirgin olive oil. Nature 2005;437:45–6. Rigacci S, Miceli C, Nediani C, Berti A, Cascella R, Pantano D, et al. Oleuropein aglycone induces autophagy via the AMPK/mTOR signaling pathway: a mechanistic insight. Oncotarget 2015;6:35344–57. Grossi C, Rigacci S, Ambrosini S, Ed Dami T, Luccarini I, Traini C, et al. The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology. PLoS One 2013;8(8):e71702. http://dx.doi.org/10.1371/ journal.pone.0071702. Luccarini I, Grossi C, Rigacci S, Coppi E, Pugliese AM, Pantano D, et al. Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates. Neurobiol Aging 2015;36(2):648–63. http://dx.doi.org/10.1016/ j.neurobiolaging.2014.08.029. Pitozzi V, Jacomelli M, Zaid M, Luceri C. Effects of dietary extra-virgin olive oil on behaviour and brain biochemical parameters in ageing rats. Br J Nutr 2010;103:1674–83. Pitozzi V, Jacomelli M, Catelan D, Servili M, Taticchi A, Biggeri A, et al. Long-term dietary extra-virgin olive oil rich in polyphenols reverses age-related dysfunctions in motor coordination and contextual memory in mice: role of oxidative stress. Rejuvenation Res 2012;15:601–12. Farr SA, Price TO, Dominguez LJ, Motisi A, Saiano F, Niehoff ML, et al. Extra virgin olive oil improves learning and memory in SAMP8 mice. J Alzheimers Dis 2012;28:81–92. Qosa H, Mohamed LA, Batarseh YS, Alqahtani S, Ibrahim B, LeVine 3rd H, et al. Extra-virgin olive oil attenuates amyloid-b and tau pathologies in the brains of TgSwDI

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

NEUROL-2116; No. of Pages 19

18

[210]

[211]

[212]

[213]

[214]

[215]

[216]

[217]

[218]

[219]

[220]

[221]

[222]

[223]

[224]

revue neurologique xxx (2019) xxx–xxx

mice. J Nutr Biochem 2015;26(12):1479–90. http:// dx.doi.org/10.1016/j.jnutbio.2015.07.022. Qosa H, Batarseh YS, Mohyeldin MM, El Sayed KA, Keller JN, Kaddoumi A. Oleocanthal enhances amyloid-b clearance from the brains of TgSwDI mice and in vitro across a human blood-brain barrier model. ACS Chem Neurosci 2015;6(11):1849–59. http://dx.doi.org/10.1021/ acschemneuro.5b00190. Pitt J, Roth W, Lacor P, Smith 3rd AB, Blankenship M, Velasco P, et al. Alzheimer’s-associated Ab oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal. Toxicol Appl Pharmacol 2009;240:189–97. Abuznait AH, Qosa H, Busnena BA, El Sayed KA, Kaddoumi A. Olive-oil-derived oleocanthal enhances b-amyloid clearance as a potential neuroprotective mechanism against Alzheimer’s disease: in vitro and in vivo studies. ACS Chem Neurosci 2013;4:973–82. Batarseh YS, Mohamed LA, Al Rihani SB, Kaddoumi A. Oleocanthal ameliorates amyloid-b oligomers’ toxicity on astrocytes and neuronal cells: in vitro studies. Neuroscience 2017;352:204–15. Li W, Sperry JB, Crowe A, Trojanowski JQ, Smith AB, Lee VM. Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau. J Neurochem 2009;110:1339–51. Monti MC, Margarucci L, Tosco A, Riccio R, Casapullo A. New insights on the interaction mechanism between tau protein and oleocanthal, an extra-virgin olive-oil bioactive component. Food Funct 2011;2:423–8. Monti MC, Margarucci L, Riccio R, Casapullo A. Modulation of tau protein fibrillization by oleocanthal. J Nat Prod 2012;75:1584–8. Casamenti F, Grossi C, Rigacci S, Pantano D, Luccarini I, Stefani M. Oleuropein aglycone: a possible drug against degenerative conditions. In vivo evidence of its effectiveness against Alzheimer’s disease. J Alzheimers Dis 2015;45(3):679–88. http://dx.doi.org/10.3233/JAD142850. Hornedo-Ortega R, Cerezo AB, de Pablos RM, Krisa S, Richard T, Garcı´a-Parrilla MC, et al. Phenolic compounds characteristic of the Mediterranean diet in mitigating microglia-mediated neuroinflammation. Front Cell Neurosci 2018;12:373. http://dx.doi.org/10.3389/ fncel.2018.00373. Leri M, Natalello A, Bruzzone E, Stefani M, Bucciantini M. Oleuropein aglycone and hydroxytyrosol interfere differently with toxic Ab1-42 aggregation. Food Chem Toxicol 2019. http://dx.doi.org/10.1016/j.fct.2019.04.015 [pii: S0278-6915(19)30214-5]. Peng Y, Hou C, Yang Z, Li C, Jia L, Liu J, et al. Hydroxytyrosol mildly improve cognitive function independent of APP processing in APP/PS1 mice. Mol Nutr Food Res 2016;60:2331–42. Crespo MC, Tome´-Carneiro J, Pintado C, Da´valos A, Visioli F, Burgos-Ramos E. Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer’s disease. Biofactors 2017;43:540–8. Bu Y, Rho S, Kim J, Kim MY, Lee DH, Kim SY, et al. Neuroprotective effect of tyrosol on transient focal cerebral ischemia in rats. Neurosci Lett 2007;414:218–22. Schwingshackl L, Hoffmann G. Adherence to Mediterranean diet and risk of cancer: an updated systematic review and meta-analysis of observational studies. Cancer Med 2015;4:1933–47. Schwingshackl L, Schwedhelm C, Galbete C, Hoffmann G. Adherence to Mediterranean diet and risk of cancer: an updated systematic review and meta-analysis. Nutrients

[225]

[226]

[227]

[228]

[229]

[230]

[231]

[232]

[233]

[234]

[235]

[236]

[237]

2017;9(10):E1063. http://dx.doi.org/10.3390/nu9101063 [pii: E1063]. Farinetti A, Zurlo V, Manenti A, Coppi F, Mattioli AV. Mediterranean diet and colorectal cancer: a systematic review. Nutrition 2017;43–44:83–8. http://dx.doi.org/ 10.1016/j.nut.2017.06.008. Reboredo-Rodrı´guez P, Varela-Lo´pez A, Forbes-Herna´ndez TY, Gasparrini M, Afrin S, Cianciosi D, et al. Phenolic compounds isolated from olive oil as nutraceutical tools for the prevention and management of cancer and cardiovascular diseases. Int J Mol Sci 2018;19(8):E2305. http://dx.doi.org/10.3390/ijms19082305 [pii: E2305]. Ornish D, Magbanua MJM, Weidner G, Weinberg V, Kemp C, Green C, et al. Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention. Proc Natl Acad Sci U S A 2008;105(24):8369–74 [doi: org/cgi/doi/10.1073]. Ornish D, Lin J, Chan JM, Epel E, Kemp C, Weidner G, et al. Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. Lancet Oncol 2013;14:1112–20. Roma´n GC. MTHFR gene mutations: a potential marker of late-onset Alzheimer’s disease? J Alzheimer’s Dis 2015;47:323–7. Roma´n GC, Mancera-Pa´ez O, Bernal C. Epigenetic factors in late-onset Alzheimer’s disease: MTHFR and CTH gene polymorphisms, metabolic transsulfuration and methylation pathways, and B vitamins. Int J Mol Sci 2019;20(2):E319. http://dx.doi.org/10.3390/ijms20020319 [pii: E319]. Mancera-Pa´ez O, Estrada-Orozco K, Mahecha MF, Cruz F, Bonilla-Vargas K, Sandoval N, et al. Differential methylation in APOE (Chr19; Exon four; from 44,909,188 to 44,909,373/hg38) and increased Apolipoprotein E plasma levels in subjects with mild cognitive impairment. Int J Mol Sci 2019;20(6):1394. http://dx.doi.org/10.3390/ ijms20061394 [pii: E1394]. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998;139(10):4252–63. Wu WF, Tan XJ, Dai YB, Krishnan V, Warner M, Gustafsson ˚ . Targeting estrogen receptor b in microglia and T cells JA to treat experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2013;110(9):3543–8. http:// dx.doi.org/10.1073/pnas.1300313110. Kowalska K, Habrowska-Go´rczyn´ska DE, Urbanek KA, Domin´ska K, Sakowicz A, Piastowska-Ciesielska AW. Estrogen receptor b plays a protective role in zearalenoneinduced oxidative stress in normal prostate epithelial cells. Ecotoxicol Environ Saf 2019;172:504–13. http:// dx.doi.org/10.1016/j.ecoenv.2019.01.115. Zhu Y, Bian Z, Lu P, Karas RH, Bao L, Cox D, et al. Abnormal vascular function and hypertension in mice deficient in estrogen receptor beta. Science 2002;295(5554):505–8. Fortini F, Vieceli Dalla Sega F, Caliceti C, Aquila G, Pannella M, Pannuti A, et al. Estrogen receptor b-dependent Notch1 activation protects vascular endothelium against tumor necrosis factor a (TNFa)-induced apoptosis. J Biol Chem 2017;292(44):18178–91. http://dx.doi.org/10.1074/ jbc.M117.790121. Wu X, Tong B, Yang Y, Luo J, Yuan X, Wei Z, et al. Arctigenin functions as a selective agonist of estrogen receptor b to restrict mTORC1 activation and consequent Th17 differentiation. Oncotarget 2016;7(51):83893–906. http://dx.doi.org/10.18632/oncotarget.13338.

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

NEUROL-2116; No. of Pages 19 revue neurologique xxx (2019) xxx–xxx

[238] Wu WF, Maneix L, Insunza J, Nalvarte I, Antonson P, Kere J, et al. Estrogen receptor b, a regulator of androgen receptor signaling in the mouse ventral prostate. Proc Natl Acad Sci U S A 2017;114(19):E3816–22. http://dx.doi.org/ 10.1073/pnas.1702211114. [239] Hartman J, Edvardsson K, Lindberg K, Zhao C, Williams C, Stro¨m A, et al. Tumor repressive functions of estrogen receptor beta in SW480 colon cancer cells. Cancer Res 2009;69(15):6100–6. http://dx.doi.org/10.1158/00085472.CAN-09-0506. [240] Ra˚dmark O, Werz O, Steinhilber D, Samuelsson B. 5Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease. Biochim Biophys Acta 2015;1851(4):331–9. http://dx.doi.org/10.1016/ j.bbalip.2014.08.012. [241] Peters-Golden M, Brock TG. 5-lipoxygenase and FLAP. Prostaglandins Leukot Essent Fatty Acids 2003;69(2– 3):99–109. [242] Vagnozzi AN, Giannopoulos PF, Pratico` D. Brain 5lipoxygenase over-expression worsens memory, synaptic integrity, and tau pathology in the P301S mice. Aging Cell 2018;17(1):12695. http://dx.doi.org/10.1111/acel.12695. [243] Menendez JA, Papadimitropoulou A, Vellon L, Lupu R. A genomic explanation connecting ‘‘Mediterranean diet’’, olive oil and cancer. Eur J Cancer 2006;42(15):2425–32. [244] Warleta F, Campos M, Allouche Y, Sa´nchez-Quesada C, Ruiz-Mora J, Beltra´n G, et al. Squalene protects against oxidative DNA damage in MCF10A human mammary epithelial cells but not in MCF7 and MDA-MB-231 human

[245]

[246]

[247]

[248]

[249]

[250]

19

breast cancer cells. Food Chem Toxicol 2010;48(4):1092– 100. http://dx.doi.org/10.1016/j.fct.2010.01.031. Casaburi I, Puoci F, Chimento A, Sirianni R, Ruggiero C, Avena P, et al. Potential of olive oil phenols as chemopreventive and therapeutic agents against cancer: a review of in vitro studies. Mol Nutr Food Res 2013;57(1):71–83. Akl MR, Ayoub NM, Mohyeldin MM, Busnena BA, Foudah AI, Liu YY, et al. Olive phenolics as c-Met inhibitors: (-)Oleocanthal attenuates cell proliferation, invasiveness, and tumor growth in breast cancer models. PLoS One 2014;9(5):e97622. http://dx.doi.org/10.1371/ journal.pone.0097622. Hassan ZK, Elamin MH, Omer SA, Daghestani MH, AlOlayan ES, Elobeid MA, et al. Oleuropein induces apoptosis via the p53 pathway in breast cancer cells. Asian Pac J Cancer Prev 2014;14(11):6739–42. Elamin MH, Daghestani MH, Omer SA, Elobeid MA, Virk P, Al-Olayan EM, et al. Olive oil oleuropein has anti-breast cancer properties with higher efficiency on ER-negative cells. Food Chem Toxicol 2013;53:310–6. http://dx.doi.org/ 10.1016/j.fct.2012.12.009. Warleta F, Quesada CS, Campos M, Allouche Y, Beltra´n G, Gaforio JJ. Hydroxytyrosol protects against oxidative DNA damage in human breast cells. Nutrients 2011;3(10):839–57. Buck K, Zaineddin AK, Vrieling A, Linseisen J, ChangClaude J. Meta-analyses of lignans and enterolignans in relation to breast cancer risk. Am J Clin Nutr 2010;92(1):141–53. http://dx.doi.org/10.3945/ ajcn.2009.28573.

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