Brain Dietary patterns and delay in onset of Alzheimer s Disease in the media?

Transcription

1 D Brain Dietary patterns and delay in onset of Alzheimer s Disease in the media? CSI CSIRO Division of Food and Nutritional Sciences RO Division of Food and Nutritional Sciences Debra Krause, Christine Margetts and Peter Roupas CSIRO Division of Food and Nutritional Sciences Werribee, Victoria, 3030 Debra Krause, Christine Margetts and Peter Roupas CSIRO Preventative Health Flagship and CSIRO Division of Food and Nutritional Sciences, Werribee, Victoria, 3030, Australia June 2011

2 Enquiries should be addressed to: Dr Peter Roupas CSIRO Food and Nutritional Sciences Private Bag 16 / 671 Sneydes Road Werribee Vic 3030 Distribution list Cassandra Szoeke Michael Fenech Copyright and Disclaimer 2011 CSIRO To the extent permitted by law, all rights are reserved and no part of this publication covered by copyright may be reproduced or copied in any form or by any means except with the written permission of CSIRO. Important Disclaimer CSIRO advises that the information contained in this publication comprises general statements based on scientific research. The reader is advised and needs to be aware that such information may be incomplete or unable to be used in any specific situation. No reliance or actions must therefore be made on that information without seeking prior expert professional, scientific and technical advice. To the extent permitted by law, CSIRO (including its employees and consultants) excludes all liability to any person for any consequences, including but not limited to all losses, damages, costs, expenses and any other compensation, arising directly or indirectly from using this publication (in part or in whole) and any information or material contained in it.

3 Contents 1. Executive Summary Dietary Patterns Dietary components Recommendation Review question Background What is dementia? How is dementia diagnosed? Current awareness information available Current research on dietary intervention Inclusion and exclusion criteria Types of participants Types of interventions / phenomena of interest Types of outcomes Types of studies Search strategy Dietary factors and AD Risk Dietary patterns Healthy eating patterns based on health policy guidelines Population specific dietary patterns Dietary components Mediterranean Diet USA cohort French cohort Reviews of the Mediterranean diet Mediterranean diet components Vegetarian Diets Paleolithic Diet Okinawa Diet Ketogenic Diet Caloric Restriction Dietary components Diet and nutritional studies Alcohol Carbohydrates Dietary Fats Olive oil Fish and (n-3) PUFA Dietary patterns and the delay in onset of Alzheimer s disease June 2011 iii

4 6.8.5 Dairy products and saturated fats Fruit, vegetables and plant foods Berries and flavanoids Legumes Nuts, seeds, grains Garlic Tea Concluding remarks About the authors Peter Roupas Christine Margetts Debra Krause Search Strategy Sources / Databases Used Search Strategies and Terminologies Search Terms for Individual Interventions Bibliography Web pages...62 List of Figures Figure 1 The Mediterranean diet pyramid...21 Figure 2 Frequency distribution of the apolipoprotein E allele ε4 in the world population Figure 3 The Okinawa diet food pyramid...29 List of Tables Table 1 Types of vegetarian diets...26 iv

5 1. EXECUTIVE SUMMARY 1.1 Dietary Patterns Levels of evidence of dietary patterns and their role in the delay in the onset of Alzheimer s Disease (AD). Population studies which examined cohorts from several countries including the USA, the Netherlands, Finland and Italy suggest that adherence to diets based on health policy guidelines may be associated with improved cognitive function Three recent reviews have concluded that while studies to date provide moderately compelling evidence that adherence to the Mediterranean Diet is associated with a reduced risk of AD, further confirmation in other study populations with different ethnicities and different dietary habits is warranted. There are currently no studies linking the vegetarian, Palaeolithic, Okinawa, ketogenic or caloric restriction diets to the prevention of cognitive decline or Alzheimer s disease. Dietary patterns and the delay in onset of Alzheimer s disease June

6 1.2 Dietary components A review of a range of dietary components that have been associated with improvements in cognition in the popular press has identified that many of the studies cited have been animal or in vitro studies of short duration, and therefore were outside the scope of this review. Many of the studies evaluating dietary components have been part of larger population studies and evaluations were based on food frequency questionnaire data, which can be affected by recall bias. Overall it was found: There is inadequate evidence to assess the association between fruit and vegetable consumption on the delay of onset of AD and a low level of evidence for the consumption of vegetables and a decreased risk for cognitive decline. Further recent studies have found that a plant-food rich diet is associated with improved performance in several cognitive abilities in a dose-dependent manner. For alcohol consumption, all drinkers had a lower risk of AD compared to nondrinkers and light to moderate alcohol use was protective for AD in both males and females. There is inadequate evidence for a role of carbohydrate intake in AD. There is preliminary evidence for an association between increased saturated fat intake and trans fat intake and risk of AD or cognitive decline. Higher n-3 polyunsaturated fatty acids (PUFA ), such as from oily fish, intake may be associated with better episodic memory over time, while higher monounsaturated fatty acids (MUFA) such as from olive oil, intake may be related to less cognitive decline. There is inadequate evidence to assess the association of consumption of berries and berry flavanoids with cognition, however, flavanoid containing foods and beverages such as wine, tea and chocolate showed overall better cognitive performance in a dose dependent manner. One prospective study reported a low intake of legumes was associated with the development of mild cognitive impairment. There were no human studies on consumption of nuts, seeds, grains and garlic and effects on cognition. The literature is beginning to reinforce the importance of studying dietary patterns rather than individual foods or nutrients due to likely synergistic effects of nutrient combinations. For example, a dietary pattern high in saturated fatty acids and also high Dietary patterns and the delay in onset of Alzheimer s disease June

7 in monounsaturated fatty acids may have opposing effects on AD risk and therefore result in an overall nil effect. Hence dietary patterns and food combinations may provide potential synergistic effects of nutrient combinations as dietary interventions for the delay of onset of AD. 1.3 Recommendation Nutritional/clinical trials with multi-nutritional interventions (addressing neuroprotective, cardiovascular and inflammatory responses), over sufficient lengths of time (12 months minimum, 18 months or longer preferable), which control for confounding dietary and lifestyle factors are required. Study designs should allow for the identification of synergistic or multi-factorial effects of the nutritional interventions being evaluated in order to substantiate the clinically-relevant effects of dietary interventions on the delay of onset of AD. 2. REVIEW QUESTION The aim of this review was to identify dietary patterns that have the potential to delay the onset of Alzheimer s Disease (AD). More specifically, the objective was to identify the effects of dietary patterns, as neuroprotective agents that could delay cognitive decline and the onset of AD. 3. BACKGROUND With the ageing population and the proportion of people aged 65 and over expected to more than double over the next few decades (Productivity-Commission, 2005), Australia has a looming dementia epidemic which poses significant economic and social challenges. Already around 296,000 Australians are affected by dementia with significant loss of productivity and participation in the community, with figures expected as high as Dietary patterns and the delay in onset of Alzheimer s disease June

8 592,000 in 2030 and by 2050, 1.13million are expected to be living with dementia (Access-Economics, 2008). The average person with dementia survives from 4-10 years with increasing disability, and direct costs of dementia have been estimated at $5.4 billion per annum (in 2008). Unless substantial numbers of dementia cases can have their onset delayed or prevented, the cost burden of dementia upon Australian society will be a staggering $83billion dollars by 2060 (in 2006/2007 dollars) and will represent around 11% of the entire health and residential aged care sector spending (Access-Economics, 2008). Nevertheless, it has been estimated that if the average age of onset of dementia could be delayed by 5 years, the prevalence would halve. There is an urgent need to identify those at risk of developing dementia and to determine safe, effective strategies and therapies to delay its onset. 3.1 What is dementia? The term dementia is used to describe the symptoms of a large group of illnesses which cause a progressive decline in a person s functioning. It is a broad term used to describe a loss of memory, intellect, rationality, social skills and normal emotional reactions. There are many different forms of dementia and each has its own cause. Neurodegenerative diseases such as Alzheimer's Disease are the most common cause of dementia, thought to be responsible for up to 70% of cases. Alzheimer's Disease is a progressive disease which can affect all areas of the brain, gradually causing memory loss and loss of abilities. Currently, 1000 new cases of Alzheimer's Disease are diagnosed each week in Australia and around one million people are involved in caring for a family member or friend with dementia. Other terms associated with dementia are Mild Cognitive Impairment (MCI) and Memory Complainers. MCI is a clinical syndrome characterized by reduced cognitive performance (often involving memory), which represents a high risk state for the development of AD (Winblad et al., 2004, Petersen et al., 1999). Memory complainers are healthy individuals without cognitive impairment who express subjective concern about their memory function. There is still disagreement in the literature as to whether memory complainers are predictive of cognitive decline (Ellis et al., 2009). Dietary patterns and the delay in onset of Alzheimer s disease June

9 3.2 How is dementia diagnosed? Neurodegenerative disorders are the result of abnormalities in the transport, degradation and aggregation of particular proteins, including amyloid-β peptides (Aβ), apolipoprotein E (APOE) and the microtubule associated protein, tau in the brain. At present, although doctors can make a diagnosis of Alzheimer's Disease based on a patient's symptoms, the only way to confirm the diagnosis is by post-mortem examination of the brain. A new imaging technology, utilising 11 C- Pittsburg compound and Positron Emission Tomography (PiB-PET) has been successfully used for early identification of Alzheimer s Disease through detection of amyloid-β (Aβ) plaques in the brain. However, the neurofibrillary tangles (NFT), neurophil threads and dystrophic neurites surrounding Aβ plaques commonly referred to as tau, are currently only detectable through post-mortem histology studies. 3.3 Current awareness information available Publications such as Mind your Mind by Alzheimer s Australia provide a guide to information on lifestyle related activities that may aid in dementia risk reduction. These lifestyle related activities include: Mental stimulation: The use it or lose it argument demonstrates that complex and precise brain activity may have a protective effect from Alzheimer s Disease later in life. Hobbies that may help keep the brain active include crosswords, puzzles, cards, reading, computer skills, sewing, painting, carpentry and many others. Exercise: Emerging evidence suggests that in addition to protection from heart disease, stroke and diabetes, regular exercise can reduce the risk of dementia. Regular physical exercise maintains good blood flow to the brain and encourages growth of new brain cells. Dietary patterns and the delay in onset of Alzheimer s disease June

10 Social engagement: Leisure activities combining physical, mental and social activity have been shown to be associated with a lower risk of developing dementia. Health and lifestyle: Regular health checks for control of blood pressure, cholesterol, blood sugar levels and weight have been shown to be effective in decreasing risk factors with dementia as well as stroke, cardiac rhythm and diabetes. Studies have also shown lifestyle factors such as smoking, stress, excessive alcohol consumption and poor sleep habits to be associated with an increased risk of dementia. Diet: A balanced diet may reduce the risk of dementia later in life. Studies have shown that people with a diet rich in saturated fats have a 2.2-fold risk of developing Alzheimer s Disease compared to those on a low fat diet. There are epidemiological and animal studies suggesting that vitamins and supplements may also have protective effects although many of these have not been confirmed in human clinical trials. This information has been drawn together from scholarly reviews of scientific studies, clinical trials and case studies, however the level of evidence has not yet been critically scrutinised. 3.4 Current research on dietary intervention There are currently no dietary or lifestyle interventions that have been proven to be efficacious in preventing the onset and incidence of AD. It has often been suggested that adopting a healthy diet and lifestyle may assist in delaying the onset of AD due to the potential contribution of vascular disease to AD (Mucke, 2009). There is a wealth of epidemiological evidence in the literature supporting a relationship between diet and AD, and that the risk of cognitive decline may be reduced by dietary interventions including vitamins and dietary supplements (Scheltens, 2009). Current research being conducted by CSIRO s Preventative Health Flagship is centred on prevention, susceptibility, early detection and diagnosis of neurodegenerative diseases such as AD. CSIRO has identified the need for a review of the scientific Dietary patterns and the delay in onset of Alzheimer s disease June

11 literature to identify dietary patterns that have the best evidence-based potential to delay the onset of AD. 4. INCLUSION AND EXCLUSION CRITERIA 4.1 Types of participants This review considered studies on effects of diet on cognition that included healthy male and female adult humans without AD. Some studies did include adults who have reported difficulties with memory (memory complainers) and/or adults with mild cognitive impairment (MCI) as a result of the ageing process, but not cognitive impairment due to brain injury. The review also included adults without AD that carry the APOE ε4 genotype, a known genetic risk factor for AD. The review did not include studies of patients with established AD, as it is believed that even so-called early clinical stages of AD reflect advanced-stage brain failure that may be impossible to reverse (Mucke, 2009). The review did not include studies using animal models. 4.2 Types of interventions / phenomena of interest This review considered studies that evaluated the effects of dietary interventions, including dietary patterns and dietary components as neuroprotective agents. 4.3 Types of outcomes The review considered studies that included both subjective measurements such as selfreporting via food frequency questionnaires as well as objective measurements such as: Cognitive function tests diagnostic of MCI and AD (Mini Mental State Examination (MMSE), Episodic Memory Score, California Verbal Learning Task Dietary patterns and the delay in onset of Alzheimer s disease June

12 (CVLT) Blood biomarkers of MCI and AD risk (e.g. plasma Aβ 42, plasma Aβ 40, tau protein). 4.4 Types of studies The review considered published systematic reviews on the dietary interventions and dietary components. The review considered any randomised controlled trials (RCTs) and pre-clinical trials. In the absence of RCTs, other research designs, such as nonrandomised controlled trials and before and after human studies, were considered for inclusion to enable the identification of current best evidence regarding the effect of dietary factors on humans that have the potential to delay the onset of AD. The review did include an evaluation of findings of population or cohort studies. Dietary patterns and the delay in onset of Alzheimer s disease June

13 5. SEARCH STRATEGY The search strategy aimed to find both published and unpublished English language studies. A three-step search strategy was utilised in each component of this review. An initial limited search of MEDLINE was undertaken followed by analysis of the text words contained in the title and abstract, and of the index terms used to describe relevant articles. A second search using all identified keywords, MESH and index terms, was then undertaken across all included databases. Thirdly, the reference list of all identified reports and articles was searched for additional studies. The detailed search strategy, including a full listing of the sources, databases, terminologies and specific search terms is provided in the appendices. The following databases were searched for systematic reviews, analytical reviews, the results of clinical trials and population and cohort studies; Medline on PubMed Cochrane Central (Database of Systematic Reviews and Cochrane Collaboration Central Register of Controlled Trials. Centre for Reviews and Dissemination Databases (Database of Reviews of Effects (DARE). NHS Economic Evaluation Database (NHS EED), Health Technology Assessment (HTA) Database) CRD Centre for Reviews and Dissemination. Joanna Briggs Institute (JBI) Library of Systematic Reviews. Agency for Healthcare Research and Quality (US Department of Health and Human Services). Records for the following were identified and either printed or downloaded for inclusion in an EndNote database. Systematic reviews and meta-analyses and their protocols, if still unpublished Analytical and critical reviews that evaluated relevant research Descriptive reviews of the area that might lead to relevant trials Randomised controlled trials Non randomised controlled trials Dietary patterns and the delay in onset of Alzheimer s disease June

14 Other trials with an identifiable intervention or dose of a review food or food group Cohort and population studies that had analysed a targeted dietary pattern or food or food group in relation to cognition Current ongoing trials and as-yet-unpublished trials that might yield data were identified using the following databases: Clinical trials.gov ISRCTN International metaregister of Current Controlled Trials which includes the following sub-files: Action Medical Research (UK) Medical Research Council (UK) UK Trials (UK) The Wellcome Trust (UK) NIHR Health Technology Assessment Program (HTA) (UK) NIH Clinical Trials.gov Register Action Medical Research (UK) The following archived files were also searched on the metaregister: Alzheimer s Society Medical Editor s Trials Amnesty National Health Service Research and Development Regional Program NHS Trust Clinical Trials Register CTSU trials being randomised by the Clinical Trial Services Unit, Oxford National Research Register (UK) Schering Health Care Limited GlaxoSmith Kline Sir Jules Thorn Charitable trust Hong Kong Health Services Research Fund Dietary patterns and the delay in onset of Alzheimer s disease June

15 South Australian Network for Research on Ageing The Health Foundation King s College London (UK) Laxdale Limited US Department of Veteran s Affairs Co-operative Studies Program Cochrane Collaboration Central Register of Controlled Trials Australian and New Zealand Clinical Trials Registry (ANZCTR) Alzheimer s Association Grants World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) portal which includes the following sub-files: Australian New Zealand Clinical Trials Registry ClinicalTrials.gov ISRCTN Chinese Clinical Trial Registry Clinical Trials Registry - India German Clinical Trials Register Iranian Registry of Clinical Trials Japan Primary Registries Network Sri Lanka Clinical Trials Register The Netherlands National Trial Register The search did look for unpublished but complete, clinical trials, where data might be available. Dietary patterns and the delay in onset of Alzheimer s disease June

16 6. DIETARY FACTORS AND AD RISK 6.1 Dietary patterns Dietary patterns in populations or ethnic cultures have been studied for their ability to lower the risk of Alzheimer s Disease Healthy eating patterns based on health policy guidelines One of the first studies to look at the association between dietary patterns and cognitive function was Huijbregts et al, (1998). The cross sectional population study consisted of 1049 elderly men (70-91 years) from five cohorts in Finland (2), the Netherlands (1) and Italy (2) from the Seven Countries Study. A healthy diet indicator (HDI) was calculated based on the WHO guidelines for the prevention of chronic diseases, where a higher HDI indicated a diet more in accordance with the WHO guidelines. Food intake was estimated by a cross-check of dietary history and cognitive function measured using the Mini-Mental State Examination (MMSE). The prevalence of cognitive impairment varied from 14.4% in Zutphen (The Netherlands) to 42.1% in Crevalcore (Italy). The study showed a tendency towards a lower prevalence of cognitive impairment with increased HDI in four out of five cohorts (except East Finland). The Zutphen group showed a borderline significance (OR=0.81; 95% CI ) after adjustment for age, education, cigarette smoking, alcohol consumption and energy intake. In Crevalcore the association was statistically significant (OR = 0.75; 95% CI ). However, since the results were not consistent over all five cohorts, further research is needed to confirm if a healthy diet might be associated with a better cognitive function in elderly men. Wengreen et al, (2009) prospectively examined associations between an index of diet quality and cognitive function and decline among 3634 resident men and women 65 years and over of the Cache County Study on Memory and Aging in Utah. The study commenced in 1995, with a baseline survey that included a 142-item food frequency questionnaire (FFQ), cognitive assessment using an adapted version of the Modified Mini-Mental State Examination and 3 subsequent interviews spanning approximately Dietary patterns and the delay in onset of Alzheimer s disease June

17 11 years. A recommended food score (RFS) and non-rfs were computed based on the Dietary Guidelines for Americans current at the time of the study. It was found that a high RFS was associated with better cognitive test scores and that this effect was strengthened over 11 years of follow-up. Those with the highest RFS declined by 3.41 points over 11 y compared with a 5.2-point decline experienced by those with the lowest RFS (P = ). The effect was more pronounced for those with at least one copy of the APOE ε-4 allele. The authors concluded that consuming a diverse diet that includes a variety of recommended foods may help to attenuate age-related cognitive decline among the elderly. Tangney, et al (2011), investigated whether adherence to a Mediterranean dietary pattern or to the Healthy Eating Index-2005 (HEI-2005) (Dietary Guidelines for Americans 2005) is associated with cognitive change in older adults. The study was based on analyses of data from the ongoing Chicago Health and Aging Project (CHAP) longitudinal study of 6158 adults aged >65 years of which 3790 participants (2280 blacks) and 1510 whites) qualified for this investigation. The results showed that white participants had higher energy-adjusted MedDiet scores but lower HEI-2005 scores than did black participants. Higher MedDiet scores were associated with slower rates of cognitive decline after adjustment for age, sex, race, education, participation in cognitive activities, and energy. No such associations were observed for HEI-2005 scores Population specific dietary patterns Lee, 2010, examined the dietary pattern of 285 community-dwellers aged 60 or older from a Hong Kong Chinese population with questionable dementia (146 subjects) and compared to cognitively normal individuals (139 subjects). Dietary habits were recorded using the Chinese Mini-Nutritional Assessment (MNA) and neither group was found to be at risk of malnutrition. Questionable dementia was diagnosed by psychogeriatricians and relevant demographic and dietary factors were examined using univariate then multivariate analyses. The questionable dementia group were found to be older, had fewer years of education, lower MMSE and Alzheimer s Disease Assessment Scale-Cognitive Dietary patterns and the delay in onset of Alzheimer s disease June

18 subscale (ADAS-cog) as well as lower MNA scores. In univariate analyses, questionable dementia was associated with a decline in food intake and appetite, eating less vegetables and fruits, and drinking less fluid. After adjustment for age, gender and education level, eating > 2 servings of vegetables / fruits per day (OR 0.26, 95% CI 0.067, 0.973) and taking > 5 cups of fluids per day (OR 0.4, 95% CI 0.204, 0.792) was associated with a lower prevalence of questionable dementia. A further clinical trial related to dietary patterns was registered in 2006 by the Chinese University of Hong Kong and completed in May The three year randomised control trial was to assess a brain preservation diet for the prevention of cognitive decline in approximately 480, 75 years old hostel residents, in Hong Kong. The diet included 3 portions of vegetables, 2 portions fruit and 6 glasses of water per day as well as 5 fish meals per week. Primary outcome measures under study were the incidence of dementia at the completion of the study compared to baseline using MMSE scores in a control and a test group. No results of the study are currently available Dietary components A recently published prospective cohort study (Gu et al, 2010) attempted to assess the association between diet and AD by analysing dietary patterns of seven potentially AD related food nutrient combinations. The nutrients were saturated fatty acids, monounsaturated fatty acids, ω-3 polyunsaturated fatty acids, ω-6 polyunsaturated fatty acids, vitamin E, vitamin B12, and folate. The study involved collecting the dietary information of 2148 elderly subjects without dementia, aged over 65 years, from New York. Their dietary information was evaluated every 1.5 years over the 4 year study, analysed and grouped into seven dietary patterns. Although 253 subjects were found to develop AD over the study, only, one of the seven dietary patterns analysed was significantly associated with a lower AD risk. A diet with high intake of salad dressing, nuts, fish, tomatoes, poultry, cruciferous vegetables, fruits, dark and green leafy vegetables and a lower intake of high-fat dairy products, red meat, organ meat, and butter was strongly associated with lower risk of Alzheimer's disease. The study reflected a dietary pattern rich in ω-3 polyunsaturated fatty acids, ω-6 polyunsaturated Dietary patterns and the delay in onset of Alzheimer s disease June

19 fatty acids, vitamin E and folate but lower in saturated fatty acids and vitamin B12. The authors also discussed the importance of studying dietary patterns rather than individual foods or nutrients due to likely effects of nutrient combinations. For example a dietary pattern high in saturated fatty acids and also high in monounsaturated fatty acids may have opposing effects on AD risk. Wegmann et al are recruiting approximately 300 elderly for a clinical trial (NCT ) registered in 2010 in Germany. The RCT study will investigate whether dietary modification (15% caloric restriction, omega-3 fatty acids or resveratrol) over 6 months can provide positive effects on cognitive functions such as learning and memory in year old people with mild cognitive impairment. The primary outcome measure will be improvement in memory testing using the Alzheimer's Disease Assessment Scale - cognitive subscale. A second phase of the trial will aim to introduce physical and cognitive training to the dietary intervention. A further trial (NCT ) was registered (but not yet recruiting) by Witte et al in 2009 from the same group in Germany. The RCT study will investigate whether dietary modification of 20-30% caloric restriction or omega-3 fatty acid supplement (2g/day DHA/EPA capsule) or a placebo (corn oil) over 6 months can provide positive effects on cognitive functions such as learning and memory in year old healthy people. The primary outcome measure will be improvement in auditory verbal learning task. 6.2 Mediterranean Diet The Mediterranean diet, a dietary pattern usually consumed among the populations bordering the Mediterranean Sea has been widely reported as a model of healthy eating for its contribution to a favourable health status and quality of life. The Mediterranean diet (MD) is characterised by high intake of vegetables, legumes, fruits, and cereals, high intake of unsaturated fatty acids (mostly in the form of olive oil), low intake of saturated fatty acids, moderately high intake of fish, low-tomoderate intake of dairy products (mostly cheese or Dietary patterns and the delay in onset of Alzheimer s disease June

20 yoghurt), low intake of meat and poultry; and regular but moderate intake of alcohol, primarily in the form of wine and generally during meals (Sofi et al, 2008). A typical Mediterranean diet pyramid is shown in figure 1. Figure 1 The Mediterranean diet pyramid It is widely reported in the literature and demonstrated through meta-analysis of population studies that a greater adherence to the MD is associated with a reduced incidence of overall mortality, cardiovascular mortality and/or incidence, cancer mortality and/or incidence, and incidence of Parkinson s disease and Alzheimer s disease (AD) (Sofi et al, 2008). There have been a series of cohort studies examining the effects of adherence to the MD on AD. There have been five studies published related to a community group from New York, USA and one study published related to a community cohort from Bordeaux, France. These studies are summarised in Table 1. Dietary patterns and the delay in onset of Alzheimer s disease June

21 Table 1 Summary of prospective cohort studies examining the effects of a Mediterranean diet on Alzheimer's disease Study Type Sample Duration Outcome Result Prospective 2258 non 18month 262 AD study demented follow up cases community over 4 years, cohort from New York Adherence to MD diet Scarmeas et al 2006a AD risk with MD diet and vascular history Scarmeas et al 2006b Mortality of AD patients with MD diet Scarmeas et al 2007 MD and physical exercise Scarmeas et al 2009a MD and cognitive decline Scarmeas et al 2009b MD and cognitive decline Feart et al 2009 Case control nested study of the prospective study community cohort from New York Prospective study community cohort from New York Prospective study community cohort from New York Prospective study community cohort from New York Prospective study community cohort from Bordeaux, France 194 AD patients (developed during study) 1,790 non demented 192 AD patients (developed during study) 1880 non demented 1393 cognitively normal 1419 non demented 65 years 18month follow up over 4 years 18month follow up over 4.4 years 18month follow up over 5.4 years 18month follow up over 4.4 years 2 year follow up over 7 years Death of 82 patients 282 AD cases 275 MCI cases 107 AD cases 99 AD cases Higher adherence to MD showed lower incidence of AD of up to 40% in the highest MD tertile group Higher adherence to MD showed lower incidence of AD regardless of previous history of stroke, diabetes, CVD etc Higher adherence to MD showed longer incidence of survival of AD patients Higher adherence to MD and physical exercise showed lower incidence of AD of up to 35%. Higher adherence to MD is associated with a reduced risk of MCI and reduced risk of MCI conversion to AD Higher adherence to MD was associated with slower cognitive decline as measured by MMSE but not with other tests. No association with MD and a reduced risk of incident dementia Dietary patterns and the delay in onset of Alzheimer s disease June

22 6.2.1 USA cohort The USA cohort consisted of approximately 3000 participants aged 65 years and over, who were selected for individual studies according to the data available. Participants were non-demented at baseline (except for one study) and the length of follow up varied from 4-7 years at 18 month intervals. Adherence to the MD was determined based on self-reported information from a semi-quantitative food frequency questionnaire (0-9 point scale with higher scores indicating higher adherence). Results were adjusted for cohort, age, sex, ethnicity, education, APOE genotype, caloric intake, smoking, medical co morbidity index and body mass index. Scarmeas et. al., (2006a) investigated the association between the MD and risk for AD. They conducted a prospective study of 2258 community-based, non-demented individuals who were evaluated every 18 months. There were 262 incident AD cases during 4 years of follow-up. Higher adherence to the MD was associated with lower risk of AD (hazard ratio = 0.91, p=0.015). Compared with subjects in the lowest MD tertile, subjects in the middle MD tertile had a hazard ratio of 0.85, and those at the highest tertile had a hazard ratio of 0.6 for AD (p for trend = 0.007). Overall, these results indicated that higher adherence to the MD was associated with a reduction in risk of AD. In a follow-up study, of 1790 non-demented subjects and 194 AD patients, Scarmeas et al (2006b), examined whether the association between AD and MD holds when a different population of AD subjects is used. This study included patients who were found to have AD at the baseline evaluation because one of the possible mechanisms by which the MD may be exerting its protective effect for AD could be vascular (MD could lower cardiovascular disease (CVD) and hence lower dementia rates). Incidence of CVD was defined by self-report or by the use of disease specific medications. In this second study, the authors examined whether the association between MD and AD was mediated by vascular co-morbidity. Results again showed that higher adherence to the MD was associated with lower risk of AD (odds ratio 0.76). Compared with subjects in the lowest MD tertile, subjects in the middle MD tertile had an odds ratio of 0.47, and those in the highest MD tertile had an odds ratio of 0.32 for AD (p for trend 0.001). Introduction of the vascular variables (stroke, diabetes, hypertension, heart disease, lipid levels) in the model did not change the magnitude of the association. The authors concluded that higher adherence to MD was associated with reduced risk of AD, and the association was not mediated by vascular co-morbidity. Dietary patterns and the delay in onset of Alzheimer s disease June

23 The association between MD and mortality in participants with AD was examined in a subsequent study (Scarmeas et al 2007). Of the 192 participants in the study, 85 patients died during the 4.4 year study. In adjusted models, those in the highest MD tertile survived longer than those in the lowest tertile with a significant reduction of 73% (HR 0.27, 95%CI ; p = 0.003). This important finding showed that adherence to MD was able to affect not only the risk of incident AD but also the subsequent clinical course of the disease and that higher adherence to the MD was associated with lower mortality in AD. The combined association of MD and physical activity was investigated in another study (Scarmeas et al 2009a) of 1,880 non-demented subjects followed up over 5.4 years. Physical activity was measured as a sum of weekly participation in various physical activities, weighted by activity type. For this study the results were also adjusted for depression, leisure activities, baseline clinical dementia rating score and the interval between 1 st dietary and 1 st physical activity measure. Over the course of the study 282 AD cases occurred. The results showed that for diet alone, high adherence to MD (compared to low MD) was associated with a lower risk of AD (HR %CI, ). This was also consistent for physical activity where a high level of physical activity was compared to no physical activity ( HR %CI, ). It was also found that compared to individuals neither adhering to diet nor participating in physical activity, those adhering to MD and participating in high levels of physical activity had a lower risk of AD. This study concluded that higher adherence to MD and a higher level of physical activity were independently associated with reducing the risk of AD. A further study by Scarmeas et al 2009b, explored the association of MD and MCI. Of the group of 1393 cognitively normal subjects followed up over 4.4 years, 275 subjects developed MCI. It was found that higher adherence to MD was associated with a 28% reduced risk of MCI. A further follow up study of 4.3 years, of the 482 subjects with MCI, 106 developed AD and it was found that those with the highest adherence to MD had a 48% less risk of developing AD. Overall the study concluded that higher adherence to MD was associated with a trend for a reduced risk of developing MCI and a reduced risk of MCI conversion to AD. Dietary patterns and the delay in onset of Alzheimer s disease June

24 6.2.2 French cohort The French cohort consisted of approximately 1410 participants aged 65years and over, from Bordeaux, France, included in the Three-City study in and reexamined at least once over 5 years. Participants were non-demented at baseline. Adherence to the MD was determined based on self-reported information from a food frequency questionnaire and 24 hour recall (0-9 point scale with higher scores indicating higher adherence). Results were adjusted for cohort, age, sex, ethnicity, marital status, education, APOE genotype, caloric intake, smoking, medical co morbidity index, physical activity, depressive symptomatology, taking 5 medications or more, cardiovascular risk factors and stroke. The French cohort study (Feart et al 2009) investigated the association of the MD with change in cognitive performance and risk for dementia in an elderly French cohort using four neuropsychological tests. The study concluded that higher adherence to MD was associated with slower MMSE cognitive decline, but not consistently with other cognitive tests. Higher adherence was not associated with risk for incident dementia. The authors noted that the sample had limited power to detect association which may explain their null finding Reviews of the Mediterranean diet Two recent reviews (Sofi et al 2010, Feart et al 2010) of several of the above papers concluded that while studies to date provide moderately compelling evidence that adherence to MD is associated with a reduced risk of AD, further confirmation in other study populations with different ethnicities and different dietary habits is warranted. A further review (Williams et al, 2010) also concluded that confirmation of the reported protective association of the Mediterranean diet is needed using an independent cohort sample Mediterranean diet components Roberts et al (2010) investigated the associations of Mediterranean diet components with MCI through a food frequency questionnaire of a population from Olmsted County, Minnesota, USA. Following clinical assessment of 1,233 non-demented persons (aged years), 163 participants were found to have MCI. The results showed that the odds ratio of MCI was reduced for high vegetable intake [0.66 (95% CI = ), p Dietary patterns and the delay in onset of Alzheimer s disease June

25 = 0.05] and for high mono- plus polyunsaturated fatty acids to saturated fatty acids ratio [0.52 (95% CI = ), p = 0.007], adjusted for confounders. The risk of incident MCI or dementia was reduced in subjects with a high MD score [hazard ratio = 0.75 (95% CI = ), p = 0.24]. The authors concluded that vegetables, unsaturated fats, and a high MD score may be beneficial to cognitive function. 6.3 Vegetarian Diets Vegetarianism is adopted for various reasons: ethical, health, environmental, religious, political, cultural, aesthetic, economic, culinary or other reasons, and there are a variety of vegetarian diets. Vegetarian diets are broadly plant-based diets including fruits, vegetables, cereal grains, nuts, and seeds, mushrooms, with or without dairy products and eggs. There are several variations of the vegetarian diet but the common theme is no consumption of red meat. A total vegetarian does not eat meat, including red meat, game, poultry, fish, crustacea, and shellfish, and may also abstain from byproducts of animal slaughter such as animal-derived rennet and gelatin. Other types of vegetarian diets are included in Table 2. Table 2 Types of vegetarian diets Type of vegetarian diet Semi Lacto-ovo Lacto Ovo Vegan Pescetarian Eden Restrictions No red meat No red meat, fish, poultry No red meat, fish, poultry, eggs No red meat, fish, poultry, dairy No red meat, fish, poultry, dairy, eggs Fish, but no other meat Similar to Vegan, eat only plant-based foods, claim to be healthier and holier One particular religious group who prescribes to a largely vegetarian diet is the Seventh-day Adventists. The first Adventist Health Study project was conducted from with a population of Californian residents. Giem et al (1993) compared the incidence of dementia between vegetarian diets and meat eating diets in two cohort sub studies in a 65+ age group. It was assumed that the initial screening procedure in Dietary patterns and the delay in onset of Alzheimer s disease June

26 1976 effectively screened out most demented people from entering the study and that participants reported all hospitalisation for assessment during the 6 year study. The first study of 272 Californian residents were matched for age, sex, and living locality to vegan, ovo-lacto vegetarian and two heavy meat eating groups. This study found that subjects who ate meat (including poultry and fish) were more than twice as likely to become demented as their vegetarian counterparts (relative risk 2.18, p = 0.065) and the discrepancy was further widened (relative risk 2.99, p = 0.048) when past meat consumption was taken into account. A further study of a group of 2,984 unmatched participants showed no significant difference in the incidence of dementia in the vegetarian versus meat-eating subjects. There was no obvious explanation for the difference between the two sub-studies. While the authors reported a trend towards delayed onset of dementia in vegetarians in both studies, there was no evidence that any standardised cognitive assessment was used to assess participants through the course of the study. This study was reported in 1993 and since then there have been no studies linking the vegetarian diets to the prevention of Alzheimer s disease. 6.4 Paleolithic Diet The Paleolithic diet is also called the Caveman Diet, Hunter-Gatherer Diet, primal diet, ancestral diet, and evolutionary diet. The Australian aboriginal diet could also possibly fit into this diet category. The Paleo diet is a simple dietary lifestyle that is based on foods from the Paleolithic Era. They include foods that were eaten prior to agriculture and animal husbandry (meat, fish, shellfish, eggs, tree nuts, vegetables, roots, fruit, berries, mushrooms, etc.). Foods that result from agriculture or animal husbandry (grains, dairy, beans/legumes, potatoes, sugar and manufactured foods) are not part of the paleo diet. The paleo diet is largely based on the optimal foraging theory whereby our ancestors mostly ate foods that were easiest to hunt or gather at that specific locale, hence as nomads they would have adapted to various mixes of foods. Consequently food consumption was based on availability in a specific locale so diets could vary considerably from season to season and availability of meat, fruits, nuts etc. Dietary patterns and the delay in onset of Alzheimer s disease June

27 There are currently no studies linking the Paleolithic diet to the prevention of Alzheimer s Disease despite the higher frequency of distribution of the APOE allele ε4 in many of the hunter-gatherer populations around the world (Figure 2). Figure 2 Frequency distribution of the apolipoprotein E allele ε4 in the world population. Source: Utermann, G. Current Biology, Volume 4, Issue 4, 1 April 1994, Pages Okinawa Diet The Okinawa diet is a nutrient-rich, low-calorie diet originating from the Japanese Ryūkyū Islands. People from the islands of Ryūkyū (of which Okinawa is the largest) have the longest life expectancy in the world, although their life expectancy has plummeted in recent years, attributed to the decline of the traditional local diet and to other variables such as genetic factors, lifestyle, and environmental factors. Traditionally, the Okinawans also ate from small plates and tended to stop eating when they are about 80 % full, a form of caloric restriction ( The traditional Okinawa diet, has an emphasis on vegetables, whole grains, fruits, legumes and relatively small amounts of fish and limited amounts of lean meats. The traditional Okinawa diet was 20% lower in calories than the Japanese average and Dietary patterns and the delay in onset of Alzheimer s disease June

28 contained al arge proportion of green/yellow vegetables (particularly heavy on sweet potatoes). The Okinawa diet is low in fat and has only 25% of the sugar and 75% of the grains of the average Japanese dietary intake. Figure 3 outlines the typical Okinawa diet, which typically includes, goya or bitter melon, imo (sweet potatoes), green leafy vegetables, turmeric tea, small amount of fish (less than half a serving per day), soy and other legumes (6% of total caloric intake), pork (with the fat boiled off) and virtually no eggs or dairy products. Figure 3 The Okinawa diet food pyramid Source: While the effects of the Okinawa diet in relation to longevity has been studied in terms of caloric restriction and nutrient intake (Willcox et al, 2006, 2007, 2009) there is no evidence for effects on prevention of AD. Yamada et al (2002) studied the incidence of dementia in a community of Japanese Brazilians who immigrated from Okinawa to Campo Grande Brazil. The study undertaken in 2000, found that in a small group of 157 elderly of 70+ years in age, the group had a 12.1% prevalence of dementia (all types). The authors compared their findings to several other Japanese communities including a population of 2217 from Okinawa (1991), where the prevalence of dementia was to 7.3%. The authors concluded that the change in dietary pattern to low fish and high meat intake could be associated with increases in dementia rather than genetic Dietary patterns and the delay in onset of Alzheimer s disease June

29 factors.. While the Brazillian group showed a 47.3% incidence of AD there were no figures available for prevalence of AD in the Okinawa population. The nine year difference between the studies and the small sample size of the Brazillian community compared to the Okinawa population may have influenced the difference in results on in the incidence of dementia in the two populations. Dodge et al (2010) compared the pattern of circulating micronutrients from stored serum/plasma of a group of 115 participants from Oregon, USA with 49 participants of an Okinawan group for possible association with successful cognitive aging. All participants were aged 85 years and older without cognitive impairment. It was found that the Okinawan elders used fewer vitamin supplements but had similar levels of vitamin B(12) and alpha-tocopherol, lower folate and gamma-tocopherol, compared with Oregonian elders. There was no uniform pattern of circulating micronutrients, hence the authors concluded that micronutrients other than those examined or other lifestyle factors could play an important role in achieving successful cognitive aging. 6.6 Ketogenic Diet The ketogenic diet (KD) is a high-fat, adequateprotein, low-carbohydrate diet that in medicine is used primarily to treat difficult-to-control (refractory) epilepsy in children. The diet mimics aspects of starvation by forcing the body to burn fats rather than carbohydrates. Normally, the carbohydrates contained in food are converted into glucose, which is then transported around the body and is particularly important in fuelling brain function. However, if there is very little carbohydrate in the diet, the liver converts fat into fatty acids and ketone bodies (β-hydroxybutyrate, acetoacetate and acetone). The ketone bodies pass into the brain and replace glucose as an energy source. An elevated level of ketone bodies in the blood, a state known as ketosis, leads to a reduction in the frequency of epileptic seizures (Balietti et al 2010). The classic ketogenic diet contains a 4:1 ratio by weight of fat to combined protein and carbohydrate. While there is no evidence to date associating the ketogenic diet with the prevention of AD, ketone bodies have been shown to be associated with improved memory scores in MCI and AD patients (Reger et al, 2004). Glucose metabolism by the brain is impaired in Alzheimer's disease, and it is proposed that ketone bodies may provide an Dietary patterns and the delay in onset of Alzheimer s disease June

30 alternative energy source. A small double-blind placebo controlled study of 20 patients with MCI or AD used medium-chain triglycerides (MCTs) to elevate plasma ketone body levels and found improvements in memory scores in APOE ε4 negative patients but not in APOE ε4 positive patients as measured by the Alzheimer s Disease Assessment Scale-Cognitive Subscale ( ADAS-cog) (Reger et al, 2004). A registered clinical trial of 152 participants produced similar findings (Henderson et al 2009). The potential of ketogenic diets in treatment of age-related neurodegenerative diseases is discussed in a recent review by Bailetti et al (2010) including the need to design specific ketogenic diets to target specific age-related disease types. 6.7 Caloric Restriction While some population-based studies suggest a link between lower caloric intake and a lower risk of AD (Ramesh et al., 2010) it is worth noting that nutrient intake is poor in older adults who progress to early stage AD in comparison to cognitively intact matched controls (Shatenstein et al., 2007). As AlD patients also frequently develop abnormal eating behaviours such as anorexia nervosa and bulimia nervosa, it has been suggested that caloric restriction as a treatment for AD may be too late and possibly counter-productive (Ramesh et al., 2010). Nevertheless, caloric restriction has been reported to improve memory performance in healthy elderly people. A small prospective interventional study has recently been published with 50 healthy, normal- to overweight elderly subjects (29 females, mean age 60.5 years, mean body mass index 28 kg/m 2 ) which were stratified into 3 groups: (i) caloric restriction (30% reduction), (ii) relative increased intake of unsaturated fatty acids (20% increase, unchanged total fat), and (iii) control. Before and after 3 months of intervention, memory performance was assessed. The study reported a significant increase in verbal memory scores after caloric restriction (mean increase 20%; P < 0.001), which was correlated with decreases in fasting plasma levels of insulin and high sensitive C-reactive protein, most pronounced in subjects with best adherence to the diet. No significant memory changes were observed in the other 2 groups (Witte et al., 2009). Dietary patterns and the delay in onset of Alzheimer s disease June

31 A relatively small randomised controlled trial (48 overweight participants, years of age) has evaluated the effects of caloric restriction on cognitive function over a 6 month period. Cognitive tests (verbal memory, visual memory, attention/concentration) were conducted at baseline and at 3 and 6 months. No consistent pattern of verbal memory, visual retention/memory, or attention / concentration deficits were observed during the trial. Daily energy deficit was not significantly associated with change in cognitive test performance. The data from this randomized controlled trial suggests that calorie restriction/dieting was not associated with a consistent pattern of cognitive impairment or improvement (Martin et al., 2007). Another 6 month randomised controlled trial has evaluated the effects of low glycaemic load and high glycaemic load energy-restricted diets on mood and cognitive performance in 42 healthy overweight adults (age y; BMI kg/m 2 ). Cognitive performance was assessed by using computerized tests of simple reaction time, vigilance, learning, short-term memory and attention, and language-based logical reasoning. The study showed that there was no significant change over time in any cognitive performance values and provided no support for differential effects of low glycaemic load versus high glycaemic load diets on cognitive performance (Cheatham et al., 2009). The effects of very short term (2 day) near-total caloric deprivation on cognitive function, satiety, activity, sleep, and glucose concentrations have been studied in a double-blind, placebo-controlled crossover trial (Lieberman et al., 2008). For those receiving the near calorie-free diets, mean calorie consumption totaled 1311 kj (313 kcal) over the testing period. During the fully fed treatment sessions, the subjects consumed a mean of 9612 kj/d (2294 kcal/d), which matched their individual, daily energy requirements. In this study, there were no detectable effects of calorie deprivation on any aspect of cognitive performance, ambulatory vigilance, activity, or sleep. Weight loss diets (Bryan and Tiggemann, 2001), including low- and highcarbohydrate weight-loss diets (Halyburton et al., 2007) have been reported to have no impact on cognitive performance in overweight (Body Mass Index BMI > 34 kg/m 2 ) individuals. Dietary patterns and the delay in onset of Alzheimer s disease June

32 A confounding factor in animal studies is that caloric restriction has been shown to result in an overall increase in physical activity (Carter et al., 2009) and this factor which may impact on cognitive function, will need to be considered if future human trials are to be undertaken to evaluate the role of caloric restriction in delaying the onset of AD. 6.8 Dietary components Diet and nutritional studies Lee et al, (2009) compiled a systematic review of the current evidence on behavioural factors predicting cognitive health in adults aged 65 and older which included components of diet and nutrition from studies on community representative samples. Analysis of a total of fourteen studies showed consistent evidence of a protective effect of vegetable and fish consumption (two studies each) whereas persons consuming a diet high in saturated fat had an increased dementia risk (three studies). Studies on vitamin C, folate, and fruit consumption were inconsistent, while other nutrients such as flavanoids, carotenes and vitamin B 12 showed no evidence of association with cognitive decline Alcohol Williams et al 2010, identified a good quality systematic review, published in 2009 by Anstey et al, that examined the association between alcohol consumption and the development of AD. The review included nine prospective community cohort studies published between 2002 and The nine studies included a total of 17,835 subjects; two were conducted in the United States, three in European countries, ande one each in Canada, Japan, Korea and China. Studies selected screened for dementia at baseline or adjusted for cognitive function at baseline, had at least a 12 month follow up period, had AD as an outcome, and measured exposure to alcohol at baseline or during the follow up period prior to the final follow up examination. Study participants were non-demented at baseline. The number of individuals with AD versus Dietary patterns and the delay in onset of Alzheimer s disease June

33 other dementias was available for the majority of the studies. The meta-analysis reported was based on current use of alcohol, although some of the included studies also collected data on those who formerly used alcohol versus those who never used alcohol. Length of follow up ranged from 2 to 7 years. The definition for light to moderate drinker varied across the studies. The main findings were: all drinkers combined had a lower risk of AD compared to non-drinkers, light to moderate drinkers had a lower risk of AD compared to non-drinkers, light to moderate alcohol use was protective for AD in both males and females, heavy / excessive drinkers showed no difference in risk compared to nondrinkers. Individuals who drink light to moderate amounts of alcohol in late life appeared to be at reduced risk of AD; however further research is needed to determine whether this association was due to confounding factors. For example, there is some evidence to suggest that those who continue to use alcohol in later life are healthier in general which may itself lead to a lower risk of dementia. Lee et al, (2010) compiled a systematic review of the current evidence on diet and lifestyle factors predicting cognitive health in adults aged 65 years and older which included alcohol. It was reported that moderate alcohol consumption tended to be protective against cognitive decline and dementia, but non-drinkers and frequent drinkers exhibited a higher risk for dementia and cognitive impairment. This review also identified a Finnish study that reported alcohol consumption had a negative effect on dementia risk for APOE ε4 carriers. However, as this study occurred during a period of time when binge drinking was common in this population group it was suggested that there may have been an interaction which increased dementia risk in the APOE ε4 group Carbohydrates Ooi et al registered a protocol with the Cochrane Collaboration in 2008 to examine the effects of carbohydrates on cognitive performance in older adults sustaining Dietary patterns and the delay in onset of Alzheimer s disease June

34 independent living. Carbohydrate is considered to be from any of the four categories: monosaccharides, disaccharides, oligosaccharides and polysaccharides, from oral or intravenous sources. Hence this review may include carbohydrate sources other than dietary. The review will aim to understand carbohydrate driven cognitive changes in normal and MCI older people over 55, focusing on the relationships between nutrition, the brain, and cognition requirements for functional independence. Kirkoran et al (2011) have recently reported the results of a carbohydrate study of 23 older adults with mild cognitive impairment. Participants were randomly assigned to either a high carbohydrate or very low carbohydrate diet. Following the 6-week intervention period, improved verbal memory performance was observed for the low carbohydrate subjects (p = 0.01) as well as reductions in weight (p < ), waist circumference (p < ), fasting glucose (p = 0.009), and fasting insulin (p = 0.005). Level of depressive symptoms was not affected. Change in calorie intake, insulin level, and weight were not correlated with memory performance for the entire sample, although a trend toward a moderate relationship between insulin and memory was observed within the low carbohydrate group. Ketone levels were positively correlated with memory performance (p = 0.04). The authors concluded that the findings indicated that very low carbohydrate consumption, even in the short term, can improve memory function in older adults with increased risk for Alzheimer's disease and while the effect may be attributable in part to correction of hyperinsulinemia, other mechanisms associated with ketosis such as reduced inflammation and enhanced energy metabolism may also have contributed to improved neurocognitive function. However, further investigation is warranted to evaluate its preventative potential and mechanisms of action in the context of early neurodegeneration. Shidler et al are recruiting for a clinical trial (NCT ) registered in 2008, for a RCT to study energy metabolism and cognitive aging. Approximately 40 participants, 66 and older, who have mild cognitive decline will be randomized to either a healthy, high carbohydrate diet or an Atkins low-carbohydrate diet for approximately 6 weeks with the hypothesis that the low-carbohydrate diet may improve memory function. The primary outcome measure will be improvement in memory testing over a 6 week time frame. The trial is due to be completed in June Dietary patterns and the delay in onset of Alzheimer s disease June

35 6.8.4 Dietary Fats A systematic review of Williams et al (2010), identified single cohort studies of a US community that examined the association between risk of AD and risk of cognitive decline and fat intake. The studies provided preliminary evidence for an association between increased saturated fat intake and trans fat intake and risk of AD or cognitive decline, however further research is needed to validate the self-report exposure measures of dietary intake and to confirm findings. Okereke et al (2010), examined prospectively the relationships of major dietary fatty acids (FAs) (saturated [SFA], mono-unsaturated [MUFA], total poly-unsaturated [PUFA], trans-unsaturated); n-6 and n-3 (omega-3) FAs; and the n-6:n-3 FA ratio to late-life cognition. A Women s Health Study of 6,183 participants aged years, were measured at baseline using a validated semi-quantitative food frequency questionnaire and assessed cognition 3 times over 5 years. After multivariable adjustment, higher SFA intake was associated with greater decline over 5 years on global score (p-trend=0.03) and episodic memory (p-trend=0.01). By contrast, higher MUFA intake was related to less decline in global cognition (p-trend=0.01) and verbal memory (p-trend=0.02); based on effect estimates of age in this cohort, being in the highest versus lowest MUFA quintile was cognitively equivalent to being 3 years younger. There were no significant associations of total fat, PUFA or trans fat intake to cognition. Total omega-3 intake was associated with less verbal memory decline (ptrend=0.03); being in the highest versus lowest omega-3 quintile was cognitively comparable to being 3 years younger. There was a non-significant trend of worse episodic memory decline with the highest versus lowest n-6 PUFA quintile (p=0.09). A higher ratio of n-6:n-3 was associated with worse episodic memory decline (ptrend=0.02). Higher saturated fat intake was associated with worse 5-year cognitive decline, while higher MUFA intake was related to less decline. Higher omega-3 intake was associated with better episodic memory over time, while higher n-6:n-3 ratio was associated with decline. These results strongly support the hypothesis that the balance of different fat types is relevant to cognitive aging. Dietary patterns and the delay in onset of Alzheimer s disease June

36 Olive oil Olive oil is a major component of the traditional Mediterranean diet. Olive oil typically contains 70-80% monounsaturated fatty acids (MUFA) or oleic acid (18:1 n-9), 8-10% of polyunsaturated fatty acids [ 6-7% linoleic acid (18:2 n-6) and 1-2% linolenic acid (18:3 n-3)] and 10-20% saturated fatty acids, however the composition changes greatly according to regional, seasonal and varietal differences. Following the 2nd international conference on olive oil and health, in 2008, a review of the new scientific evidence was reported by Lopez-Miranda et al, (2009). One observation reported was that dietary MUFA s may be protective against age-related cognitive decline and Alzheimer s disease, following reports from the Mediterranean cohort studies (see section 6.2). It was noted that the US and French studies used a ratio of MUFA : saturated fat to inform their Mediterranean diet score rather than olive oil consumption, hence olive oil could not be linked to these studies (Lopez-Miranda et al, 2009). Berr et al (2009) examined the association between olive oil use, cognitive deficit and cognitive decline as part of the Three-city study French cohort. Participants with moderate or intensive use of olive oil compared to those who never used olive oil showed lower odds of cognitive deficit for verbal fluency and visual memory. For cognitive decline during the 4-year follow-up, the association with intensive use was significant for visual memory (adjusted OR = 0.83, 95% CI: ) but not for verbal fluency (OR = 0.85, 95% CI: ) in multivariate analysis. It was concluded that although the olive oil-cognition association needs to be confirmed by further studies, olive oil in the Mediterranean diet may have beneficial effects on health. Dietary patterns and the delay in onset of Alzheimer s disease June

37 Fish and (n-3) PUFA It has been reported that high intake of fish and (n-3) PUFA may protect against age-related cognitive decline. Fotuhi et al (2009) conducted a systematic review to establish the association between eating fish or taking (n-3) PUFA supplements and the risk of cognitive decline or Alzheimer s disease (AD). The data suggested a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD). The review favoured the recommendation of fish consumption 2-3 times per week and use of (n-3) PUFA supplements such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in elderly individuals for maintenance of cognitive function during ageing. Huang, (2010) completed a critical review of (n-3) PUFA s, including a series of prospective cohort studies on fish intake. Ten of the eleven studies examined showed protective effects associated with dementia, AD or cognitive decline, with 7 studies indicating 1-2 fish meals per week were required to show an effect. Five studies showed a dose responsive decline in dementia or AD with increasing fish consumption. The non significant findings in 3 populations may have been due to the type of fish consumed, as a further study showed protection against AD and dementia from fatty fish but not from lean fried fish. The authors concluded that findings with fish intake have been more consistently protective for cognitive decline and AD than n-3 PUFA s from other sources. This may be due to fish intake being easier to measure than n-3 PUFA s from multiple sources or that there may be important nutrients in fish that are fundamental to optimal absorption and use of DHA and/or EPA. Gonzalez et al, (2010) had similar findings to the 2010 review of Huang, where he examined whether the intake of different types of fatty acids is associated with cognitive status. A cohort of 304 institutionalized elderly people (127 men and 177 women), with a mean age of y, were studied. Subjects were evaluated for global cognitive functions (Mini-Mental State Examination [MMSE], Spanish version). Fatty acid intake was assessed with a semi-quantitative food frequency questionnaire. Intake of EPA and DHA was found to be a predictor of cognitive impairment as EPA and DHA were negatively associated with the MMSE score. In accordance with this, Dietary patterns and the delay in onset of Alzheimer s disease June

38 fish intake was inversely associated with cognitive impairment. In contrast, the n-6 : n-3 polyunsaturated fatty acid ratio was positively related to the MMSE score. These results could not be explained by differences in age, sex, education, smoking behaviour, inactivity, alcohol, institution or energy intake. van de Rest et al ( 2009), assessed the association between fatty fish intake as well as (n-3) PUFA intake with cognitive performance and cognitive change over 6 years in 1025 elderly men from the Veterans Affairs Normative Aging Study. Cognitive function was assessed with a battery of cognitive tests focusing on factors representing memory/language, speed, and visuospatial attention. Dietary intakes were assessed with a validated food frequency questionnaire. Models were adjusted for age, education, body mass index (BMI), smoking, diabetes, and intake of alcohol, saturated fat, vitamin C, and vitamin E. The mean age of participating men was 68 years at baseline. Median fish consumption ranged from 0.2 to 4.2 servings/ week across quartiles. Cross-sectional analyses showed no association between fatty fish or (n-3) PUFA intake and cognitive performance. Longitudinal analyses, over 6 y of follow-up, also did not show any significant associations between fatty fish or (n-3) PUFA intake and cognitive change. In this population of elderly men, intake of neither fatty fish nor (n-3) PUFA was associated with cognitive performance. These findings differ from the review of Huang, (2010) Dairy products and saturated fats Crichton et al (2010) completed a systematic review of the association between dairy intake and cognitive functioning. Following review of 3 cross-sectional and 5 prospective studies they concluded that there was an association between poor cognitive function and increased risk of vascular dementia and low consumption of dairy and milk products but that consumption of high fat dairy products may be associated with cognitive decline in the elderly. Their final conclusion was that variations in methodology and limitations of the studies analysed does not really allow for any conclusions on cognitive performance and optimal intake of dairy. Further RCTs are required to make definitive conclusions on cause and effect between cognition and dairy intake. Dietary patterns and the delay in onset of Alzheimer s disease June

39 At the 2010 International Conference on Alzheimer s Disease, Okereke et al reported on findings from the Women s Health Study participants (aged 65-95) years that indicated that higher saturated fat intake from dietary sources was associated with cognitive decline over a 5 year period. Wang et al (2010) found a significant association between low intake of animal oils (defined as any oil obtained from animal substances) and the development of mild cognitive impairment in a Chinese population of 90+ year olds Fruit, vegetables and plant foods Fruit and vegetable consumption in general dietary patterns and effects on cognition was covered by Williams et al in their 2010 systematic review. They found that there was inadequate evidence to assess the association between fruit and vegetable intake on the delay of onset of AD, following review of studies by Dai et al (2006) and Hughes et al (2009). The Kame cohort study (Dai et al, 2006) compared consumption of fruit and vegetable juices with a high concentration of polyphenols in a population-based prospective study and concluded that frequent consumption of fruit and vegetable juices (i.e. 3 or more times per week) was associated with a decrease risk of AD. Hughes et al (2010), as part of a Swedish twins study, examined the role of fruit and vegetable consumption in midlife in relation to development of dementia and AD. They found a medium or greater proportion of fruits and vegetables in the diet was associated with decreased risk of dementia and AD, in women but not men or those with angina pectoris in mid-life. The Williams et al (2010) review also found a low level of evidence for vegetable intake and a decrease in risk for cognitive decline. There have however been a number of subsequent studies in this general area either RCTs for single fruit and vegetables or population studies that addresses this area that were not considered in the Williams (2010) review. Since the Williams review, a population study by Nurk et al (2010) evaluated the effects on cognition of a Norwegian population s (70-74 years old) total intake of fruit and Dietary patterns and the delay in onset of Alzheimer s disease June

40 vegetables as well as the association with individual plant foods. Those with an intake of fruits, vegetables, grain products and mushrooms of >10 th percentile did significantly better in cognitive tests than those with low or no intake. There was a marked dosedependent relationship up to about 500g per day. The most positive associations for individual foods were for consumption of carrots, cruciferous vegetables, citrus fruits and high fibre breads. Their conclusion was that a plant-food rich diet is associated with improved performance in several cognitive abilities in a dose-dependent manner. Roberts et al (2010) also found that higher vegetable intake reduced the odds of onset of MCI. Fruit also showed reduced odds of the onset of MCI, however the results were not statistically significant Berries and flavanoids A double-blind placebo-controlled randomised parallel group clinical trial by Crews et al (2005) gave a 27% cranberry beverage or placebo to 2 groups of 25 to 60 year old cognitively intact volunteers. The study found no significant interactions after 6 weeks of cranberry juice or placebo for a range of standardised neuropsychological assessments, although twice as many participants who received the cranberry self-reported an overall improvement in their cognitive abilities. Krikorian et al (2010a) investigated the outcome of daily consumption of wild blueberry juice for 12 weeks by 9 elderly adults, with MCI who were compared with a demographically matched sample placebo group. This preliminary study found improved paired associate learning and word list recall. Although the placebo group had similar results for paired associate learning, the authors concluded that the results of supplementation by blueberry for a moderate period of time was a basis for more comprehensive trials to establish neurocognitive benefits. Krikorian at al (2010b) gave 12 adults with declining memories Concord grape juice for 12 weeks. The double-blind randomised placebo controlled trial indicated a possible role for juice enhancing cognitive function. They measured significant improvements Dietary patterns and the delay in onset of Alzheimer s disease June