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  1. 1. Alzheimer’s disease June 4, 2004 William B. Grant, Ph.D. www.sunarc.org Alzheimer’s disease (AD), first described in 1906 by German psychiatrist Alois Alzheimer, is a progressive brain disorder that causes a gradual and irreversible decline in memory, language skills, perception of time and space, emotional stability, pattern recognition, coordination, and, eventually, the ability to care for oneself. AD is associated with abnormal changes in the brain involving plaques, tangles, beta-amyloid protein, and free radicals. The risk factors for AD include both genetic and environmental factors. The primary genetic risk factor is the presence of the apolipoprotein E epsilon4 (APOE ε4) allele, which is more common among: • Africans • Inuits • AmerIndians • Northern Europeans than southern Europeans This allele can be considered a “thrifty gene,” one that helps store excess energy as fat, which is a survival factor for hunter-gatherer peoples. The primary dietary risk factors are total energy and some types of fat, while the primary risk reduction factors are fish and some types of fat. Some studies have also reported that diets high in cereals and grains are associated with reduced rates of AD [Grant, 1997; Luchsinger et al., 2002; Chandra et al., 1998]. Among fats, the good ones are [Morris et al., 2003a,b]: • linoleic acid (found in safflower, sunflower, hemp, soybean, walnut, pumpkin, sesame, and flax seed oil [Erasmus, 1993]) • alpha-linolenic acid (found in fish, canola, flax, hemp seed, soy bean, and walnut oil and dark green leaves [Erasmus, 1993]) • docosahexanoic acid (DHA) and eicosapentanoic acid (EPA), largely found in fish oil • olive oil The bad ones are saturated fats (found in solid fats such as butter and cheese) and trans- fatty acids (found in many processed foods and labeled as partially-hydrogenated vegetable oils) [Kalmijn et al., 1997a,b, 2000; Morris et al., 2003a]. Antioxidant vitamins C and E, as well as flavonoids, found in fruits and vegetables, and resveratrol, found in red wine, play a protective role. Obesity, smoking, cholesterol, and homocysteine are also risk factors, while exercise reduces the risk. Thus, even if one has a genetic predisposition for AD, there are many ways that one can reduce the risk. 1
  2. 2. For those who want to reduce their risk of AD, the most important thing appears to be to maintain a low body mass index by eating a diet low in total energy, low in bad fats, adequate in good fats, high in fruits, vegetables and antioxidants. Added sugars should also be avoided since they lead to obesity [Grant, in press]. The traditional diet in the Mediterranean provides an example of a good diet [Simopoulos, 2004]. Adequate folate consumption, perhaps via supplements, should also be included. In addition, antioxidant and folate supplements would be beneficial. Finally, keeping both the mind and body active is very helpful. An Introduction to Alzheimer’s Disease AD is a disease in which the mind deteriorates to the point where one has no memory and a limited ability to function. It is one form of dementia. Another common type of dementia is called vascular dementia (VaD). However, the two types of dementia are sometimes present simultaneously, and both are sometimes considered to represent variations of the same disease. The pathology of AD is linked to tangles and plaques in the brain, and these structures are associated with beta-amyloid protein. AD brain tissue contains higher levels of free radicals and oxidative stress. In the early 1990s, Alan Roses’ group discovered that the APOE ε4 allele is closely associated with risk for AD. The APOE ε4 allele was also found to be associated with oxidative insults to the brain. Those with higher risk of having the APOE ε4 allele include those with African or American Indian ethnic background. Those with genetic roots in northern Europe have a somewhat lower probability than the first two ethnic groups, and the probability is lower among southern Europeans [Ewbank, 2004]. The likely reason for this variation with ethnicity is based on the role of the APOE alleles in regulating the metabolic process of food assimilation and generation of lipids, as well as other functions. The APOE ε4 allele is associated with the storage of excess energy as fat, which is an important survival trait among hunter-gatherers or those who live in regions with harsh winters. ApoE acts as a cholesterol transporter in the brain [Lahiri et al., 2004], and cholesterol is a risk factor for AD [Sparks, 1997]. Studies with cells found results consistent with APOEε4 forming a reactive molecular intermediate that avidly binds phospholipid and may insert into the lysosomal membrane, destabilizing it and causing lysosomal leakage and apoptosis in response to Abeta1-42 [Ji et al., 2002]. APOEε4 may also be a risk factor for increased transition metal (iron, mercury, zinc, etc.) and aluminum ion concentrations in the body and brain [Godfrey et al., 2003]. While the strong connection between genetics and AD is very important, it suffered a setback in terms of being the only important risk factor for AD in 1996 with the publication of a report from the Honolulu-Asia Aging Study showing that Japanese- American men living in Hawaii had 2.5 times the prevalence of AD of native Japanese [White et al., 1996]. 2
  3. 3. At the time that I read the account of this finding, I was studying the adverse effects of ozone and acid rain on eastern oak and hickory forests and learned that acid deposition lowers the pH of the soil and, in doing so, dissolves some aluminum and transition metal oxides, thereby releasing these metal ions into the soil where trees and other plants can readily absorb them. I was also aware that those diagnosed with AD had increased aluminum in their brains. I quickly reasoned that since the Japanese had the same genetic traits no matter where they lived, they had to have experienced some environmental factor in Hawaii that led to their AD. I also thought that the most important environmental factor in the broadest sense was the food they ate. In my forest studies, I had developed a facility with the ecologic approach for studying links between environmental factors and disease outcomes. I reasoned that I should be able to apply the ecologic approach to examine the correlation of major dietary factors on AD prevalence by assembling data from a number of countries. In the ecologic approach, populations defined geographically are treated as entities, and population average values for various factors are compared with disease outcomes in regression analyses. Armstrong and Doll [1975] did this for cancer, thereby providing an example to follow. I didn’t realize until a few years later that the health research community had essentially discarded the ecologic approach after an influential paper by Doll and Peto [1981] stated that it was not very reliable or useful in determining causal factors for disease. Note that, more recently, the ecologic approach has largely been vindicated after case- control and cohort approaches confirmed the findings by Burkitt [1971] and Armstrong and Doll [1975] that dietary fiber reduces the risk of colorectal cancer and that meat and milk are risk factors for breast cancer [Grant, 2003]. Dietary Risks for Alzheimer’s Disease I found AD prevalence data for 11 countries and obtained dietary data from the Food Balance Sheets [FAO, 1991]. The linear regression results indicated that total energy and total fat were the primary risk factors, while cereals or grains and fish were the primary risk reduction factors. I gave a seminar on my findings to the AD group at the University of Kentucky in early 1997 and convinced them that I had an interesting finding. James Geddes accepted my manuscript for publication in the Alzheimer Disease Review, and it appeared in print on the web on June 17, 1997 [Grant, 1997 (http://www.mc.uky.edu/adreview/Vol2/Grant/grant.pdf)]. The results were not immediately accepted, in part because I employed the largely abandoned ecologic approach, and in part because I was an independent researcher from a different field (atmospheric sciences). 3
  4. 4. A paper published shortly after mine found total fat as a risk factor for VaD and fish as a risk reduction factor for AD [Kalmijn et al., 1997b; Kalmijn, 2000]. Slowly, the interest of the rest of the AD research community was prodded [Grant, 1998, 2001], and, in 2002, a group at Columbia University confirmed three of the four dietary links to the development of AD (energy, fat, and an inverse association for cereals) [Luchsinger et al., 2002], very likely inspired by a letter to the editor commenting on their earlier study [Tang et al., 1998] suggesting that dietary factors were likely involved [Grant, 1998]. Fish and Fish Oil Reduce AD Risk The role of fish in reducing the risk of AD was further discussed in Grant [2000] and confirmed by a French team [Barberger-Gateau et al., 2002], as well as by a team at the Rush Alzheimer's Disease Center in Chicago [Morris et al., 2003b]. The French team extended their work on fish and AD, finding that those who ate fish at least once a week had a relative risk of AD of about 0.7 compared to those who didn’t [Larrieu et al., 2004]. Fish consumption was found inversely correlated with cognitive impairment among middle-aged Dutch, while cholesterol was positively associated [Kalmijn et al., 2004]. The benefits of the primary n-3 fish oils, DHA and EPA, appear to include providing the lipids required for proper brain development and maintenance [Crawford et al., 1999; Bourre, 2004] and reducing inflammation [Das et al., 2003]. Fatty Acids and AD It should be noted that one of the first signs of impending AD is what is called cognitive impairment (CI). Thus, studies of dietary links to CI are useful regarding AD, and, indeed, they find much the same results as the AD studies [e.g., Kalmijn et al., 1997a,b]. Such results, as well as some for AD, indicate that there are good fats and bad fats, as mentioned above. However, the ratio of n-6 to n-3 fatty acids is also important, with a ratio of LA to ALA (n-6 to n-3) of about 4:1 being optimal [Haag, 2003; Yehuda, 2003]. This value is nearer to the 1:1 or 2:1 ratio found in the diet of our ancestors than the 10:1 to 25:1 found in present day Western diets [Simopoulos, 2000]. Also, extra virgin olive oil, with its strong antioxidant properties, is a good choice. Virgin olive oil should be considered a risk reduction factor for AD since it has plenty of phenols with high antioxidant capabilities [Briante et al., 2003; Covas et al., 2003]. These compounds have been suggested to be very useful when free transition metal ions are involved in oxidation processes [Briante et al., 2003], as is the case in AD (see discussion below). Obesity Increases Risk of AD In addition, there has been further support of the finding that total energy consumption is a risk factor for AD [Grant, 1999a; 2002]. Mark Mattson has long championed the idea of caloric restriction for reducing the risk of AD [Mattson, 2003], and a recent paper 4
  5. 5. identified obesity as a risk factor for AD [Gustafson et al., 2003] with the comment that it was likely related to diet [Grant, 2004]. The epidemic of obesity in the U.S. appears to be linked to increased consumption of convenience food, which is energy-dense [Grant, in press]. These foods are rich in sweeteners (fructose and sucrose), other refined carbohydrates, and animal products high in fat. Sugar is also implicated as a risk factor for AD through the finding that type 2 diabetes mellitus is associated with increased risk of AD [Messier, 2003; Arvanitakis et al., 2004]. Wine Consumption Two recent studies reported that risk of AD decreased markedly with wine consumption for mild and moderate drinkers [Larrieu et al., 2004; Luchsinger et al., 2004]. The risk ratio for AD for moderate drinkers was 0.53 (95% C.I. 0.30-0.95) compared to non- drinkers [Larrieu et al., 2004]. Very similar results were found for up to three glasses of wine per day, but not for other alcohol beverages in another study [Luchsinger et al., 2004]. Also, these results were limited to those who did not have the APOEε4 allele. It is likely that antioxidants in wine that were responsible for this result. Wine has been proposed as an explanation for the “French paradox” regarding coronary heart disease [Renaud et al., 1992]. However, another possibility for the brain is that resveratrol in red wine is responsible. A recent paper reported that resveratrol was able to significantly induce heme oxygenase 1, thereby reducing the oxidative stress on neurons [Zhuang et al., 2003]. Resveratrol also exerts an anti-oxidative action by enhancing the intracellular free-radical scavenger glutathione [Savaskan et al., 2003]. Resveratrol is also available from grape juice, but is not as readily absorbed as from wine [Pace-Asciak et al., 1996; Meng et al., 2004]. Why Antioxidants are Useful for Alzheimer’s Disease Since AD is to some extent a disease of oxidative stress, it would be expected that antioxidants would reduce the risk of developing AD. That is indeed the case. One prospective study found that a high intake of flavonoids found in tea, fruits, and vegetables reduced the risk of AD by about half [Commenges et al., 2000]. A prospective cohort study in Rotterdam found that high consumption of vitamins C and E reduced the risk of AD by 20 percent to 40 percent, with the most pronounced benefit found for smokers [Engelhart et al., 2002]. Antioxidants are, of course, useful in reducing the risk of a large number of degenerative diseases [Krajcovicova-Kudlackova et al., 2003]. An observational study found peripheral levels and activities of all antioxidants reduced in those with mild cognitive impairment and AD [Rinaldi et al., 2003]. A recent study reported that those taking large amounts of vitamins C and E in combination had one- quarter to one-third the risk for AD as those not taking the vitamin supplements [Zandi et al., 2004]. 5
  6. 6. Cholesterol and AD Cholesterol has been a known risk factor for AD since the early 1990s [Sparks, 1997]. Cholesterol is often elevated by a diet high in fats [Fuentes et al., 2001] and/or high in sugars [Marckmann et al., 2000]. The role of cholesterol in the etiology of AD was recently reviewed by Marx [2001] and Simons [2001]. The mechanisms are still under review [Chaney et al., 2003; Gibson Wood et al., 2003]. Paradoxically, however, it may be the high-density lipoprotein (HDL) rather than the low-density lipoprotein (LDL) cholesterol that is the bad actor [Michikawa, 2003], the reverse of the case for heart disease. In heart disease, LDL can clog the arteries, and oxidized LDL can break off the arterial walls and block blood flow to the heart. Thus, use of statins, which act primarily to reduce LDL cholesterol, may not reduce the risk of developing AD [Hoglund et al., 2004]. Since cholesterol is implicated as a risk factor for AD, statins, which reduce serum cholesterol levels, especially the LDL fraction, may be useful in reducing the risk of AD [Wolozin, 2002]. Some studies support this hypothesis [e.g., Zamrini et al., 2004] and others are underway [Sparks et al., 2002]. Homocysteine Increases the Risk of Alzheimer’s Homocysteine is another risk factor for AD. Homocysteine was first identified as a risk factor for arteriosclerosis from autopsy studies by Kilmer McCully [1969]. For his important pioneering work, he was dismissed from Harvard and black-listed for several years. Homocysteine levels are elevated when there are deficiencies of vitamin B6, folate, and vitamin B12 [Ellis and McCully, 1995; McCully, 2004]. A prospective study found that elevated homocysteine levels were associated independently with increased risk for AD [Seshadri et al., 2002]. Conversely, patients with AD have been found to have elevated levels of homocysteine [McIlroy et al., 2002; Selley 2003]. Also, patients with stroke and VaD also have elevated levels of homocysteine [McIlroy et al., 2002]. The Role of Metal Ions Including Aluminum Metal ions are also involved in the pathology of AD. It is well known that aluminum is elevated in the brains of AD patients [Markesbery and Ehmann, 1994]. Less well known, but well documented, is that transition metal ions (e.g., copper, iron, and zinc) are also elevated, while base cations (e.g., calcium and magnesium) are at lower concentrations [Markesbery and Ehmann, 1994, and that they are involved in the pathology of AD [4]. I have attributed this phenomenon to a high consumption of acid-forming foods, such as animal products, which are high in protein (amino acids) and fat (fatty acids). These acids may dissolve the aluminum or transition metal oxides in the food we eat and, thus, permit the ions to be absorbed into the blood [Grant, 1999b; Grant et al., 2002]. 6
  7. 7. There is also the possibility that aluminum from aluminum soft drink cans can be ingested, since carbonated drinks are highly acidic and can leach out aluminum [Lopez et al., 2002]. In addition, some soft drinks also contain moderate levels of fluoride, and, in combination with aluminum, can be a risk factor for AD [Varner et al., 1998]. These transition metal ions and aluminum ions increase the production of free radicals such as hydroxyl [Kanner et al., 1987], both in the body and in the brain, and, thus, are involved in oxidative damage to the brain [Markesbery and Carney, 1999; Savory et al., 1999; Suh et al., 2000; Campbell et al., 2001; Perry et al., 2002, 2003; Squitti et al., 2004; Todorich and Connor, 200]. It has been suggested that the transition metal ions can be removed from the body by chelation in a manner that reduces the oxidative damage to the brain [Cuajungco et al., 2000]. A clinical intervention using clioquinol, a metal-protein- attenuating compound (MPAC) that inhibits zinc and copper ions from binding to beta- amyloid, thereby promoting beta-amyloid dissolution and diminishing its toxic properties [Ritchie et al., 2003]. Inflammation and NSAIDs Inflammation appears to be one of the risk factors for AD, and is related to free radicals and oxidative stress from beta-amyloid [Butterfield et al., 2001, 2003] or, transition metal ions [Perry et al., 2002, 2003]. One of the ways that fish oil may reduce the risk of AD is by reducing inflammation in the brain. The use of non-steroidal anti-inflammatory drugs (NSAIDs) to reduce the risk of AD has been studied [Grundman et al., 2002; Etminan et al., 2003] following the finding that those with rheumatoid arthritis had a reduced risk of AD [McGeer et al., 1996]. The reader is cautioned that use of NSAIDs including aspirin and COX-2 inhibitors carries the not-insignificant risk of gastrointestinal bleeding [Atkinson, 2002; Deeks et al., 2002; Laine, 2002; Stollberger and Finsterer, 2004]. A recent paper reports that those with H. pylori increase their risk of gastrointestinal tract bleeding by a factor of two to four times [Chan and Graham, 2004], so anyone planning to take NSAIDs on a regular basis should be checked for H. pylori. A better policy is to eat in a manner so as to reduce the risk of oxidative stress in the first place, rather than have to treat it later. Dietary Recommendations AD is rare in Africa [Hendrie et al., 2001] and India [Chandra et al., 1998], but Africans generally consume far fewer calories than would be tolerated in the United States, and Indians are generally vegetarians with high rates of diabetes and heart disease due to large fractions of carbohydrates in their diets. The Mediterranean diet [Renaud et al., 1995; Willett et al., 1995; Trichopoulou and Lagiou, 1997; Simopoulos, 2001, 2004; Trichopoulou, 2001; Kok and Kromhout, 2004] is associated with a risk of cognitive impairment and AD intermediate between those of Southeast Asia and the United States. 7
  8. 8. In addition to diet, additional risk reduction can be achieved by taking antioxidant and B- vitamin supplements as well as a few other substances that one can find described in the literature. Physical Exercise Reduces Risk Regular physical exercise is another way to reduce the risk of AD. A study in Canada found that those who engaged in high levels of physical activity had half the risk of developing AD of those who did not [Laurin et al., 2001]. Smoking Doubles AD Risk Smoking was associated with double the normal risk for AD in a cohort study in Hawaii [Tyas et al., 2003]. Since those in the United States who smoke generally have poorer dietary habits than those who don’t, it could be that dietary factors explain some of the risk. However, since smoking reduces the body’s stores of antioxidants, it could well be a direct effect. Ethnic Differences in AD Prevalence It is noteworthy that African Americans have the highest AD rate of any ethnic group in the United States [Tang et al., 1998; Hendrie et al., 2001], while Japanese Americans have the lowest [Graves et al., 1996; White et al., 1996]. This result is probably a combination of both genetic and dietary factors. African Americans have a higher frequency of APOE ε4 than European Americans, who, in turn, have a higher frequency than Asians. In addition, there are very likely ethnic differences in diet, with Asian Americans eating less total energy and animal products and more vegetable products than European Americans. Black Americans may eat more convenience foods and fewer fruits and vegetables than European Americans [Lovejoy et al., 2001; Forshee et al., 2003]. A predisposing gene combined with poor diet is the worst combination in terms of risk for AD. Prevalence of AD in the United States Hebert et al. estimated that of the number of people with AD in the United States in 2000 was 4.5 million [Hebert et al., 2003]. According to the authors, by 2050 this number will increase by almost three-fold, to 13.2 million. I have criticized both estimates [Grant, in press]. The 4.5-million estimate was based on incidence rates in a biracial community, with African Americans making up about 40 percent of the sampled population. The authors used education level to extrapolate the results to the entire United States. 8
  9. 9. As shown by Tang et al. [2001], ethnic origin is a much better way, especially since African Americans have a frequency of APOE ε4 that is two to three times that for European Americans. In addition, Hebert et al. seemed to classify nearly everyone with dementia as having AD. That classification is not consistent with what is normally found in Western developed countries [Jorm et al., 2001]. In Asian countries, VaD rates are about the same as AD rates since VaD is more related to hypertension, and hypertension is more related to dietary sodium than to dietary fat, and Asian diets are different from Western Developed Country diets. As for the 2050 estimate, it is likely high as well. If Americans find a way to reverse the obesity epidemic that is sweeping the country, the numbers need not reach that high. Other studies have also estimated AD prevalence in the United States. The East Boston Study, which estimated 4 million with AD [Evans et al., 1989] was criticized by Brookmeyer et al. [1998], who found 2.3 million in 1997, for having incidence values much higher than any other U.S. study. The ecologic study [Grant, 1997] gave an estimate of about 2.1 million with AD in the early 1990s. In my opinion, some prevalence estimates are intentionally inflated in order to persuade Congress to appropriate more funding for AD research. Diet and Lifestyle Play an Important Role While genetics plays a role in the risk of developing Alzheimer’s disease, diet and lifestyle also play important roles. Since genetics can’t be changed, those who would like to reduce their risk of Alzheimer’s disease should make lifestyle choices. For those who want to reduce their risk of AD, the most important thing appears to be related to dietary factors, including fruits vegetables and moderate intake of fatty fish (or fish oil). Olive oil also appears to be beneficial. In addition, antioxidant and folate supplements would be beneficial. The red wine ingredient resveratrol is also helpful. Finally, keeping body mass index low and keeping both the mind and body active are very helpful. William B. Grant has a Ph.D. in physics from U.C. Berkeley and has worked at the level of senior research scientist in the fields of optical and laser remote sensing of the atmosphere and atmospheric sciences at SRI International, the Jet Propulsion Laboratory, and the NASA Langley Research Center. He is the author or coauthor of over 60 articles in peer-reviewed journals, has edited two books of reprints, and contributed half a dozen chapters to other books. He published the first paper linking diet to Alzheimer's disease and identifying the major dietary components that are risk and risk reduction factors. He has also studied the links between dietary sugars and heart disease and obesity, diet and breast, colon and prostate cancer, and UVB/vitamin D and cancer and autoimmune diseases. He recently retired from NASA and founded 9
  10. 10. Sunlight, Nutrition and Health Research Center (SUNARC) (www.sunarc.org), where he will continue and extend his health research and educational efforts. References (note that abstracts to these papers are generally available at PubMed: http://www.ncbi.nlm.nih.gov/pubmed/) Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes Mellitus and Risk of Alzheimer Disease and Decline in Cognitive Function. Arch Neurol. 2004;61:661-6. Atkinson HG. COX-2 inhibitors: better than traditional NSAIDs? Vioxx and Celebrex may be no less risky than NSAIDs. Health News. 2002;8:5. Barberger-Gateau P, Letenneur L, Deschamps V, Pérès K, Jean-François Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study. BMJ 2002;325:932-3. Berrino F. [Western diet and Alzheimer's disease] Epidemiol Prev. 2002;26:107-15. Italian. Bourre JM. Roles of Unsaturated Fatty acids (Especially Omega-3 Fatty Acids) in the Brain at Various Ages and During Ageing. J Nutr Health Aging. 2004;8:163-74. Briante R, Febbraio F, Nucci R. Antioxidant properties of low molecular weight phenols present in the mediterranean diet. J Agric Food Chem. 2003;51:6975-81. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337-42. Burke JR, Roses AD. Genetics of Alzheimer's disease. Int J Neurol. 1991-1992;25-6:41-51. Burkitt DP. Possible relationships between bowel cancer and dietary habits. Proc R Soc Med. 1971;64:964-5. Butterfield DA, Drake J, Pocernich C, Castegna A. Evidence of oxidative damage in Alzheimer's disease brain: central role for amyloid beta-peptide. Trends Mol Med. 2001;7:548-54. Butterfield DA. Amyloid beta-peptide [1-42]-associated free radical-induced oxidative stress and neurodegeneration in Alzheimer's disease brain: mechanisms and consequences. Curr Med Chem. 2003;10:2651-9. Campbell A, Smith MA, Sayre LM, Bondy SC, Perry G, Mechanisms by which metals promote events connected to neurodegenerative diseases. Brain Res Bull. 2001;55:125-32. 10
  11. 11. Chan FK, Graham DY. Prevention of non-steroidal anti-inflammatory drug gastrointestinal complications - review and recommendations based on risk assessment. Aliment Pharmacol Ther. 2004;19:1051-61. Chandra V, Ganguli M, Pandav R, Johnston J, Belle S, DeKosky ST. Prevalence of Alzheimer's disease and other dementias in rural India: the Indo-US study. Neurology. 1998 Oct;51(4):1000-8. Chaney MO, Baudry J, Esh C, et al. A beta, aging, and Alzheimer's disease: a tale, models, and hypotheses. Neurol Res. 2003;25:581-9. Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, Barberger-Gateau P, Dartigues JF. Intake of flavonoids and risk of dementia. Eur J Epidemiol. 2000;16:357-63. Corder EH, Lannfelt L, Bogdanovic N, Fratiglioni L, Mori H. The role of APOE polymorphisms in late-onset dementias. Cell Mol Life Sci. 1998;54:928-34. Covas MI, Miro-Casas E, Fito M, et al. Bioavailability of tyrosol, an antioxidant phenolic compound present in wine and olive oil, in humans. Drugs Exp Clin Res. 2003;29:203-6. Crawford MA, Bloom M, Broadhurst CL, et al. Evidence for the unique function of docosahexaenoic acid during the evolution of the modern hominid brain. Lipids. 1999;34:S39-47. Cuajungco MP, Faget KY, Huang X, Tanzi RE, Bush AI. Metal chelation as a potential therapy for Alzheimer's disease. Ann N Y Acad Sci. 2000;920:292-304. Das UN, Ramos EJ, Meguid MM. Metabolic alterations during inflammation and its modulation by central actions of omega-3 fatty acids. Curr Opin Clin Nutr Metab Care. 2003;6:413-9. de la Torre JC. Vascular basis of Alzheimer's pathogenesis. Ann N Y Acad Sci. 2002;977:196-215. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ. 2002;325:619. Demirovic J, Prineas R, Loewenstein D, et al. Prevalence of dementia in three ethnic groups: the South Florida program on aging and health. Ann Epidemiol. 2003;13:472-8. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981;66:1191-308 Ellis JM, McCully KS. Prevention of myocardial infarction by vitamin B6. Res Commun Mol Pathol Pharmacol. 1995;89:208-20. 11
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