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The MIND Dietto prevent dementia

Martha Clare Morris, Sc.D.

Director, Rush Institute for Healthy Aging and The MIND Center for Brain HealthRush University Medical Center

Illinois Osteopathic Medical Society 2018 Winter Scientific SeminarWestin 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

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Alzheimer’s Disease Prevalence

Exponential increase with ageOldest age categories are fastest growingNo cureIneffective treatmentPrevention research critical

0

10

20

30

40

50

65-74 75-84 85+

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

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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

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Predictors of Late Onset Alzheimer’s Disease

Risk FactorsAgeEducationAPOE-ε4CVD risk factorsObesityHead InjuryDepression,

neuroticism

Protective FactorsExerciseCognitive ActivitiesSocial participationAnti-inflammatory

agentsCholesterol/Statins

**Dietary Factors**

Summary: Nutrition for a Healthy BrainNUTRIENT FOOD SOURCES

Evidence Strong

Dietary tocopherols (vitamin E) Nuts, oils, seeds, green leafy vegetables, whole grains

DHA Fish – 1 meal /week

Folate Vegetables, whole grains

Saturate FatU/S Fats

Commercial products, baked goods, red meats, high fat dairy

Moderate / Limited Evidence

Carotenoids (β-carotene, lutein,lycopene)

Green leafy vegetables, bright colored fruit, vegetables

Flavonoids Berries, tea, chocolate,

Vitamin D Fish, dairy

Trans fats Commercial products, baked goods

Monounsaturated fat Olive oil

Polyphenols Olive oil, red wine, teas, vegs, fruits

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VITAMIN E

VITAMIN C

CAROTENOIDS

POLYPHENOLS

Antioxidant Nutrients

Morris MC et al. Arch Neurol 2003; 59:1125-32

Relative Risks* of Incident Alzheimer’s Disease by Quintiles of Vitamin E -

Foods

0.1

1

10

Quintiles of Intake

Rel

ativ

e R

isk

1 2 3 4 5

0.8 0.8 0.8

0.4

*Adjusted for age, sex, race, apoE, education, observation time

7.7 8.6 9.6

11.46.2

Morris et al. JAMA 2002

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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 changeDevore, 2010 AD

DietDiet

++

--

+-

+-

Wengreen, 2007 cognitive change total + + +

Dai, 2006, AD total - - -

Corrada, 2005, AD total + - -

Helmer, 2003 dementiaCommenges, 2000

plasmadiet

+ ++

Luchsinger, 2003 AD diet - - -

Morris, 2002 cognitive changeMorris, 2002 AD

dietdiet

++

+-

--

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 changeMorris, 2002 AD

+*-

+-

-

-

Englehart, 2002 AD - -

Morris, 2000 AD - -

NUTRITION AND PHYSIOLOGIC FUNCTION

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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; 166:2462-8

Willett, WC: 1998; Nutritional Epidemiology

Baseline nutrient level

Treatment nutrient level

No effect

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Willett, WC: 1998; Nutritional Epidemiology

Large Effect

Tocopherol Food Sources

Green leafy vegetables

Whole grains

Wheat germ

Nuts

Seeds

Oils

6-Year Change in Cognitive Function by Vitamin E Type

Model* Difference in Rate

per ln (mg) Increase

Standard

Error

P-value

Total Tocopherols

.027 .007 .0001

α-Tocopherol .023 .007 .002

γ-Tocopherol .015 .007 .03

β–Tocopherol .006 .007 .41

δ- Tocopherol .010 .006 .12

All models adjusted for age, sex, race, education, and initial level of cognitive score

Morris et al. 2005 AJCN

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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

Memory and Aging Project (MAP)

Brain α-Tocopherol and NeuropathologyTertile 1 Tertile 2

β(P-value)

Tertile 3β

(P-value)

LinearTerm

AmyloidLoad

1.0(referent)

-0.35(.37)

-0.18(.64)

-0.27(.56)

TangleSeverity

1.0(referent)

-0.50(.08)

-.46(.11)

-0.41(.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 2β

(P-value)

Tertile 3Β

(P-value)

LinearTerm

AmyloidLoad 1.0

(referent)-0.02(.95)

-1.07(.01)

-2.10(.002)

TangleSeverity

1.0(referent)

-0.24(.40)

-0.61(.04)

-1.12(.02)

Models adjusted for age, sex, education, PMI, and APOE-ε4

Morris M.C. et al, Alz & Dementia 2014

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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

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n-3 Polyunsaturated Fatty Acids

C:18:3 n-3α-linolenic acid

C:20:5 n-3eicosapentaenoic acid

C:22:6 n-3

docosahexanoic acid

leaves, algae, oils (linseed, rapeseed, soy)

Fish,marine

organisms

EPA

DHA

α-linolenic acid (18:3n-3)

Wheat Germ

Soybeans, walnuts

Black current oilCanola oilMustard seed oilsSoybean oilWalnut oilWheat germ oil

Human milk

Fish: Brain Food50% to 60% Lipid

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Fish: Brain Food50% to 60% Lipid

DHAcerebral cortex

synaptosomes

mitochondria

Fish: Brain Food50% to 60% Lipid

DHAcerebral cortex

synaptosomes

mitochondria

FunctionStructural and functional

maintenance ofneuronal membranes

Neurotransmission

Membrane fluidity

Modulation of ion channels, receptors, ATPase

DHA and Brain Aging:Animal Models

DHA composition in brain decreases with ageDietary DHA increases brain levels

hippocampal nerve growthfluidity of synaptic membranesantioxidant enzymestranscription of transthyretin (amyloid protein scavenger)

oxidation of lipid membranesischemic damage to neuronsinflammationamyloid burdenimpaired learning

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CHAP: Fish Intake and 4-Year Incidence of AD

FISH INTAKE

Never 1-3/month 1/week 2+/week

RR (95% CI)

1.0

0.6

(0.3-1.3)

0.4*

(0.2-0.9)

0.4*

(0.2-0.9)

* adjusted for age, sex, race, education, total energy intake, APOE4

Morris, MC. Arch Neurol 2003

STUDY Exp Outcome n FY n-3 FISH

van de Rest , 2016 Diet Test Battery 915 4.9 y

Ammann, 2013 WHICSA RBC Test Battery 2157 5.9 --

Ronnemaa, 2012 ULSAM Serum AD/dementia 2009 35 y --

Kroger, 2009 CHS Erythrocyte Dementia 663 5y --

Van de Rest, 2009 V.A.NAS

Diet Test Battery 1025 6y − --

Samieri, 2008 3-City Plasma Dementia 1214 4y

Whalley, 2008 Erythrocyte Globcog 120 4y

Eskelinen, 2008 CAIDE Diet Global/mem 1449 21y ↓ p=.06

Roberts, 2010 Mayo Diet MCI 889 2.7 y --

Beydoun, 2007 ARIC Plasma Globcog 2251 6y --

Wd Fluency

Van Gelder, 2007 Zutphen Diet MMSE 210 5y

Heude, 2003 EVA Erythrocyte MMSE 246 4y

Morris, 2003 CHAP Diet Globcog 3718 3y --

Prospective Studies: n-3 FA/Fish and Cognitive Decline

Fish intake and Risk of Alzheimer’s diseaseProspective Epidemiologic Studies

0 1.00.2 0.4 0.6 0.8

1 fish meal / week

2+ fish meals /week vs less

1 fish meal / week

DHA in the upper 25%

Rotterdam

CHS

Paquid

Framingham

CHAP 1 fish meal / week

ODDS RATIO

3-City 2-3 fish meals/week vs none

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Fish Oil Randomized Trials Study Participants Result

Van de Rest, 2008 302 Healthy DHA/EPA -

Andreeva, 2011 1748 CVD DHA&EPA/ B-vits/placebo

-

Geleijnse, 2012 2911 Coronary DHA&EPA/ ALA/placebo

-

Sinn, 2012 50 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

BackgroundDietary fats effect blood cholesterol– high ratio of saturated to unsaturated fats

increase LDL- and decrease HDL-cholesterol

Animal models: High Sat Fat/Chol Diet

impaired memory

Aβ deposition

neuroinflammation

neurotoxicity

Impaired Blood Brain Barrier

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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 - -

Prospective Studies of Fats and Cognitive Decline

Vitamin B12 and

Folate

BACKGROUNDB-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

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Study n FU Exposure Folate B12

Kivipelto, 2009 228 6.7 y plasma -

Nelson, 2009 5092 9 y diet - -

Luchsinger, 2007 965 6.1 y diet -

Kim, 2007 518 2.4 y serum -

Morris, 2006 1041 3.9 y diet - -

Ravaglia, 2006 816 4 y serum -

Corrada, 2005 579 9 y diet -

Seshadri, 2002 1092 8 y serum - -

Wang, 2001 370 3 y serum

Prospective Studies of B-Vitamins and Incident Alzheimer’s Disease

adjusted for age, sex, education and other variables

Study n Sample Treatment Effect (tests)

Fiorvanti, 1997 30 low FA, CI FA 8 wk + (4/16)

Bryan, 2002 38 normal FA 5 wk ND

Durga, 2007 818 low FA FA 3 y + (5/6)

Randomized Trials of Folic Acid and Cognition

FOOD GROUPS

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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 + -

Joseph JA, British Journal of Nutrition 2015

8 weeks on diet

19 months – 21 months old

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

0.8

1.5

2.1

2.8

4.1

Morris et al. 2005 Neurology

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QUINTILE OF INTAKE P-Value

1 2 3 4 5 for trend

0.08 0.22 0.36 0.65 1.08Green Leafy Vegetables

Servings Per Day

*Difference in Rates (p-value)

Yellow Vegetables

Servings Per Day

*Difference in Rates (p-value)

Cruciferous Vegetables

Servings Per Day

*Difference in Rates (p-value)

Legumes

Servings Per Day

*Difference In Rates (p-value)

0.08 0.16 0.28 0.42 0.79

.17

0.0 0.08 0.16 0.22 0.43

.008

.04

0.0 0.08 0.16 0.22

.22

*Models adjusted for age, sex, race, education, cognitive activities, physical activity, and alcohol consumption

Chicago Health & Aging Project Morris et al., Neurology 2006; 67:1370-1376

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0 1 2 3 4 5 6 7 8 9 10

Glo

bal C

ogni

tive

Scor

e

Years on study

Greenleafy Q1

Greenleafy Q5

DIET PATTERNS

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Prospective Studies: Mediterranean DietSTUDY N TESTS COGNTIVE

DECLINEDEMENTIA

Berendsen, 2018; 16,058 4-tel --

Morris, 2015; MAP 960 ↓ ↓

Trichopoulou, 2014; 401 MMSE ↓

Olsson, 2014; Swedes 1,138 --

Tangney, 2014; MAP 960 19 ↓

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 1,233 --

Feart, 2009, 3-Cities 1,410 1 --/↓ -

Scarmeas, 2006; WHICAP 1,884 ↓

Prospective Studies: Other Diet Patterns & Dementia

STUDY DIET N COGNTIVEDECLINE

DEMENTIA

Shakersain, 2018; Nordic Prudent 2,223 ↓

Haring, 2016; WHIS DASH 6,425 --

Morris, 2015; MAP DASH 994 ↓

Tangney, 2014; MAP DASH 960 ↓

Wengreen, 2013; Cache Co DASH 3,831 --

Tangney, 2010; CHAP HEI 3,790 --

Gardener, 2014; AIBL Westernized 527 ↑

Olsson, 2014 WHO 1,138 --

Low Carb --

Gu, 2010 Reduced Rank*

2,048 ↓

DIET INTERVENTION TRIALS: COGNITION

SECONDARY AIM

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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 +0.62 (p=0.005) +0.57 (p=0.01)

Clock Drawing Test

+0.51 (p=0.001) +0.33 (p=0.05)

Versus low-fat control group; cross-sectional difference after 6.5 y intervention

ENCOREDASH Diet/Aerobic activity intervention in hypertensive overweight adults (mean age 52 y)

– 4 month intervention; n=124

– 3 groupsDASH diet;

DASH + weight management (aerobic 30 min x 3/wk

Control: usual care

– 8 tests: learning/memory and psychomotor speed ; measured pre- /-post intervention

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ENCORE RESULTS

MIND DIET

DASH Mediterranean MIND

Total Grains 42+/wk Nonrefined Grains >32/wk Whole Grains 21+/wk

Vegetables 28+/wkVegetables >33/wkPotatoes >18/wk

Green Leafy 7+/wkOther Vegetables 14+/wk

Fruits 28+/wkFruits >22/wk Berries (1/2 c 2-5/wk)

Dairy ≥14/wkFull-fat Dairy .≤10/wk

Regular Cheese ≤1 oz/wkButter <1 t/d

Nuts, seeds & legumes ≥4/wk Legumes, nuts & beans >6/wkBeans 3+/wk

Nuts 1 oz 2-5/wk

Lean meat, poultry fish ≤6/wkRed meat ≤ 1/wk

Fish >6/wkPoultry ≤3/wk

Lean Red Meats <4/wkFish 1+/wk

Poultry 2+/wk

Total Fat ≤ 27% of kcalSaturated Fat ≤ 6% of kcal

Sweets ≤ 5/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

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MAP NUTRITION ANALYTIC SAMPLES

Cognitive Decline:

– 994 with baseline FFQ and 2 cognitive assessments; mean of 4.5 years follow-up; range 2-10 years

Incident AD

– 114 incident AD cases

MIND Diet Score and Cognitive Decline

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0 1 2 3 4 5 6 7 8 9 10

Glo

bal C

ogni

vtiv

e Sc

ore

Years on study

Mindscore_tertile1

Mindscore_tertile2

Mindscore_tertile3

MIND, MedDi and DASHCognitive Decline Comparison

Global Score

MIND MedDi DASH

β/SE* 4.4 2.44 2.76

P-Value 0.003 0.01 0.02

*Adjusted for age, sex, education, cognitive activities, caloric intake

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Diet Patterns and Incident ADTertile 1 Tertile 2 Tertile 3

MIND Score

HR1.0 0.65* 0.47*

DASH

HR 1.00.98 0.61*

Mediterranean

HR 1.00.81 0.46*

Adjusted for age, sex, education, cognitive activities, physical activity, calories. Morris et al. Alz & Dementia epub Feb 11, 2015

MIND AIMSTest 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

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MULTI-CENTER

Rush University

Chicago

HSPH

Boston

Harvard Brigham

DCC

Biochemical Laboratories: University of Washington Harvard

Imaging LaboratoryRush University

MIND Funding

National Institute on Aging

Food donations – High Bush Blueberry Commission

– Innoliva

– Peanut Inst

– Tree Nut Inst

• Mild calorie restriction (250 kcal deficit/ day)

Usual Diet + mild weight loss (n=302)

MIND diet + mild weight loss (n=302)

Randomization (n=604)

Chicago and Boston, 3-year period, randomized parallel intervention trial

Extra virgin olive oil, blueberries, mixed nuts are provided

store vouchers provided

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MIND PARTICIPANTS

65-84 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 micro-structural 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 AIMSInvestigate 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

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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 engagementDiet and body weight tracking on website

Social mediaFacebook groups, each diet group separate