The MIND Diet. Dr. Morris has no relevant conflicts of interest to disclose OVERVIEW 11/26/2018. to prevent dementia

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1 The MIND Diet to prevent dementia Martha Clare Morris, Sc.D. Director, Rush Institute for Healthy Aging and The MIND Center for Brain Health Rush University Medical Center Illinois Osteopathic Medical Society 2018 Winter Scientific Seminar Westin Lombard Yorktown Center, IL December 1, 2018 Dr. Morris has no relevant conflicts of interest to disclose OVERVIEW Background on Alzheimer s Disease Identify nutrients and foods important in cognitive aging Describe the MIND diet and supporting evidence of protection against neurodegenerative diseases Describe the MIND diet intervention trial 1

2 Alzheimer s Disease Prevalence Exponential increase with age Oldest age categories are fastest growing No cure Ineffective treatment Prevention research critical AD Alzheimer s Disease Gradual decline in memory and other cognitive abilities Neuropathology linked to oxidative and infllammatory damage: Aβ plaques Neurofibrillary tangles Neuron loss Synapse loss 2

3 Alzheimer s Disease Brain Normal Brain Theory of Cognitive Reserve One third of individuals with AD brain neuropathology have no clinical evidence of AD Theory of cognitive reserve Use of neural tissue leads to more efficient, flexible cognitive networks Leads to improved or maintained performance in the face of neuropathology 3

4 Predictors of Late Onset Alzheimer s Disease Risk Factors Age Education APOE-ε4 CVD risk factors Obesity Head Injury Depression, neuroticism Protective Factors Exercise Cognitive Activities Social participation Anti-inflammatory agents Cholesterol/Statins **Dietary Factors** Summary: Nutrition for a Healthy Brain Evidence Strong NUTRIENT Dietary tocopherols (vitamin E) DHA Folate Saturate Fat U/S Fats Moderate / Limited Evidence Carotenoids (β-carotene, lutein, lycopene) Flavonoids Vitamin D Trans fats Monounsaturated fat Polyphenols FOOD SOURCES Nuts, oils, seeds, green leafy vegetables, whole grains Fish 1 meal /week Vegetables, whole grains Commercial products, baked goods, red meats, high fat dairy Green leafy vegetables, bright colored fruit, vegetables Berries, tea, chocolate, Fish, dairy Commercial products, baked goods Olive oil Olive oil, red wine, teas, vegs, fruits 4

5 Antioxidant Nutrients VITAMIN E VITAMIN C CAROTENOIDS POLYPHENOLS Morris MC et al. Arch Neurol 2003; 59: Relative Risks* of Incident Alzheimer s Disease by Quintiles of Vitamin E - Foods 10 Relative Risk Quintiles of Intake *Adjusted for age, sex, race, apoe, education, observation time Morris et al. JAMA

6 ANTIOXIDANTS IN DIET PROSPECTIVE STUDIES Exposure Vit E Vit C βcar Flav Noguchi-Shinohara, 2018 cognitive change blood + + Mangialasche, 2013 dementia Serum + Devore, 2012, 2012 cognitive change Devore, 2010 AD Diet Diet Wengreen, 2007 cognitive change total Dai, 2006, AD total Corrada, 2005, AD total Helmer, 2003 dementia Commenges, 2000 plasma diet Luchsinger, 2003 AD diet Morris, 2002 cognitive change Morris, 2002 AD diet diet Englehart, 2002 AD diet Kalmijn, 1997 MMSE diet La Rue, 1997 cognition diet VITAMIN SUPPLEMENTS: Prospective and RCT STUDY Vit E Vit C β-car Devore, 2012 cognitive change Kang, 2009, cognitive change Gray, 2008, AD, dementia - - Kang, 2006 cognitive change -* Fillenbaum, 2005 AD - - Peterson, 2005 AD - Zandi, 2004 AD + + Luchsinger, 2003 AD - - Laurin, 2002 AD,dementia - - Morris, 2002 cognitive change Morris, 2002 AD Englehart, 2002 AD - - Morris, 2000 AD - - +* NUTRITION AND PHYSIOLOGIC FUNCTION 6

7 Willett, WC: 1998; Nutritional Epidemiology Women s Health Study Randomized Clinical Trial 600 IU α-tocopherol versus placebo 9.6 years cognitive change No effect overall Interaction with dietary intake Below median <6.1 mg/d β=.05 (.01,.09)* Above median >6.1 mg/d β= -.01(-.06,.03) Kang JH et al. Arch Intern Med 2006; 166: No effect Baseline nutrient level Treatment nutrient level Willett, WC: 1998; Nutritional Epidemiology 7

8 Large Effect Willett, WC: 1998; Nutritional Epidemiology Tocopherol Food Sources Oils Nuts Seeds Whole grains Wheat germ Green leafy vegetables 6-Year Change in Cognitive Function by Vitamin E Type Model* Total Tocopherols Difference in Rate per ln (mg) Increase Standard Error P-value α-tocopherol γ-tocopherol β Tocopherol δ- Tocopherol All models adjusted for age, sex, race, education, and initial level of cognitive score Morris et al AJCN 8

9 Memory and Aging Project (MAP) 1,200 Chicago residents of retirement communities Clinical-pathologic studies linking risk factors during life to cognitive and motor performance and to brain pathology at death Brain α-tocopherol and Neuropathology Tertile 1 Tertile 2 β (P-value) Tertile 3 β (P-value) Linear Term Amyloid Load 1.0 (referent) (.37) (.64) (.56) Tangle Severity 1.0 (referent) (.08) -.46 (.11) (.23) Models adjusted for age, sex, education, PMI and APOE-ε4 Morris M.C. et al, Alz & Dementia 2014 Brain γ-tocopherol & Neuropathology Tertile 1 Tertile 2 β (P-value) Tertile 3 Β (P-value) Linear Term Amyloid Load 1.0 (referent) (.95) (.01) (.002) Tangle Severity 1.0 (referent) (.40) (.04) (.02) Models adjusted for age, sex, education, PMI, and APOE-ε4 Morris M.C. et al, Alz & Dementia

10 PRESYNAPTIC PROTEINS BRAIN TOCOPHEROLS AND PRESYNAPTIC PROTEINS SNARE SYNTAXIN VAMP SNAP-25 SYNAPTOPHYSIN Total Tocopherol αt - γt Adjusted for age at death, sex, education Fish and n-3 Fatty Acids 10

11 n-3 Polyunsaturated Fatty Acids leaves, algae, oils (linseed, rapeseed, soy) C:18:3 n-3 α-linolenic acid Fish, marine organisms C:20:5 n-3 eicosapentaenoic acid C:22:6 n-3 docosahexanoic acid EPA DHA α-linolenic acid (18:3n-3) Wheat Germ Black current oil Canola oil Mustard seed oils Soybean oil Walnut oil Wheat germ oil Soybeans, walnuts Human milk Fish: Brain Food 50% to 60% Lipid 11

12 Fish: Brain Food 50% to 60% Lipid DHA cerebral cortex synaptosomes mitochondria Fish: Brain Food 50% to 60% Lipid DHA cerebral cortex synaptosomes mitochondria Function Structural and functional maintenance of neuronal membranes Neurotransmission Membrane fluidity Modulation of ion channels, receptors, ATPase DHA and Brain Aging: Animal Models DHA composition in brain decreases with age Dietary DHA increases brain levels hippocampal nerve growth fluidity of synaptic membranes antioxidant enzymes transcription of transthyretin (amyloid protein scavenger) oxidation of lipid membranes ischemic damage to neurons inflammation amyloid burden impaired learning 12

13 CHAP: Fish Intake and 4-Year Incidence of AD FISH INTAKE Never 1-3/month 1/week 2+/week RR * 0.4* (95% CI) ( ) ( ) ( ) * adjusted for age, sex, race, education, total energy intake, APOE4 Morris, MC. Arch Neurol 2003 Prospective Studies: n-3 FA/Fish and Cognitive Decline STUDY Exp Outcome n FY n-3 FISH van de Rest, 2016 Diet Test Battery y Ammann, 2013 WHICSA RBC Test Battery Ronnemaa, 2012 ULSAM Serum AD/dementia y -- Kroger, 2009 CHS Erythrocyte Dementia 663 5y -- Van de Rest, 2009 V.A. NAS Diet Test Battery y -- Samieri, City Plasma Dementia y Whalley, 2008 Erythrocyte Globcog 120 4y Eskelinen, 2008 CAIDE Diet Global/mem y p=.06 Roberts, 2010 Mayo Diet MCI y -- Beydoun, 2007 ARIC Plasma Globcog y -- Wd Fluency Van Gelder, 2007 Zutphen Diet MMSE 210 5y Heude, 2003 EVA Erythrocyte MMSE 246 4y Morris, 2003 CHAP Diet Globcog y -- Fish intake and Risk of Alzheimer s disease Prospective Epidemiologic Studies Rotterdam 3-City CHS 1 fish meal / week 2-3 fish meals/week vs none 2+ fish meals /week vs less Paquid 1 fish meal / week Framingham DHA in the upper 25% CHAP 1 fish meal / week ODDS RATIO 13

14 Fish Oil Randomized Trials Study Participants Result Van de Rest, Healthy DHA/EPA - Andreeva, CVD DHA&EPA/ B-vits/placebo Geleijnse, Coronary DHA&EPA/ ALA/placebo Sinn, MCI DHA/ EPA / LA ***No trial restricted recruitment to non-fish consumers or limited fish intake to less than once per week Other Dietary Fats Background Dietary fats effect blood cholesterol high ratio of saturated to unsaturated fats increase LDL- and decrease HDLcholesterol Animal models: High Sat Fat/Chol Diet impaired memory Aβ deposition neuroinflammation neurotoxicity Impaired Blood Brain Barrier 14

15 Prospective Studies of Fats and Cognitive Decline STUDY Exposure Outcome SAT TRANS MUFA PUFA U/S Nooyens, 2018 Doetinchem Diet Global Okereke, 2012 WHS Diet Global - - Devore, 2009 NHS Diet Global - Eskelinen, 2008 Finland Diet Global Beydoun, 2007 ARIC Plasma Global - Morris, 2006 CHAP Diet Global Solfrizzi, 2006 ILSA Diet MMSE - Heude, 2003 EVA Erythro MMSE - - Bowman, 2012 Oregon Plasma Global Roberts, 2012 MAYO Diet MCI Vercambre, 2010 WACS Diet Global - - Naqvi, 2011 WHI Diet - - Vitamin B12 and Folate BACKGROUND B-Group Vitamin Insufficiencies Vitamin B-12: dementia, neuropathy, increased homocysteine, myelin Folate : increased homocysteine, impaired DNA repair Population differences in deficiencies in these nutrients may account for inconsistencies in study findings 1998 US grain fortification with folic acid 15

16 Prospective Studies of B-Vitamins and Incident Alzheimer s Disease Study n FU Exposure Folate B12 Kivipelto, y plasma - Nelson, y diet - - Luchsinger, y diet - Kim, y serum - Morris, y diet - - Ravaglia, y serum - Corrada, y diet - Seshadri, y serum - - Wang, y serum adjusted for age, sex, education and other variables Randomized Trials of Folic Acid and Cognition Study n Sample Treatment Effect (tests) Fiorvanti, low FA, CI FA 8 wk + (4/16) Bryan, normal FA 5 wk ND Durga, low FA FA 3 y + (5/6) FOOD GROUPS 16

17 Prospective Studies Fruits & Vegetables Study Outcome Vegetables Fruits Chen 2012 Cognitive Change + - Nooyens 2011 Cognitive Change + - Roberts 2010 MCI + - Kang 2005 Cognitive Change + - Morris 2006 Cognitive Change weeks on diet Enhanced working memory, improved motor performance with balance and fine coordination. Protection against spatial deficits, better balance and coordination Improved learning and fewer memory errors, better psychomotor coordination 19 months 21 months old Joseph JA, British Journal of Nutrition 2015 Morris et al Neurology

18 QUINTILE OF INTAKE P-Value Green Leafy Vegetables Servings Per Day for trend *Difference in Rates (p-value).008 Yellow Vegetables Servings Per Day *Difference in Rates (p-value) Cruciferous Vegetables Servings Per Day *Difference in Rates (p-value).04 Legumes Servings Per Day *Difference In Rates (p-value) *Models adjusted for age, sex, race, education, cognitive activities, physical activity, and alcohol consumption Chicago Health & Aging Project Morris et al., Neurology 2006; 67: Global Cognitive Score Greenleafy Q Greenleafy Q Years on study DIET PATTERNS 18

19 Prospective Studies: Mediterranean Diet STUDY N TESTS COGNTIVE DECLINE Berendsen, 2018; 16,058 4-tel -- DEMENTIA Morris, 2015; MAP 960 Trichopoulou, 2014; 401 MMSE Olsson, 2014; Swedes 1, Tangney, 2014; MAP Koyama, 2014; HealthABC 2,326 3MS (b) Tsivgoulis, 2013; REGARDS 17,478 Samieri, 2013; WHS 6,174 4-tel -- Wengreen, 2013; Cache Co 3,831 3MS -- Vercambre, 2012; WACS 2,504 4-tel -- Samieri, 2012; NHS 16,058 4-tel -- Tangney, 2011; CHAP 3,790 4 Roberts, 2010; Mayo 1, Feart, 2009, 3-Cities 1, / - Scarmeas, 2006; WHICAP 1,884 Prospective Studies: Other Diet Patterns & Dementia STUDY DIET N COGNTIVE DECLINE Shakersain, 2018; Nordic Prudent 2,223 DEMENTIA Haring, 2016; WHIS DASH 6, Morris, 2015; MAP DASH 994 Tangney, 2014; MAP DASH 960 Wengreen, 2013; Cache Co DASH 3, Tangney, 2010; CHAP HEI 3, Gardener, 2014; AIBL Westernized 527 Olsson, 2014 WHO 1, Gu, 2010 Low Carb -- Reduced Rank* 2,048 DIET INTERVENTION TRIALS: COGNITION SECONDARY AIM 19

20 PREDIMED Primary CVD prevention trial, >7,000 Spaniards Med Diet + olive oil; Med Diet + nuts Low-fat control diet 6.5 years intervention Substudy n=522 with cognitive testing MMSE and Clock Drawing Test at 6.5 years PREDIMED FINDINGS Med Diet + Olive Oil Med Diet + Mixed Nuts MMSE (p=0.005) (p=0.01) Clock Drawing Test (p=0.001) (p=0.05) Versus low-fat control group; cross-sectional difference after 6.5 y intervention ENCORE DASH Diet/Aerobic activity intervention in hypertensive overweight adults (mean age 52 y) 4 month intervention; n=124 3 groups DASH diet; DASH + weight management (aerobic 30 min x 3/wk Control: usual care 8 tests: learning/memory and psychomotor speed ; measured pre- /-post intervention 20

21 ENCORE RESULTS MIND DIET DASH Mediterranean MIND Total Grains 42+/wk Nonrefined Grains >32/wk Whole Grains 21+/wk Vegetables 28+/wk Vegetables >33/wk Potatoes >18/wk Green Leafy 7+/wk Other Vegetables 14+/wk Fruits 28+/wk Dairy 14/wk Fruits >22/wk Full-fat Dairy. 10/wk Berries (1/2 c 2-5/wk) Regular Cheese 1 oz/wk Butter <1 t/d Nuts, seeds & legumes 4/wk Legumes, nuts & beans >6/wk Beans 3+/wk Nuts 1 oz 2-5/wk Lean meat, poultry fish 6/wk Total Fat 27% of kcal Saturated Fat 6% of kcal Sweets 5/wk Red meat 1/wk Fish >6/wk Poultry 3/wk Lean Red Meats <4/wk Fish 1+/wk Poultry 2+/wk Commercial Pastries, sweets <5/wk Sodium 2400mg/d Olive oil 3-4 T/d Olive Oil>1 T/d Alcohol < 300mL/d but >0 Alcohol/wine 1/d 21

22 MAP NUTRITION ANALYTIC SAMPLES Cognitive Decline: 994 with baseline FFQ and 2 cognitive assessments; mean of 4.5 years followup; range 2-10 years Incident AD 114 incident AD cases MIND Diet Score and Cognitive Decline Global Cognivtive Score Years on study Mindscore_tertile1 Mindscore_tertile2 Mindscore_tertile3 MIND, MedDi and DASH Cognitive Decline Comparison Global Score MIND MedDi DASH β/se* P-Value *Adjusted for age, sex, education, cognitive activities, caloric intake 22

23 Diet Patterns and Incident AD Tertile 1 Tertile 2 Tertile 3 MIND Score HR * 0.47* DASH HR * Mediterranean HR * Adjusted for age, sex, education, cognitive activities, physical activity, calories. Morris et al. Alz & Dementia epub Feb 11, 2015 MIND AIMS Test the effects of 3 year intervention of MIND diet on cognitive decline Test the effects of the MIND diet on: brain changes (using brain imaging) Blood biomarkers for dementia, inflammation & oxidation Other conditions: diabetes, hypertension, BMI, cholesterol, depression, chronic psychological distress 23

24 MULTI-CENTER Rush University Chicago HSPH Boston Harvard Brigham DCC Biochemical Laboratories: University of Washington Harvard Imaging Laboratory Rush University MIND Funding National Institute on Aging Food donations High Bush Blueberry Commission Innoliva Peanut Inst Tree Nut Inst Chicago and Boston, 3-year period, randomized parallel intervention trial Randomization (n=604) MIND diet + mild weight loss (n=302) Extra virgin olive oil, blueberries, mixed nuts are provided Usual Diet + mild weight loss (n=302) store vouchers provided Mild calorie restriction (250 kcal deficit/ day) 24

25 MIND PARTICIPANTS years No cognitive impairment Overweight or obese (BMI 25) Suboptimal diet (bottom half of MIND scores) SECONDARY AIMS Test the effects of the MIND diet on 3-year change in MRI-derived macro- and microstructural integrity normalized measures of total brain volume and hippocampal volume normalized volumes of white/gray matter, segmented gray matter regions, while matter lesions, and thickness of segmented cortical regions Test the effects of the MIND diet on cardiovascular related conditions EXPLORATORY AIMS Investigate potential mediators of the MIND diet effects on cognitive decline. brain MRI measures plasma Abeta 42/Abeta 40 BDNF CRP, IL-6 oxidized LDL, adiponectin HbA1c, blood pressure, weight loss, cholesterol (total, HDL) depression and psychological distress 25

26 TRIAL DESIGN FOR SUCCESS Diet counseling using behavior modification techniques Recipes Group cooking demonstrations Tools for tracking food intake Family/Friend inclusion Frequent assessments of diet intake, blood levels of nutrients Home visits MIND Intervention Equal intervention intensity both groups Remote consultation (by phone) Month 1-6: Weekly Month 7-12: Every other week Years 2-3: Monthly In person consultation (0,6,12,24 month) Group Sessions monthly Online engagement Diet and body weight tracking on website Social media Facebook groups, each diet group separate 26