Does Diet Play a Role in Dementia Prevention Data From the Nurses Health Study

1. Does Diet Play a Role in Dementia Prevention?Data From the Nurses� Health Study Jae Hee Kang, ScD Instructor in Medicine Channing Laboratory Department of Medicine Brigham and Women�s Hospital, Boston MA May 21, 2007 Good afternoon. My name is Olivia Okereke. I am a geriatric psychiatrist by training and completed a master�s degree in epidemiology here at the School of Public Health three years ago. Since then, I have been working on epidemiologic studies of cognitive function across the street at Brigham and Women�s Hospital�s Channing Laboratory. I would like to thank Dr. Willett for inviting me to speak today for such a distinguished group.Good afternoon. My name is Olivia Okereke. I am a geriatric psychiatrist by training and completed a master�s degree in epidemiology here at the School of Public Health three years ago. Since then, I have been working on epidemiologic studies of cognitive function across the street at Brigham and Women�s Hospital�s Channing Laboratory. I would like to thank Dr. Willett for inviting me to speak today for such a distinguished group.

2. Objectives Cognitive function cohort studies: Purpose: to determine relations between key epidemiologic risk factors and cognitive aging Particular interest: to identify risk factors for earliest stages of cognitive decline Why nutrition is a good target: It can be changed It is under control of the individual First, I would like to introduce the concept of cohort studies of cognitive function, such as those conducted at Channing Laboratory. The value of these studies lies in their ability to monitor over time the cognitive function in large numbers of healthy people living in the community and to relate changes in their function as they age to key risk factors. Examples of such cohort studies include the Nurses� Health Study, which I will be discussing in detail during this talk. In addition, these types of studies allow us to look at modifiable factors for even the most subtle, early cognitive changes in older people. This is so valuable because there are still no highly effective treatments for people once they develop dementia. Therefore, we must focus on preventive strategies or targets for early intervention. Nutrition is an excellent target for research as a factor in cognitive aging, because it can be changed, and it is under the control of the individual. Preliminary data from our research group and others show that this is a highly promising area for additional research, and in this talk I will lay out some of the major evidence.First, I would like to introduce the concept of cohort studies of cognitive function, such as those conducted at Channing Laboratory. The value of these studies lies in their ability to monitor over time the cognitive function in large numbers of healthy people living in the community and to relate changes in their function as they age to key risk factors. Examples of such cohort studies include the Nurses� Health Study, which I will be discussing in detail during this talk. In addition, these types of studies allow us to look at modifiable factors for even the most subtle, early cognitive changes in older people. This is so valuable because there are still no highly effective treatments for people once they develop dementia. Therefore, we must focus on preventive strategies or targets for early intervention. Nutrition is an excellent target for research as a factor in cognitive aging, because it can be changed, and it is under the control of the individual. Preliminary data from our research group and others show that this is a highly promising area for additional research, and in this talk I will lay out some of the major evidence.

3. Objectives Four topic areas: Fruits, vegetables, and antioxidants Fat consumption Insulin and diets that promote insulin resistance Moderate alcohol intake These are the four major nutrition areas that I will be discussing today in relation to cognitive aging: fruit, vegetable and antioxidant intake, insulin levels and diets that promote abnormal insulin levels, types of fat consumption, and moderate alcohol intake.These are the four major nutrition areas that I will be discussing today in relation to cognitive aging: fruit, vegetable and antioxidant intake, insulin levels and diets that promote abnormal insulin levels, types of fat consumption, and moderate alcohol intake.

4. Impact of onset delay on US AD population projections Intervention (1998) delay of 6 months delay of 1 year delay of 2 years delay of 5 years An interesting study was done by Brookmeyer and colleagues to look at what the effect would be for a modest intervention against Alzheimer�s disease. They projected what would happen to the numbers if a given intervention was implemented. What was striking is that this study shows that interventions that cause modest delays in onset can have significant impact in terms of reducing the burdens and costs associated with this disease. So, for example, an intervention implemented in 1998 that delayed the onset of Alzheimer�s by 1 year would translate to 200,000 fewer cases by 2007. Delaying onset an average of 5 years would translate to well over one million fewer cases by that time � a staggering impact and over a quarter of the total number of Alzheimer�s cases right now. An interesting study was done by Brookmeyer and colleagues to look at what the effect would be for a modest intervention against Alzheimer�s disease. They projected what would happen to the numbers if a given intervention was implemented. What was striking is that this study shows that interventions that cause modest delays in onset can have significant impact in terms of reducing the burdens and costs associated with this disease. So, for example, an intervention implemented in 1998 that delayed the onset of Alzheimer�s by 1 year would translate to 200,000 fewer cases by 2007. Delaying onset an average of 5 years would translate to well over one million fewer cases by that time � a staggering impact and over a quarter of the total number of Alzheimer�s cases right now.

5. Now, let�s back to the nutrition evidence, now that we have an overview of the scope of the dementia problem. First off, I�ll discuss the evidence on fruits, vegetables and antioxidants, and their relation to cognitive function in older people.Now, let�s back to the nutrition evidence, now that we have an overview of the scope of the dementia problem. First off, I�ll discuss the evidence on fruits, vegetables and antioxidants, and their relation to cognitive function in older people.

6. Antioxidants: Background Oxidants Products of normal aerobic metabolism and the inflammatory response Oxidative damage in Alzheimer�s disease One of the earliest pathophysiologic events Antioxidants neutralize the activity of oxidant compounds. Oxidants are also sometimes called free radicals, or reactive oxygen species, since they usually involve unpaired electrons of oxygen atoms. Oxidants are formed by the body�s normal metabolism, by the immune system in its response to viruses and bacteria, and by environmental factors such as pollution or cigarette smoke. The key aspect is that these compounds involve certain types of chemical bonds that are relatively less stable. Simply, the oxygen atoms in these free radicals may sometimes try to get out of these highly unstable bonds by linking up to other molecules � on the surface of cells for example - in a way that can cause damage to important cell structures and tissue. Free radical damage accumulates with age, and there is evidence that oxidative damage is involved in Alzheimer's disease pathology.Antioxidants neutralize the activity of oxidant compounds. Oxidants are also sometimes called free radicals, or reactive oxygen species, since they usually involve unpaired electrons of oxygen atoms. Oxidants are formed by the body�s normal metabolism, by the immune system in its response to viruses and bacteria, and by environmental factors such as pollution or cigarette smoke. The key aspect is that these compounds involve certain types of chemical bonds that are relatively less stable. Simply, the oxygen atoms in these free radicals may sometimes try to get out of these highly unstable bonds by linking up to other molecules � on the surface of cells for example - in a way that can cause damage to important cell structures and tissue. Free radical damage accumulates with age, and there is evidence that oxidative damage is involved in Alzheimer's disease pathology.

7. How might antioxidants prevent Alzheimer�s? Reduce free radicals that harm brain cells Decrease the toxicity of the amyloid protein Lower cardiovascular disease risk Fortunately, the body possesses natural defense mechanisms to combat oxidative stress, including antioxidant proteins and nutrients. Antioxidants reduce free radicals that damage the brain, help neutralize the toxicity of beta amyloid, which is the protein found in the pathology of Alzheimer�s, and also they have positive impact by way of reducing risk of cardiovascular disease � which is itself linked to risk of developing Alzheimer�s.Fortunately, the body possesses natural defense mechanisms to combat oxidative stress, including antioxidant proteins and nutrients. Antioxidants reduce free radicals that damage the brain, help neutralize the toxicity of beta amyloid, which is the protein found in the pathology of Alzheimer�s, and also they have positive impact by way of reducing risk of cardiovascular disease � which is itself linked to risk of developing Alzheimer�s.

8. Where do we find antioxidants? Beta Carotene: in foods that are orange in color (carrots, cantaloupe, squash, pumpkin) and some green leafy vegetables Lutein: in green leafy vegetables (spinach, collard greens, kale) Lycopene: in tomatoes, watermelon, papaya, apricots, and pink grapefruit Selenium: in rice, wheat and brazil nuts Vitamin C: in fruits and vegetables Vitamin E: in almonds, wheat germ, safflower, corn, and soybean oils, nuts, and broccoli Generally, dietary antioxidants such as vitamin C and vitamin E, beta-carotene and other carotenoids, and selenium are found in fruits and vegetables and nuts.Generally, dietary antioxidants such as vitamin C and vitamin E, beta-carotene and other carotenoids, and selenium are found in fruits and vegetables and nuts.

9. Antioxidants: Epidemiological studies Several studies have shown that higher intake of antioxidants, is associated with a lower risk of cognitive decline and Alzheimer disease Levels of antioxidants tend to be lower in those who are affected by Alzheimer�s or by a condition called mild cognitive impairment, or MCI, in which some notable level of impairment is present but not quite meeting the clinical criteria for dementia. And epidemiologic studies have shown that higher intake of antioxidants, such as from fruits and vegetables, may reduce risk of Alzheimer�s and cognitive impairment. Levels of antioxidants tend to be lower in those who are affected by Alzheimer�s or by a condition called mild cognitive impairment, or MCI, in which some notable level of impairment is present but not quite meeting the clinical criteria for dementia. And epidemiologic studies have shown that higher intake of antioxidants, such as from fruits and vegetables, may reduce risk of Alzheimer�s and cognitive impairment.

10. Fruits and vegetables and cognitive function in NHS Nurses� Health Study (NHS): prospective cohort of 121,700 RNs, began in 1976; followed biennially Cognitive study: ~ 20,000 NHS participants free of stroke and aged 70-81 years at baseline (1995+) For example, Dr. Fran Grodstein and her colleagues studied fruits, vegetables and cognitive function in the Nurses Health Study. This is a cohort of over 120,000 female nurses across several states who have been followed since 1976 by a health and lifestyle information questionnaire completed every 2 years. Of these, Dr. Grodstein recruited over 20,000 women who were at the age of greatest risk for developing dementia (that is, over age 70) and free of any major known reason for already having cognitive impairment, such as stroke. Since 1995, there have been 2 additional waves of testing, and data are complete for the first 2 assessments.For example, Dr. Fran Grodstein and her colleagues studied fruits, vegetables and cognitive function in the Nurses Health Study. This is a cohort of over 120,000 female nurses across several states who have been followed since 1976 by a health and lifestyle information questionnaire completed every 2 years. Of these, Dr. Grodstein recruited over 20,000 women who were at the age of greatest risk for developing dementia (that is, over age 70) and free of any major known reason for already having cognitive impairment, such as stroke. Since 1995, there have been 2 additional waves of testing, and data are complete for the first 2 assessments.

11. NHS: Telephone Cognitive Assessment Brief telephone interview cognitive tests: ?Telephone Interview of Cognitive Status � TICS Verbal Memory: immediate and ? delayed recall of TICS 10-word list, East Boston Memory Test- ? immed. and ? delayed Category Fluency: ? Animal naming test Working Memory: ? Digit span backwards Global score of all of the above tests Participation rate: 93% follow-up Given that there thousands of participants broadly dispersed, the cognitive assessment was modified to be administered by phone. The Telephone interview of cognitive status � or the TICS � is a general cognitive screen. In addition, there are tests of verbal memory � such as asking for recall of a list of words or items in a paragraph. The fluency tasks taps into recall of semantic knowledge by asking people to list as many different animals as they can in one minute. The working memory task involves reciting a list of numbers in reverse order. It is notable that both the fluency and digit span tasks require that an individual keep a certain amount of information �online� � that is, they have to keep in mind what numbers they have already heard while learning the new numbers, or they need to keep in mind animals they already named to avoid repeating themselves and wasting time. These are considered tasks of attention and executive function. Lastly, a global score is calculated that averages performance on all these tests. The participation rates over the first 2 sets of assessment, as you can see, has been very high.Given that there thousands of participants broadly dispersed, the cognitive assessment was modified to be administered by phone. The Telephone interview of cognitive status � or the TICS � is a general cognitive screen. In addition, there are tests of verbal memory � such as asking for recall of a list of words or items in a paragraph. The fluency tasks taps into recall of semantic knowledge by asking people to list as many different animals as they can in one minute. The working memory task involves reciting a list of numbers in reverse order. It is notable that both the fluency and digit span tasks require that an individual keep a certain amount of information �online� � that is, they have to keep in mind what numbers they have already heard while learning the new numbers, or they need to keep in mind animals they already named to avoid repeating themselves and wasting time. These are considered tasks of attention and executive function. Lastly, a global score is calculated that averages performance on all these tests. The participation rates over the first 2 sets of assessment, as you can see, has been very high.

12. NHS: Measurement of Fruit & Vegetable Intake and Cognitive Function The first set of cognitive assessments � or the baseline � was completed between 1995 and 2001. The second assessments were done roughly from 1998 to 2003 and these were conducted an average of 2 years later for most of the participants. Below on the timeline, you can see the years when fruit and vegetable intake was assessed by diet questionnaire. The strategy in this study was to pull together all that diet information over the period from 1980, when diet assessments began, to 1998, to cover the overall pattern of fruit and vegetable intake leading up to the first cognitive assessment.The first set of cognitive assessments � or the baseline � was completed between 1995 and 2001. The second assessments were done roughly from 1998 to 2003 and these were conducted an average of 2 years later for most of the participants. Below on the timeline, you can see the years when fruit and vegetable intake was assessed by diet questionnaire. The strategy in this study was to pull together all that diet information over the period from 1980, when diet assessments began, to 1998, to cover the overall pattern of fruit and vegetable intake leading up to the first cognitive assessment.

13. FFQ: food frequency questionnaire Validation: 4 1-week weighed diet records vs. FFQ correlation (r) was 0.9 Long-term average intake: Fruits + vegetables: Median 5.6 servings/day Green leafy vegetables: Median 0.8 servings/day Cruciferous vegetables: Median 0.4 servings/day The food questionnaire is a well validated instrument that, as I�m sure you know, Dr. Willett worked very hard and tirelessly on. It correlates very well with diet diaries. In the Nurses� health study, over the long term, the median or average, intake of ALL fruits and vegetables was between 5 and 6 servings a day. It was just under one serving a day for green leafy veggies and just less than half for cruciferous vegetables. Examples of a single serving of fruit would be like one apple, one orange, � a grapefruit, or � a cup of fresh blueberries. A vegetable serving would be like one tomato, � a cup of spinach (which is a green leafy vegetable) or � a cup of broccoli or cauliflower, which are examples of cruciferous vegetables.The food questionnaire is a well validated instrument that, as I�m sure you know, Dr. Willett worked very hard and tirelessly on. It correlates very well with diet diaries. In the Nurses� health study, over the long term, the median or average, intake of ALL fruits and vegetables was between 5 and 6 servings a day. It was just under one serving a day for green leafy veggies and just less than half for cruciferous vegetables. Examples of a single serving of fruit would be like one apple, one orange, � a grapefruit, or � a cup of fresh blueberries. A vegetable serving would be like one tomato, � a cup of spinach (which is a green leafy vegetable) or � a cup of broccoli or cauliflower, which are examples of cruciferous vegetables.

14. NHS: Results No association with all fruits Modest inverse associations between high intake of total vegetables and specific types of vegetables and cognitive decline Green Leafy Vegetables: consumption at highest vs. lowest quintile was cognitively equivalent to being 1.7 years younger Cruciferous Vegetables: consumption at highest vs. lowest quintile was cognitively equivalent to being 1.3 years younger There was no association between combined consumption of all fruits and vegetables and cognitive change across the two assessments. However, when certain categories were investigated, it appears that there was less cognitive decline over time with higher levels of green, leafy and cruciferous veggie intake. When compared to effect of age on cognitive change, consumption at the highest quintile of green, leafy vegetables was equivalent to staying 1.7 years younger, compared to consumption at the lowest quintile. This quantity equates to roughly 1 to 1 and 1/2 servings of green, leafy vegetables per day. Similarly, the effect of consuming cruciferous vegetables at the highest quintile was similar to staying 1.3 years younger than those in the lowest quintile of consumption. The top quintile of intake would be about 3/4 of a cup per day.There was no association between combined consumption of all fruits and vegetables and cognitive change across the two assessments. However, when certain categories were investigated, it appears that there was less cognitive decline over time with higher levels of green, leafy and cruciferous veggie intake. When compared to effect of age on cognitive change, consumption at the highest quintile of green, leafy vegetables was equivalent to staying 1.7 years younger, compared to consumption at the lowest quintile. This quantity equates to roughly 1 to 1 and 1/2 servings of green, leafy vegetables per day. Similarly, the effect of consuming cruciferous vegetables at the highest quintile was similar to staying 1.3 years younger than those in the lowest quintile of consumption. The top quintile of intake would be about 3/4 of a cup per day.

15. Chicago Health and Aging Project confirms finding with vegetables

16. ANTIOXIDANTS: ROTTERDAM STUDY Similarly, in the Rotterdam, Netherlands cohort study, investigators followed 5,395 people, who were initially free of Alzheimer�s, for an average of 6 years. They found that those with highest intake of vitamin E had a 40% relative reduction in their rate of Alzheimer�s Similarly, in the Rotterdam, Netherlands cohort study, investigators followed 5,395 people, who were initially free of Alzheimer�s, for an average of 6 years. They found that those with highest intake of vitamin E had a 40% relative reduction in their rate of Alzheimer�s

17. ANTIOXIDANTS: ROTTERDAM STUDY These investigators found a similar relative reduction in rate of Alzheimer�s for the highest intake of vitamin C � or about 35%.These investigators found a similar relative reduction in rate of Alzheimer�s for the highest intake of vitamin C � or about 35%.

18. In the Nurses� Health Study, the impact of combined vitamin C and E intake was assessed in 15,000 participants in the cognitive cohort who had completed nutrition questionnaire items. The global cognitive score was significantly higher (P = 0.03) among the women who had regularly taken vitamins E and C for 10 or more years than among those who had never taken vitamins E or C. For these long-term users, the effect of taking vitamins E and C was cognitively equivalent to staying1.5 years younger, compared to those who never used C and E. Performance was also significantly better on tasks of verbal recall and verbal fluency � which is noted by the asterisks. There was no effect for vitamin C alone.In the Nurses� Health Study, the impact of combined vitamin C and E intake was assessed in 15,000 participants in the cognitive cohort who had completed nutrition questionnaire items. The global cognitive score was significantly higher (P = 0.03) among the women who had regularly taken vitamins E and C for 10 or more years than among those who had never taken vitamins E or C. For these long-term users, the effect of taking vitamins E and C was cognitively equivalent to staying1.5 years younger, compared to those who never used C and E. Performance was also significantly better on tasks of verbal recall and verbal fluency � which is noted by the asterisks. There was no effect for vitamin C alone.

19. However, Ron Petersen and colleagues reported in a recent randomized controlled trial, there were no significant differences between the vitamin E and placebo groups in the risk of progressing from mild cognitive impairment to Alzheimer�s disease during the 3 year study period. At no point during this study do the curves for vitamin E and placebo really separate. As you know, randomized controlled trials are considered a very high level of evidence, since the randomization scheme gets rid of a lot of potential bias that is difficult to know or to measure and can sometimes affect cohort studies. ******************************************************************************************** In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer�s disease; secondary outcomes were cognition and function. A total of 769 subjects were enrolled, and possible or probable Alzheimer�s disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer�s disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer�s disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41;P=0.91).However, Ron Petersen and colleagues reported in a recent randomized controlled trial, there were no significant differences between the vitamin E and placebo groups in the risk of progressing from mild cognitive impairment to Alzheimer�s disease during the 3 year study period. At no point during this study do the curves for vitamin E and placebo really separate. As you know, randomized controlled trials are considered a very high level of evidence, since the randomization scheme gets rid of a lot of potential bias that is difficult to know or to measure and can sometimes affect cohort studies. ******************************************************************************************** In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer�s disease; secondary outcomes were cognition and function. A total of 769 subjects were enrolled, and possible or probable Alzheimer�s disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer�s disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer�s disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41;P=0.91).

20. Limitation of studies Duration of follow-up Later food frequency questionnaires with possible cognitive dysfunction (responses require sustained motivation, attention and memory) Unmeasured confounders Antioxidant intake from food vs. supplement sources � why different results? Summary: Fruits, Vegetables and Antioxidants Some important limitations for all these studies should be mentioned. For example, in the case of the cohort studies, ability to observe risk relations can often be affected by insufficient follow-up time of cognitive change. Also, cohort studies can be affected by unmeasured factors, or confounders, that could bias results. With regard to the difference between the recent randomized trial and the earlier cohort study evidence, it is very important to highlight that the studies addressed fundamentally different questions. In the trial, these were older people who already had known cognitive impairment and vitamin E was being assessed in terms of its ability to forestall progression to full-blown Alzheimer�s over a very small time frame of 3 years. However, the cohort studies, such as the Nurses� Health Study, address the impact of longer-term patterns of intake on cognitive aging among healthy people. So, overall, most investigators agree that further clinical studies, based on larger cohorts studying cognitive change over a longer period of time, would help here.Some important limitations for all these studies should be mentioned. For example, in the case of the cohort studies, ability to observe risk relations can often be affected by insufficient follow-up time of cognitive change. Also, cohort studies can be affected by unmeasured factors, or confounders, that could bias results. With regard to the difference between the recent randomized trial and the earlier cohort study evidence, it is very important to highlight that the studies addressed fundamentally different questions. In the trial, these were older people who already had known cognitive impairment and vitamin E was being assessed in terms of its ability to forestall progression to full-blown Alzheimer�s over a very small time frame of 3 years. However, the cohort studies, such as the Nurses� Health Study, address the impact of longer-term patterns of intake on cognitive aging among healthy people. So, overall, most investigators agree that further clinical studies, based on larger cohorts studying cognitive change over a longer period of time, would help here.

21. INSULIN AND PROMOTERS OF INSULIN RESISTANCE Next, I�ll turn our attention to the potential impact of insulin and diet patterns that promote insulin resistance � which is a precursor to type 2 diabetes.Next, I�ll turn our attention to the potential impact of insulin and diet patterns that promote insulin resistance � which is a precursor to type 2 diabetes.

22. Epidemiologic evidence links diabetes to dementia Elevated insulin secretion and insulin resistance may also be risk factors for cognitive decline Factors that promote insulin resistance and elevated blood insulin levels: Obesity, especially �spare tire� distribution Dietary: high glycemic index pattern and excess intake of sugary foods Insulin and cognitive function Over two dozen epidemiologic studies have shown a strong link between type 2 diabetes and the risk of dementia. But we wondered, what about the cognitive impact of high levels of insulin secretion in the blood and insulin resistance, even in people without any diabetes? This is the focus of the next 2 studies that I�ll present. As a background, we already know some factors that promote insulin resistance and persistent elevations of blood insulin. These include obesity, particularly the spare tire pattern of abdominal obesity, as well as diet patterns. Such diet patterns are typified by the foods with a high glycemic index. The glycemic index is a measure of how quickly the food source is converted to blood sugar. Foods, like white bread, highly processed carbohydrates, and some of the other culprits in the photos we just saw, have high glycemic indices, among numerous other undesirable qualities. High glycemic index foods cause sharp spikes in blood sugar right after eating them � unlike low glycemic index foods, such as brown rice, whole grains, or fiber-rich foods, that deliver more gradual, gentler changes in blood glucose. This is extremely important because high glycemic index patterns have been strongly linked to developing insulin resistance, chronically high levels of blood insulin, and eventually type 2 diabetes.Over two dozen epidemiologic studies have shown a strong link between type 2 diabetes and the risk of dementia. But we wondered, what about the cognitive impact of high levels of insulin secretion in the blood and insulin resistance, even in people without any diabetes? This is the focus of the next 2 studies that I�ll present. As a background, we already know some factors that promote insulin resistance and persistent elevations of blood insulin. These include obesity, particularly the spare tire pattern of abdominal obesity, as well as diet patterns. Such diet patterns are typified by the foods with a high glycemic index. The glycemic index is a measure of how quickly the food source is converted to blood sugar. Foods, like white bread, highly processed carbohydrates, and some of the other culprits in the photos we just saw, have high glycemic indices, among numerous other undesirable qualities. High glycemic index foods cause sharp spikes in blood sugar right after eating them � unlike low glycemic index foods, such as brown rice, whole grains, or fiber-rich foods, that deliver more gradual, gentler changes in blood glucose. This is extremely important because high glycemic index patterns have been strongly linked to developing insulin resistance, chronically high levels of blood insulin, and eventually type 2 diabetes.

23. Insulin secretion and cognitive function in NHS Study population: Women who had blood drawn between 1989-1990 and had plasma c-peptide measured C-peptide is an excellent measure of insulin secretion Exclusions: anyone with diabetes Total of 718 women Average age at blood draw: 64 years Average interval between blood draw and cognitive testing: 10 years So, as I mentioned, we examined mid-life levels of insulin secretion in the blood with respect to the impact on later-life cognitive function in people without diabetes. In the Nurses� Health Study, we had a sample of 718 women who all had previous blood measures of plasma c-peptide, which is an excellent marker of insulin production, and who later participated in the cognitive study. None of the women had any diabetes.So, as I mentioned, we examined mid-life levels of insulin secretion in the blood with respect to the impact on later-life cognitive function in people without diabetes. In the Nurses� Health Study, we had a sample of 718 women who all had previous blood measures of plasma c-peptide, which is an excellent marker of insulin production, and who later participated in the cognitive study. None of the women had any diabetes.

24. Mean Differences in Cognitive Function, by C-peptide Quartile There was a consistent finding that women with higher levels of insulin secretion had lower mean scores, both for the global score � which again averages performance across all cognitive domains � and a for verbal memory score, which averaged performance on the individual tasks of verbal recall. The effect of being in the highest quartile of c-peptide was cognitively equivalent to being 5-6 years older than those in the lowest quartile.There was a consistent finding that women with higher levels of insulin secretion had lower mean scores, both for the global score � which again averages performance across all cognitive domains � and a for verbal memory score, which averaged performance on the individual tasks of verbal recall. The effect of being in the highest quartile of c-peptide was cognitively equivalent to being 5-6 years older than those in the lowest quartile.

25. Relative Risk of Poor Cognitive Performance, by C-peptide Quartile Then, we looked at the relative risk of having the worst cognitive performance, that is, of landing in the bottom 10% of participants. Being in the highest quartile of insulin secretion meant having two and a half to 3 times higher relative risk of poor global cognitive and verbal memory performance, compared to being in the lowest quartile. The asterisks on the graph denote that these results were statistically significant for the top c-peptide quartile on both the global and verbal memory scores.Then, we looked at the relative risk of having the worst cognitive performance, that is, of landing in the bottom 10% of participants. Being in the highest quartile of insulin secretion meant having two and a half to 3 times higher relative risk of poor global cognitive and verbal memory performance, compared to being in the lowest quartile. The asterisks on the graph denote that these results were statistically significant for the top c-peptide quartile on both the global and verbal memory scores.

26. Third on our list is fat consumption. As pictured, there are many different types of fat and many different sources. These include nuts, such as almonds and walnuts; fatty fish, such as mackerel, trout, salmon, and swordfish (all of which are dark meat fish); and oils. Oils also vary in their composition. Some, like olive oil and soybean oil, are rich in healthier unsaturated fats. Others, like partially hydrogenated oils and shortening, contain trans fats, which are very bad actors. Lastly, other major fat sources are dairy, such as milk and butter, and meat sources. These animal fat sources tend to contain saturated fats.Third on our list is fat consumption. As pictured, there are many different types of fat and many different sources. These include nuts, such as almonds and walnuts; fatty fish, such as mackerel, trout, salmon, and swordfish (all of which are dark meat fish); and oils. Oils also vary in their composition. Some, like olive oil and soybean oil, are rich in healthier unsaturated fats. Others, like partially hydrogenated oils and shortening, contain trans fats, which are very bad actors. Lastly, other major fat sources are dairy, such as milk and butter, and meat sources. These animal fat sources tend to contain saturated fats.

27. Fat: mechanisms Different fats may raise or reduce risk of cardiovascular disease � for example, by impact on balance of good/bad cholesterol Possible interactions with APOE gene status High intake of saturated fats may promote insulin resistance and high insulin concentrations High intake of some fats may induce oxidative stress � implicated in Alzheimer and coronary artery diseases The different types of fat may impact cardiovascular disease risk by altering the balance of good vs. bad cholesterol. The unsaturated fats � including monounsaturated fats like olive oil, and the polyunsaturated fats that you find in fish and safflower and soybean oils � tend to raise the good cholesterol and lower the bad. Saturated fat tends to increase both. But those deadly trans fats not only raise bad cholesterol, they also sink the good cholesterol! Fat consumption can impact cognitive function by way of its larger impact on cardiovascular health. In addition, high intake of saturated fats may promote insulin resistance and high insulin levels, which we just learned about. And getting back to our first topic, high intake of some fats can induce oxidant damage, which we know has been implicated in Alzheimer�s disease pathology.The different types of fat may impact cardiovascular disease risk by altering the balance of good vs. bad cholesterol. The unsaturated fats � including monounsaturated fats like olive oil, and the polyunsaturated fats that you find in fish and safflower and soybean oils � tend to raise the good cholesterol and lower the bad. Saturated fat tends to increase both. But those deadly trans fats not only raise bad cholesterol, they also sink the good cholesterol! Fat consumption can impact cognitive function by way of its larger impact on cardiovascular health. In addition, high intake of saturated fats may promote insulin resistance and high insulin levels, which we just learned about. And getting back to our first topic, high intake of some fats can induce oxidant damage, which we know has been implicated in Alzheimer�s disease pathology.

28. Columbia Aging Project In this study from the Columbia aging project, 980 elderly people were assessed for their total fat intake and studied for 4 years for the risk of developing Alzheimer�s disease. Alzheimer�s risk was highest for those in the highest quartiles of total fat and calorie intake, but this was really brought out by separating out those people who carried the epsilon 4 allele for the APO E gene, which has been identified as a genetic risk factor for Alzheimer�s. Among those in the highest quartile of total fat intake and who carried a copy of this gene allele, risk of Alzheimer�s was more twice than for those in the lowest quartile. This is an example of an interaction between diet and genetics.In this study from the Columbia aging project, 980 elderly people were assessed for their total fat intake and studied for 4 years for the risk of developing Alzheimer�s disease. Alzheimer�s risk was highest for those in the highest quartiles of total fat and calorie intake, but this was really brought out by separating out those people who carried the epsilon 4 allele for the APO E gene, which has been identified as a genetic risk factor for Alzheimer�s. Among those in the highest quartile of total fat intake and who carried a copy of this gene allele, risk of Alzheimer�s was more twice than for those in the lowest quartile. This is an example of an interaction between diet and genetics.

29. Chicago Health and Aging Project But as I mentioned earlier, type of fat is more important than total fat intake. In the Chicago Health and Aging Project, Martha Clare Morris and colleagues studied 815 healthy individuals, who were 65 years and older, over 4 years. Her study found that high intakes of saturated and trans fats were associated with a high relative risk, denoted by RR, of Alzheimer�s, and high intake of the polyunsaturated fats was associated with substantially lower relative risk. In this study, these relations were observed regardless of the APOE gene allele status.But as I mentioned earlier, type of fat is more important than total fat intake. In the Chicago Health and Aging Project, Martha Clare Morris and colleagues studied 815 healthy individuals, who were 65 years and older, over 4 years. Her study found that high intakes of saturated and trans fats were associated with a high relative risk, denoted by RR, of Alzheimer�s, and high intake of the polyunsaturated fats was associated with substantially lower relative risk. In this study, these relations were observed regardless of the APOE gene allele status.

30. Consumption of Fish and Omega-3 Fatty Acids: Chicago Health and Aging Project: 815 people, aged 65-94 years Highest intake of fish (once or more weekly) vs. rare/never: RR=0.4 (CI 0.2-0.9) Highest intake of omega-3 fatty acids vs. lowest: RR=0.4 (CI 0.1-0.9) Furthermore, when these investigators looked at fish intake per se and specifically at the impact of the omega-3 type of polyunsaturated fats, they found that the relative risk of developing Alzheimer�s was 60% lower for those with the highest intake of both of those.Furthermore, when these investigators looked at fish intake per se and specifically at the impact of the omega-3 type of polyunsaturated fats, they found that the relative risk of developing Alzheimer�s was 60% lower for those with the highest intake of both of those.

31. However, not all findings in this area have been uniform. Fat intake of any type was not related to dementia or Alzheimer�s disease in a study of more than 5000 people age 55 years and older from the Rotterdam cohort. Among the 100 or so cases for which they had at least 2 years of follow-up available, none of the different types of fat had a significant relationship to risk of getting Alzheimer�s during the total 6 years of the study. It is notable, however, that the investigators themselves were quick to state in their paper that it would be premature to conclude that different types of fats are not associated with dementia based on their single observational study. And they called for additional, prospective studies on this subject, with longer follow-up periods to accrue cases, in order to confirm their findings. ****************************************************************************** {The table lists the amount that is considered a standard deviation for a given fat, and the relative risk is listed to the right as the effect associated with a one standard deviation change in intake of that fat.} However, not all findings in this area have been uniform. Fat intake of any type was not related to dementia or Alzheimer�s disease in a study of more than 5000 people age 55 years and older from the Rotterdam cohort. Among the 100 or so cases for which they had at least 2 years of follow-up available, none of the different types of fat had a significant relationship to risk of getting Alzheimer�s during the total 6 years of the study. It is notable, however, that the investigators themselves were quick to state in their paper that it would be premature to conclude that different types of fats are not associated with dementia based on their single observational study. And they called for additional, prospective studies on this subject, with longer follow-up periods to accrue cases, in order to confirm their findings. ****************************************************************************** {The table lists the amount that is considered a standard deviation for a given fat, and the relative risk is listed to the right as the effect associated with a one standard deviation change in intake of that fat.}

32. Nurses� Health Study: bad fats are associated with worse performance among diabetics (n=1486) Difference in Performance (Global Score) Sat. fat -0.12 (-0.22, -0.01) P:S ratio 0.08 (0.01, 0.16) Trans fat -0.15 (-0.24, -0.06)

33. Summary: Fat intake Still limited data re: cognition and dementia Cardiovascular health : low in saturated and trans fatty acids and high in monounsaturated and polyunsaturated (fish) fats, especially omega-3 Randomized trial data are not available To summarize, there are overall relatively few studies that have looked at fat intake and longitudinal outcomes on cognitive function. In addition, there are no randomized trial data yet available on the impact of omega-3 fat supplements on cognitive health, but such studies are underway, including two in Europe. For now, it makes sense to stick with cardiovascular recommendations of low intake of saturated fats and virtually none of trans fats, and increased consumption of mono and poly-unsaturated fats, especially the omega-3s.To summarize, there are overall relatively few studies that have looked at fat intake and longitudinal outcomes on cognitive function. In addition, there are no randomized trial data yet available on the impact of omega-3 fat supplements on cognitive health, but such studies are underway, including two in Europe. For now, it makes sense to stick with cardiovascular recommendations of low intake of saturated fats and virtually none of trans fats, and increased consumption of mono and poly-unsaturated fats, especially the omega-3s.

34. Lastly, I will discuss what we know about alcohol intake and cognitive aging.Lastly, I will discuss what we know about alcohol intake and cognitive aging.

35. High intake of alcohol ? adverse Neurotoxic at higher doses to brain structures Light to moderate drinking ? protective Increases �good� cholesterol Decreases platelet adhesiveness Protects against heart disease, stroke Wine: flavonoids act as antioxidants Alcohol: Mechanism Alcohol intake in excessive amounts is of course detrimental to the body, most notably the liver, and also to brain health. It can even result in dementia. However, light to moderate consumption of alcohol has been found to have numerous health-promoting qualities. It tends to increase the good, or HDL, cholesterol; it reduces the stickiness of blood platelets, which in turn reduces their tendency to form harmful clots; and it protects against cardiovascular disease. In addition, the flavonoids in wine may act as antioxidants.Alcohol intake in excessive amounts is of course detrimental to the body, most notably the liver, and also to brain health. It can even result in dementia. However, light to moderate consumption of alcohol has been found to have numerous health-promoting qualities. It tends to increase the good, or HDL, cholesterol; it reduces the stickiness of blood platelets, which in turn reduces their tendency to form harmful clots; and it protects against cardiovascular disease. In addition, the flavonoids in wine may act as antioxidants.

36. Alcohol and Dementia: Rotterdam Study In the Rotterdam Study, just under 8,000 people aged 55 and over were followed for 6 years to evaluate the relation between drinking and the risk of developing dementia. A moderate alcohol intake pattern of 1 to 3 drinks per day was associated with a 42% relative risk reduction in developing any kind of dementia, when moderate drinkers were compared to non drinkers. Findings did not vary by alcohol type.In the Rotterdam Study, just under 8,000 people aged 55 and over were followed for 6 years to evaluate the relation between drinking and the risk of developing dementia. A moderate alcohol intake pattern of 1 to 3 drinks per day was associated with a 42% relative risk reduction in developing any kind of dementia, when moderate drinkers were compared to non drinkers. Findings did not vary by alcohol type.

37. Other Evidence Honolulu Asia Aging Study: 3,556 men age 71-93 years who had been followed for 18 years Drinkers up to 1/day had better scores than non-drinkers, but 4+/day was associated with cognitive impairment Columbia Aging Study: 980 people without dementia studied for 4 yrs Light to moderate (1-3 /day) pattern: reduced risk by 40% Similarly, in the Honolulu Asia Aging Study � another longitudinal cohort study � moderate drinking of 1 drink per day was associated with better cognitive performance, compared to non-drinkers. However, excessive drinking � characterized by 4 or more drinks per day � was associated with impairment. In the Columbia Aging Project, light to moderate consumption of 1 to 3 drinks maximum per day was associated with a 40% relative risk reduction of developing dementia.Similarly, in the Honolulu Asia Aging Study � another longitudinal cohort study � moderate drinking of 1 drink per day was associated with better cognitive performance, compared to non-drinkers. However, excessive drinking � characterized by 4 or more drinks per day � was associated with impairment. In the Columbia Aging Project, light to moderate consumption of 1 to 3 drinks maximum per day was associated with a 40% relative risk reduction of developing dementia.

38. Nurses� Health Study Participants 12,480 subjects at baseline 11,102 with follow-up cognitive data Measurement of alcohol intake Administered 1980, 84, 86, 90, 94, 98 Frequency of wine, liquor, beer consumption Dr. Grodstein�s group looked at the connection between moderate alcohol intake and cognitive function in the women of the Nurses� Health Study. Here, there were over 11,000 women with complete cognitive data over 2 waves of assessment, as well as dietary data on alcohol consumption pattern from the food frequency questionnaires.Dr. Grodstein�s group looked at the connection between moderate alcohol intake and cognitive function in the women of the Nurses� Health Study. Here, there were over 11,000 women with complete cognitive data over 2 waves of assessment, as well as dietary data on alcohol consumption pattern from the food frequency questionnaires.

39. When performance on both the first and second waves of testing was considered, women who had the light pattern of drinking had significantly lower relative risk of substantial decline between the first and second assessments on both the TICS and the verbal memory scores. Results were borderline for the global score, but not statistically significant. It is worth noting at this point that these epidemiologic studies highlight that there is a difference in what we think of as light to moderate alcohol consumption in men versus in women. Now, the differences between men and women on the topic alcohol and its effects is a very important discipline unto itself � but to suffice it to say at this point that we tend to think of moderate pattern of alcohol intake as one drink per day for women and two drinks per day for men.When performance on both the first and second waves of testing was considered, women who had the light pattern of drinking had significantly lower relative risk of substantial decline between the first and second assessments on both the TICS and the verbal memory scores. Results were borderline for the global score, but not statistically significant. It is worth noting at this point that these epidemiologic studies highlight that there is a difference in what we think of as light to moderate alcohol consumption in men versus in women. Now, the differences between men and women on the topic alcohol and its effects is a very important discipline unto itself � but to suffice it to say at this point that we tend to think of moderate pattern of alcohol intake as one drink per day for women and two drinks per day for men.

40. Summary: Alcohol intake Consistent associations with moderate alcohol intake in observational studies Randomized trials unlikely Pay attention to health risks (may overshoot with excessive intake) However, if current consumption is 1-2 drinks a day, there should be no need to reduce (if no other medical reason to reduce) So, to summarize, we can observe very consistent associations between moderate alcohol intake and positive cognitive outcomes in several large observational studies. Randomized trials in this area are unlikely, though, for obvious reasons, so these observational studies represent our best evidence to date. It is, of course, important not to overshoot the target with alcohol intake and to avoid any kind of excessive drinking � and certain people for medical reasons must avoid drinking altogether. Nevertheless, for most people, alcohol consumption at 1 to 2 drinks per day sounds like a good idea.So, to summarize, we can observe very consistent associations between moderate alcohol intake and positive cognitive outcomes in several large observational studies. Randomized trials in this area are unlikely, though, for obvious reasons, so these observational studies represent our best evidence to date. It is, of course, important not to overshoot the target with alcohol intake and to avoid any kind of excessive drinking � and certain people for medical reasons must avoid drinking altogether. Nevertheless, for most people, alcohol consumption at 1 to 2 drinks per day sounds like a good idea.

41. Summary To date, preliminary data show nutrition is a promising research focus in cognitive aging Future research directions Mediterranean diet pattern Carbohydrate balance and the glycemic index Gene-diet interactions (e.g., types of fat and apolipoprotein E genotype) Overall, the data I have described today show that nutrition is a highly promising research focus in studies of cognitive aging. And there are many exciting questions yet to be addressed � which Dr. Grodstein, and my colleagues and I at Channing lab plan to explore. For example, it would be great to look at the cognitive impact of the famous Mediterranean diet pattern, is characterized by high intake of monounsaturated fat from olive oil, omega-3s from fish, and low intake red meat, and moderate wine consumption, among other things. Also, it would be very interesting to look at the glycemic index and carbohydrate balance from the diet questionnaires and cognitive outcomes. Lastly, additional work should be done looking at gene and diet interactions � for example, the way that an increased risk of Alzheimer�s was observed in the Columbia University study for those with high levels of fat consumption and an apolipoprotein E susceptibility gene.Overall, the data I have described today show that nutrition is a highly promising research focus in studies of cognitive aging. And there are many exciting questions yet to be addressed � which Dr. Grodstein, and my colleagues and I at Channing lab plan to explore. For example, it would be great to look at the cognitive impact of the famous Mediterranean diet pattern, is characterized by high intake of monounsaturated fat from olive oil, omega-3s from fish, and low intake red meat, and moderate wine consumption, among other things. Also, it would be very interesting to look at the glycemic index and carbohydrate balance from the diet questionnaires and cognitive outcomes. Lastly, additional work should be done looking at gene and diet interactions � for example, the way that an increased risk of Alzheimer�s was observed in the Columbia University study for those with high levels of fat consumption and an apolipoprotein E susceptibility gene.

42. Summary Overall, we need more studies of preventive approaches, including diet UNTIL THEN - get 5 servings of fruits & vegetables a day - lay off sweets and eat more whole grains - consume heart-healthy fats - don�t stop light to moderate drinking So, overall we need to more of the type of work I just suggested. But until then, be sure to get at least 5 fruit and vegetable servings a day, lay off the sweets and the refined carbohydrates, eat more heart-healthy fats, and drink in moderation.So, overall we need to more of the type of work I just suggested. But until then, be sure to get at least 5 fruit and vegetable servings a day, lay off the sweets and the refined carbohydrates, eat more heart-healthy fats, and drink in moderation.

43. Acknowledgements Advisors, Mentors, Colleagues Francine Grodstein Olivia Okereke Elizabeth Devore Meir Stampfer Thank you for your time today. I would like to briefly acknowledge some people. Dr. Francine Grodstein is my primary mentor and leader of the cognitive function study for the Nurses� Health Study and other cohorts. Other folks listed here are collaborators and co-authors who were instrumental in some of the work I presented. Thanks again.Thank you for your time today. I would like to briefly acknowledge some people. Dr. Francine Grodstein is my primary mentor and leader of the cognitive function study for the Nurses� Health Study and other cohorts. Other folks listed here are collaborators and co-authors who were instrumental in some of the work I presented. Thanks again.