NIKOS SCARMEAS MD, MSc · •Vitamin B12 •Crystal, Ortof et al. 1994, Seshadri, Baser et al. ... step of analysis Nutrients : SFA, MUFA, -3 PUFA, -6 PUFA, Vit E, Vit B12, Folate

Dietary Intervention – Evidence in AD – How can we improve?

NIKOS SCARMEAS MD, MSc Associate Professor of Neurology Columbia University, New York, USA

National and Kapodistrian University of Athens, Greece

Disclosures: None

Research Support: NIA RO1: AG028506, / Alzheimer’s Association IIRG-04-1353

RASAD conference Melbourne, March 2012

Dietary Intervention – Evidence in AD – How can we improve?

• Literature review (brief)

• Limitations of current state of the art

• Attempts to partially address some of these issues

• Future roadmap – some thoughts

Lower risk of AD or slower cognitive decline

•Vitamin C •Masaki, Losonczy et al. 2000; Engelhart, Geerlings et al. 2002; Zandi, Anthony et al. 2004; Morris, Beckett et al. 1998

•Vitamin E •Masaki, Losonczy et al. 2000; Engelhart, Geerlings et al. 2002; Morris, Beckett et al. 1998; Morris, Evans et al. 2002; Morris, Evans et al. 2002; Zandi, Anthony et al. 2004; Corrada, Kawas et al. 2005

•Vitamin B12 •La Rue, Koehler et al. 1997; Clarke, Smith et al. 1998; Wang, Wahlin et al. 2001; Haan et al. 2007; Tangney 2009

•Vitamin B6 •Corrada, Kawas et al. 2005

•Folate •Clarke, Smith et al. 1998; Wang, Wahlin et al. 2001; Ravaglia 2005; Corrada, Kawas et al. 2005; Balk 2007 (metaanal-interv).

•Modest to Moderate ETOH •Orgogozo, Dartigues et al. 1997; Ruitenberg, van Swieten et al. 2002; Truelsen, Thudium et al. 2002; Mukamal, Kuller et al. 2003; Luchsinger, Tang et al. 2004; Ganguli , Vander Bilt et al. 2005; Espeland, Gu et al. 2004; Stampfer Kang et al 2005

•Flavonoids •Commenges, Scotet et al. 2000

•Caroten •Barberger-Gateau et al 2007;

•Fish •Barberger-Gateau, Letenneur et al. 2002; Morris, Evans et al. 2003; Morris, Evans et al. 2005; Huang, Zandi et al; 2005;

Barberger-Gateau et al 2007;

•Unsaturated fatty acids •Kalmijn, Feskens et al. 1997; Morris, Evans et al. 2003; Morris, Evans et al. 2003; Schaefer, Bongard et al. 2006; Laitinen et al.

2006; Barberger-Gateau et al 2007;

•Lower total fats, cholesterol, saturated fats

•Kalmijn, Launer et al. 1997; Kalmijn, vanBoxtel et al. 2004; Morris, Evans et al. 2003; Luchsinger, Tang et al. 2002; Laitinen et al. 2006

•Coffee •Maia, de Mendonca 2002

•Fruits •Dai, Borenstein et al 2006; Barberger-Gateau et al 2007;

•Vegetables (polyphenol antioxidants?) •Dai, Borenstein et al 2006, Kang, Grodstein; Research-Practice AD 2007, Barberger-Gateau et al 2007;

•Curry (curcumin - antiinflammatory? antioxidant?)

•Tze-Pin Ng et al 2006

Risk for AD or cognitive decline not associated with

•Vitamin C •Luchsinger, Tang et al. 2003, Masaki, Losonczy et al. 2000, Heart Protection Study 2002; Laurin, Masaki et al. 2004; Dai, Borenstein et al 2006; Yaffe 2004

•Vitamin E

•Sano 1997; Luchsinger, Tang et al. 2003, Masaki, Losonczy et al. 2000; Heart Protection Study 2002; Laurin, Masaki et al. 2004; Yaffe 2004; Dai, Borenstein et al 2006; Kang 2006

•Vitamin B12

•Crystal, Ortof et al. 1994, Seshadri, Baser et al. 2002; Morris 2006; Ravaglia 2005; Balk 2007 (metaanal-interv); Aisen 2008

•Vitamin B6 •Seshadri, Baser et al. 2002; Morris 2006; Balk 2007 (metaanal-interv); Aisen 2008

•Folate •Seshadri, Baser et al. 2002; Balk 2007 (metaanal-interv); Haan 2007; Middleton 2007; Morris 2006; Aisen 2008

•Fish •Schaefer, Bongard et al. 2006;

•Fats •Engelhart, Geerlings et al. 2002

•Omega-3 •O.van de Rest et al. 2008

•Carotenes •Heart Protection Study 2002; Luchsinger, Tang et al. 2003; Laurin, Masaki et al. 2004; Yaffe 2004.

•Calcium (high worse) •Van Vliet 2004.

•Wine •Dai, Borenstein et al 2006; Barberger-Gateau et al 2007;

•Flavonoids •Laurin, Masaki et al. 2004.

•Tea •Forster, Newens et al. 1995; Rogers, Simon et al. 1999

•Fruits •Kang, Grodstein; Research-Practice AD 2007

Limitations - Issues


• Nutrients – Cognition U-shaped curve

– Stratification by different levels of nutrient intake

– Consideration of efficacy of supplementation in subgroup analyses

Morris, M. C. et al. JAMA 2011;305:1348-1349 Copyright restrictions may apply.

Nutrient levels are rarely considered in trial inclusion criteria. Further, trial volunteers are typically healthy behavior–seeking individuals and are unlikely to have low nutrient intake. More probably, intake levels are already at the level for optimal functioning (Figure, point a) and further supplementation provides no additional benefit (Figure, point b).

http://jama.ama-assn.org.ezproxy.cul.columbia.edu/content/305/13/1348.full

http://jama.ama-assn.org.ezproxy.cul.columbia.edu/content/305/13/1348.full

Copyright restrictions may apply.

Kang, J. H. et al. Arch Intern Med 2006;166:2462-2468.

Mean Difference in Rate of Decline in Global Score Between Vitamin E and Placebo Groups: Effect Modification by Major Risk Factors for Cognitive Decline

Characteristics

Mean difference in cognitive decline between groups (95% CI)2

Global Score Verbal score TICS score Category fluency score

Dietary folate intake

<279 mg/d (n = 293) 0.14 (–0.01, 0.29) 0.14 (–0.04, 0.31) 1.24 (0.47, 2.00) –0.19 (–0.61, 0.24)

≥279 mg/d (n = 1637) 0.01 (–0.05, 0.07) 0.00 (–0.06, 0.07) –0.04 (–0.34, 0.26) 0.00 (–0.99, 0.99)

P3 0.11 0.16 0.002 0.73

Dietary vitamin B-6 intake

<1.9 mg/d (n = 524) 0.02 (–0.05, 0.08) 0.07 (–0.05, 0.20) 0.56 (0.03, 1.10) –0.69 (–1.43, 0.05)

≥1.9 mg/d (n = 1406) 0.05 (–0.06, 0.15) 0.01 (–0.07, 0.08) 0.00 (–0.33, 0.33) 0.03 (–0.43, 0.49)

P3 0.63 0.35 0.08 0.10

Dietary vitamin B-12 intake

<2.4 µg/d (n = 82) 0.19 (–0.06, 0.44) 0.10 (–0.21, 0.41) 1.35 (0.16, 2.54) 1.62 (0.11, 3.13)

≥2.4 µg/d (n = 1848) 0.02 (–0.04, 0.08) 0.02 (–0.04, 0.09) 0.10 (–0.18, 0.39) –0.24 (–0.64, 0.17)

P3 0.19 0.62 0.05 0.02

Overall dietary vitamin B intake

Low (n = 573)4 0.09 (–0.01, 0.20) 0.12 (0.00, 0.24) 0.74 (0.23, 1.25) –0.39 (–1.10, 0.32)

Adequate (n = 1357)5 0.00 (–0.07, 0.06) –0.02 (–0.09, 0.06) –0.10 (–0.43, 0.24) –0.07 (–0.54, 0.40)

P3 0.11 0.06 0.01 0.46

TABLE 4 Mean decline between B vitamin and placebo groups: effect modification by major risk factors for cognitive decline1

Kang JH, et al. . A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. Am J Clin Nutr. 2008;88(6):1602–1610.

…….targeted individuals who were found to have insufficient folate nutriture based on a stringent set of biochemical criteria


• Clinical trials vs. Observational epidemiological studies – Lack of randomization

– Residual confounding

– Reverse causality

• But if trials (particularly 1ary or 2ary prevention) to be done for nutritional factors – High Cost

– Timing

– Long Duration

– Additional difficulty of implementation - behavioral intervention (if diet and not just supplement)


• Outcome (Cognitive decline - Dementia - AD diagnosis) issue – Accuracy– lack of diagnostic biomarker

– Subjectivity of clinical judgment

– Limitation of objective measures (slopes of cognitive decline)

• Variability of cognitive performance

• Learning effects

– Error / noise increases required sample size

– “The last doctor is the smartest one” – increasing challenge – error/noise with earlier diagnosis


• Exposure - Dietary assessment issues

– Noise in FFQ recordings

• Please fill in your average total consumption of peaches or plums (1 fresh or ½ cup canned) during the last year. Please try to average your seasonal use of foods during the entire year

• <1 serving/month,

• 1-3 servings/month,

• 1 serving/week,

• 2-4 servings/week,

• 5-6 servings/week,

• 1 serving/day,

• 2-3 servings/day,

• 4-5 servings/day,

• >6 servings/day.


• Exposure - Dietary assessment issues

– Reporting accuracy – cognition / informant

– Limited number of foods – nutrients • If specific effect of a specific food – nutrient, will be lost in the FFQ

questions

• Underestimation of total amounts - calories

– Blood nutrient biomarkers – bioavailable levels of nutrients • Interaction of intake + inherent absorption / metabolism etc

• Still not reflective of cerebral penetration – CSF?

• More practical difficulties (blood, urine, transport, freezing, maintenance)

• Cost

• Interactions: ‘foods are more than their nutrients’

• Chemical composition of foods not completely known


• Multiplicity of foods – nutrients

– Individuals do not consume foods or nutrients in isolation but rather as components of their overall daily diet.

– Interactions • Fish consumption had a greater effect in reducing platelet aggregation when part of a

low-fat rather than a high-fat diet (Mori, Beilin et al. 1997).

• Effect of fish consumption in lowering blood pressure (Vandongen, Mori et al. 1993) and blood lipids (Mori, Vandongen et al. 1994) seems to be much more pronounced in subjects following a low fat diet.

• Higher copper consumption associated with faster cognitive decline only among subjects with high intake of saturated and trans fats (Morris, Evans et al. 2006).

– Multiple comparisons

– Colinearity

– Difficulty controlling for dietary cofounding in studies examining other parameters.


• Multiplicity of biological mechanisms – processes leading to cognitive decline

• Potential nutritional effects of opposing directionality

Nutrient (Vit E)

Metabolic

Vascular

Cognition Cognition

Inflammatory

Oxidative

Amyloid

Tau

A - synuclein Harmful Helpful Neutral


• Multiplicity of interactions among many foods-nutrients and many mechanisms

Nutrient A Vit E

Metabolic

Vascular

Cognition Cognition

Inflammatory

Oxidative

Amyloid

Tau

A - synuclein

Harmful Helpful Neutral

Nutrient B …..

Metabolic

Vascular

Cognition Cognition

Inflammatory

Oxidative

Amyloid

Tau

A - synuclein

Cognition

– Multiplicity of nutrients – food groups

• DIETARY PATTERNS

– FFQ noise

• Nutrient biomarkers

– Explore – clarify mechanisms

• Clinical tools

• Plasma tools

• CSF tools

• Imaging tools

Attempts to partially address some of these issues



– FFQ noise



• Clinical tools

• Plasma tools

• CSF tools

• Imaging tools


Dietary Pattern approach

• Can be developed a posteriori on the basis of already existing data (empirical aggregation of individuals with similar diets based on their reported intake of food) – Use of various multivariate methods such as discriminant

analyses, principal components analyses or cluster analyses

• Can be developed a priori on the basis of previous knowledge concerning a favorable or adverse health effect of various dietary constituents

• Or combination of a posteriori and a priori methods: reduced rank regression (RRR) or maximum redundancy analyses

Observed variables used in current step of analysis

Nutrients:SFA, MUFA, ω-3 PUFA, ω-6 PUFA,Vit E, Vit B12, Folate

Alzheimer’s Disease/Cognitive Performance



30 Food groups:Fruits, Fish,Nuts, Red Meat, etc.

Principal Components Analysis

Response variables(Nutrient Factors)

Factor Scores

(Dietary Patterns)

Regression


Response variables(Nutrient factors)


Factor Scores

(Dietary Patterns)


Response variables(Nutrient factors)

Outcome Risk Estimation Model





Latent variables used in current step of analysis

Observed variables not used in current step of analysis

Latent variables not used in current step of analysis

New latent variables developed from current step of analysis

RRR Step 1

RRR Step 2

RRR Step 3

Biological Mechanism


Gu, Y. et al. Arch Neurol 2010;67:699-706.

Explained Variations of Nutrients and Food Groups by Extracted DPs and Correlations Between Nutrients and DP Scores

Dietary Pattern 2

NUTRIENTS

SFA,

B12

Ω3 PUFA

Ω6 PUFA

Vit E

Folate

↓

↑

Dietary Pattern

higher intakes ↑ salad dressing

nuts

fish

tomatoes

poultry

cruciferous vegetables

fruits

dark and green leafy vegetables

lower intake ↓

high-fat dairy

red meat

organ meat

butter

NUTRIENTS

SFA,

B12

Ω3 PUFA

Ω6 PUFA

Vit E

Folate

↓

↑


Gu, Y. et al. Arch Neurol 2010;67:699-706.

Survival curves based on Cox analysis comparing cumulative Alzheimer disease incidence in subjects belonging to each dietary pattern (DP) score 2 tertile (P for

trend <.001)‏

Dietary Pattern approach

•Disadvantages •Subjectivity in selection / weighting •Due to above, issues with external reproducibility •Limited elucidation of our understanding of the biological mechanisms that mediate their association with disease.

•Advantages •Interaction – confouding reduction •Colinearity •Multiple comparisons – type I error •Public health •Summarize diet (to be used as a covariate ) in other


Scarmeas, N. et al. JAMA 2009;302:627-637.

Cox Proportional Hazard Ratios (HRs) for Alzheimer Disease (AD) Incidence by Physical Activity and Mediterranean-Type Diet Scores


Scarmeas, N. et al. JAMA 2009;302:627-637.

Alzheimer Disease (AD) Incidence in Individuals by No, Some, or Much Physical Activity and Low, Middle, and High Mediterranean-Type Diet Adherence Scores

Unadjusted HR: 0.78 (0.53-1.14) 0.63 (0.43-0.92) 0.46 (0.31-0.69) 0.33 (0.19-0.57) Trend: 0.77 (0.69-0.85) p<0.001

Adjusted HR: 0.96 (0.60-1.55) 0.92 (0.59-1.43) 0.58 (0.36-0.95) 0.39 (0.20-0.76) Trend: 0.80 (0.71-0.90) p<0.001



– FFQ noise



• Clinical tools

• Plasma tools

• CSF tools

• Imaging tools


Tangney et al. Neurology® 2011;77: 1276–1282



– FFQ noise



• Clinical tools

• Plasma tools

• CSF tools

• Imaging tools


Diet

Metabolic Insulin

Adiponectin

Vascular Clinical

Homocysteine

Alzheimer’s disease Inflammatory

IL-6 IL-1 CRP

Oxidative Isoprostanes

MeDi

Vascular Variables

Heart disease,

Stroke,

Diabetes,

Hypertension

HDL, TG, LDL

Alzheimer’s disease

MeDi Alzheimer’s

disease

Simple Model

Vascular Mediation Model


Scarmeas, N. et al. Arch Neurol 2006;63:1709-1717.

Odds Ratios for Subjects With Alzheimer Disease vs, Nondemented Subjects by Mediterranean Diet Score in Continuous and Tertile Form



– FFQ noise



• Clinical tools

• Plasma tools

• CSF tools

• Imaging tools


Diet

Metabolic Insulin

Adiponectin

Vascular Clinical,

Homocysteine MRI SCI, WMH


IL-6 IL-1 CRP


MeDi Alzheimer’s

disease

Initial Simple Model

MeDi Mediating Variables

hs CRP

Insulin

Adiponectin

Alzheimer’s disease

Inflammatory / Metabolic Mediation Model

• 1219 non demented subjects

• hsCRP, Insulin, Adiponectin measured at baseline

• 118 incident AD cases after 4 years of follow-up

Diet

Vascular

Cognition

Inflammatory

Oxidative

Metabolic

Amyloid

Nutrients‏intake‏and‏plasma‏β-amyloid Yian Gu, PhD1, Nicole Schupf, PhD1,2,3, Stephanie A. Cosentino, PhD1,2,4,

Jose A. Luchsinger, MD 1,2,5, Nikolaos Scarmeas, MD 1,2,4

Gu et al. Neurology. In press.

ABSTRACT

Objective: The widely-reported associations between various nutrients and cognition may occur through many biological

pathways including those of beta-amyloid (Aβ). However, little is known about the possible associations of dietary factors with

plasma Aβ40 or Aβ42. The current study aims to evaluate the association between nutrients intake and plasma Aβ levels.

Methods: In this cross-sectional study, plasma Aβ40 and Aβ42 and dietary data were obtained from 1219 cognitively healthy

elderly (age>65), who were participants of a community-based multi-ethnic cohort. Information on dietary intake was obtained 1.2

years, on average, before Aβ assay. The associations of plasma Aβ40 and Aβ42 levels and dietary intake of 10 nutrients were

examined using linear regression models, adjusted for age, gender, ethnicity, education, caloric intake, Apolipoprotein E genotype,

and recruitment wave. Nutrients examined included saturated fatty acid, mono-unsaturated fatty acid, ω-3 poly-unsaturated fatty

acid (PUFA), ω-6 PUFA, vitamin E, vitamin C, β-carotene, vitamin B12, folate, and vitamin D.

Results: In unadjusted models that simultaneously included all nutrients, higher intake of ω-3 PUFA was associated with lower

levels of Aβ40 (β=-24.7, p<0.001) and lower levels of Aβ42 (β=-12.3, p<0.001). In adjusted models, ω-3 PUFA remained a strong

predictor of Aβ42 (β=-7.31, p=0.02), while its association with Aβ40 was attenuated (β=-11.96, p=0.06). Other nutrients were not

associated with plasma Aβ levels.

Conclusions: Our data suggest that higher dietary intake of ω-3 PUFA is associated with lower plasma levels of Aβ42, a profile

linked with reduced risk of incident AD and slower cognitive decline in our cohort.


Model‡ Predictor

Number β p Number β

Model 1 Vitamin E 1219 -0.34 0.68 1208 -0.1

Vitamin C -0.01 0.69 0.02

Folate 0 0.86 0

Vitamin B12 0.21 0.34 0

Vitamin D 0.02 0.29 0.01

β carotene 0 0.86 0

ω-6 PUFA 1.94 0.09 0.63

SFA 0.93 0.15 0.53

MUFA -1.21 0.11 -0.65

ω-3 PUFA -24.74 <0.001 -12.31

Model 2 Vitamin E 1200 -0.06 0.93 1189 -0.01

Vitamin C -0.03 0.24 0.01

Folate -0.01 0.65 -0.01

Vitamin B12 0.31 0.11 0.07

Vitamin D 0.02 0.38 0


ω-6 PUFA 0.33 0.74 0.07

SFA -0.47 0.41 -0.06

MUFA 0.33 0.62 0

ω-3 PUFA -11.96 0.06 -7.31

Model 3 Vitamin E 1137 -0.62 0.41 1137 -0.12

Vitamin C -0.02 0.36 0.02

Folate -0.01 0.61 -0.01

Vitamin B12 0.33 0.11 0.07

Vitamin D 0.01 0.44 0


ω-6 PUFA 0.03 0.98 -0.02

SFA -0.6 0.32 -0.06

MUFA 0.57 0.41 0.03

ω-3 PUFA -10.13 0.13 -7.7

0.96

0.84

0.92

0.02

p

0.75

0.13

0.26

0.45

0.75

0.78

0.69

0.86

0.88

0.83

0.99

0.02

0.07

<0.001

0.97

0.22

0.44

0.46

0.87

0.96

0.57

0.84

0.23

0.08

Aβ40 (dependent variable) Aβ42 (dependent variable)

0.78

0.1

‡: Model 1, unadjusted. Model 2, adjusted for age, sex, education, ethnicity, caloric intake, APOE genotype, and recruitment wave. Model 3,

adjusted for all the covariates in Model 2, plus alcohol drinking, use of medications (medications affecting blood vessel thrombus formation

propensity and anti-diabetic agents), and use of nutrients from supplements. A total of 563, 594, 518, 497, 464, 449, 18, and 7 subjects in

the study sample reported taking vitamin E, vitamin C, folate, vitamin B12, vitamin D, β carotene, ω-6, and ω-3 PUFA supplements,

respectively.



– FFQ noise



• Clinical tools

• Plasma tools

• CSF tools

• Imaging tools


Copyright restrictions may apply. Galasko, D. R. et al. Arch Neurol 2012;0:archneurol.2012.85v1-6.

Copyright restrictions may apply. Galasko, D. R. et al. Arch Neurol 2012;0:archneurol.2012.85v1-6.

Vitamin C Vitamin E

ALA

Tau Cognition ? Cognition ?

Amyloid

Oxidation

Inflammation?

Metabolic ?

A – synuclein ? Harmful Helpful Neutral Unknown



– FFQ noise



• Clinical tools

• Plasma tools

• CSF tools

• Imaging tools


High vit B (B1, B2, B6, Folate, B12), C, D, E

Bowman G et al. Neurology 2012;78:241-249

©2012 by Lippincott Williams & Wilkins

High transfat

High omega 3


The homocysteine-global cognition effect was modified and no longer statistically significant with adjustment for white matter volume or cerebral infarcts. The effect of homocysteine on cognitive performance may be mediated through increased white matter hyperintensity and cerebral infarcts. The methylmalonate-global cognition effect was modified and no longer significant with adjustment for total brain volume. Methylmalonate, a specific marker of B12 deficiency, may affect cognition by reducing total brain volume Vitamin B12 status may affect the brain through multiple mechanisms.

Payne ME et al. Nutrition Research 28 (2008) 285–292

Honolulu-Asia Aging Study (HAAS) , Honolulu Heart Program (HHP); Cognitive Abilities Screening Instrument (CASI)

White LR et al. Journal of the American College of Nutrition, 2000;19(2): 242–255

Virtanen et al. Neurology® 2008;71:439–446

Figure 2 White matter grades according to fish consumption Adjustments were made for fried

fish or tuna/other fish consumption and age, sex, race, enrollment center, diabetes,

education, smoking status, pack-years of smoking, body mass index, coronary heart...

Virtanen J K et al. Neurology 2008;71:439-446 ©2008 by Lippincott Williams & Wilkins


Paul, C. A. et al. Arch Neurol 2008;65:1363-1367.

Mean total cranial brain volume, including confidence intervals illustrated as error bars, adjusted for age, sex, body mass index (calculated as weight in kilograms divided by height in meters

squared), and Framingham Stroke Risk Profile (slope = -0.25; P < .01; R2 = 0.96)



Mean values for total cranial brain volume, including confidence intervals illustrated by error bars, for men (slope = -0.20; P = .02) and women (slope = -0.025; P = .02), adjusted for age, sex, body mass index (calculated as weight in kilograms divided by height in meters squared), and

Framingham Stroke Risk Profile

Population Alcohol WMH Infarcts Atrophy Stratified analysis

Mukamal

KJ, 2001

Stroke

Cardiovascular

Health Study

(CHS), 3660

adults ≥65 years

, mean 75 yrs,

none, former,

<1, 1-7, 7-15,

and ≥15

drink/week.

moderate 1-

7/wk ↓ WMH,

U-shape

heavy

(>=15/wk) ↓

infarcts

heavy (>=15/wk)

↑ atrophy

(↑ventricular and

sulcal sizes)

No modification by

sex, race, APOE.

Types of alcohol have

similar results.

Ding J

2004

Stroke.

Atherosclerosis

Risk in

Communities

(ARIC) Study;

1909 middle-

aged adults

(40% men and

49% blacks)

never, former,

<1, 1-7, and ≥7

drinks/week.

No linear

association

No association

after ajdustment

↑ atrophy

(↑ventricular and

sulcal sizes)

No modification by

sex or race. No types

of alcohol

information.

den Heijer

T, 2004

Am J Clin

Nutr

Rotterdam Scan

Study. 1074

persons aged 60-

90 without

dementia

Lifetime

abstention,

former, <1, 1-7,

7-28, and ≥28

drinks/week

moderate 1-

7/wk ↓ WMH,

U-shape

moderate 1-

7/wk ↓ infarcts

(not

signnificant)

↑ hippocampal

and amygdalar

volumes in

carriers APOE

e4 only.

Modified by APOE.

Modification by sex

not tested. No types of

alcohol information.

Paul CA,

Arch

Neurol.

2008

Framingham

Offspring

Study;1839

(861M); 60 yrs

(range33-88)

abstainers,

former, 1-7, 8-

14, and ≥ 14

drink/week N/A N/A

↑ atrophy

(↓TCBV),

stronger in

women than in

men.

Modified by sex; No

types of alcohol.

Fukuda K,

2009 J

Neuro Sci

385 Japan >or=

40 years, mean

67.2

non-drinkers,<7,

and moderate

drinkers (≥7

drinks/week)

moderate ↑

WMH

moderate ↑

infarcts

moderate ↑

atrophy (↓brain

volume)

Modification by sex

not tested. No types of

alcohol information.

ETOH

Metabolic ?

Atrophy Neuronal death

Cognition ? Cognition ?

Infarcts Vascular

WMH Vascular? Amyloid?

Amyloid ?

Tau ?

A – synuclein ?

Harmful Helpful Unkonwn


Gardener, H. et al. Arch Neurol 2012;69:251-256.

Association Between Mediterranean Diet and White Matter Hyperintensity Volume


Gardener, H. et al. Arch Neurol 2012;69:251-256.

Association Between Each Component of the Mediterranean Diet Score and White Matter Hyperintensity Volume

Small infarct (<1cm)

Large infarct (>1cm)

Scarmeas et al. Annals of Neurology, 2010



– FFQ noise



• Clinical tools

• Plasma tools

• CSF tools

• Imaging tools


Roadmap

• Continue to investigate specific neurobiological mechanisms (plasma, CSF, imaging etc)

• Select best (in terms of strength and consistency of association) nutrients, foods, patterns.

• Replicability in other datasets • Prospective component • Combine multiple datasets in ‘nutritional meta-

analyses’ • Biomarker-powered preliminary interventional

randomized studies • Large trials informed by above



Distribution of Alcohol Consumption in the Total Sample, Men, and Women

Payne ME et al. Nutrition Research 28 (2008) 285–292

Gray and white matter lesion areas were selected based upon a set of rules that allows trained analysts to reliably select lesion regions. Periventricular lesions were defined as regions that were contiguous with lateral ventricle and did not extend into the white matter tracts. These lesions were classified as white matter lesions. Deep white matter lesions were located in the white matter tracts and may or may not have adjoined periventricular lesions. Subcortical gray matter lesions were defined as lesions within the basal ganglia or thalamus. Total lesion volumes were composed of both gray matter lesions and white matter lesions, although white matter lesions predominated.



Initial N:1410 (vs. 2258)

Incident AD: 66 (vs. 262)

Medicare Spending on Alzheimer’s Disease (in billions)

$62$91

$160 $189$229

$294

$394

$529

$696

$879

$1.049

$0

$200

$400

$600

$800

$1.000

$1.200

2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

Source: “Saving Lives, Saving Money: Dividends for Americans Investing in

Alzheimer’s Research”, The Lewin Group & the Alzheimer’s Association,

June 2004.

P-value*

<0.0001

/

0.001‡,║

0.004‡,║

0.08

0.56

0.44

0.73

0.22

0.29

0.78

76.3 (6.5)

76.3 (6.5)

Aβ40 tertiles

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

76.3 (6.5)

SRT total recall 38.28 (9.9) 38.78 (9.93) 38.33 (9.47)

SRT delayed recall 5.47 (2.59) 5.53 (2.57) 5.48 (2.53)

Moderate alcohol intake,

N (%) 413 (34) 144 (35) 145 (36)

Memory

Others, N (%) 13 (1) 5 (1) 5 (1)

APOE -ε4 +, N (%) 314 (26) 110 (27) 99 (25)

Black, N (%) 388 (32) 131 (32) 119 (29)

Hispanic, N (%) 458 (38) 149 (37) 149 (37)

Ethnicity

White, N (%) 360 (30) 122 (30) 133 (33)

Caloric intake (Kcal/day),

mean(SD) 1433(525) 1453(539) 1461(506)

Female, N (%) 831 (68) 279 (69) 269 (66)

Age (years), mean(SD) 75.4 (6.1) 74.6 (5.7) 75.1 (5.8)

Education (years),

mean(SD) 10.1 (4.8 ) 10.5 (4.7) 10.3 (4.9)

range 9-588 9-51.4 51.5-101 101.1-588

Aβ40 (pg/mL), mean(SD) 81.9 (58) 26.5 (15) 76.2 (15) 143.0 (54)

N 1219 407 406 406

Total lowest middle highest


lowest middle highest P-value*

403 403 402

14.5 ( 5.3 ) 33.9 ( 5.3 ) 67.9 ( 26 ) <0.0001

25-May 25-43 44-272 /

74.8 (5.7) 75.0 (6.0) 76.2 (6.3) 0.002‡,║

10.4 ( 4.7 ) 10.3 (4.7 ) 9.6 ( 4.9 ) 0.045‡

1434 ( 529 ) 1453 ( 561) 1412 ( 483) 0.55

287 (71) 259 (64) 277 (69) 0.1

0.73

119 (30) 105 (33) 132 (30)

132 (33) 142 (26) 111 (32)

148 (37) 151 (38) 155 (38)

4 (1) 5 (1) 3 (1)

108 (27) 106 (26) 97 (24) 0.68

147 (37) 134 (33) 127 (32) 0.33

38.96 (10.04) 38.3 (9.47) 37.6 (10.19) 0.21

5.58 (2.57) 5.52 (2.59) 5.33 (2.6) 0.43SRT-delayed recall 5.49 (2.58)

Memory

SRT-total recall 38.33 (9.9)

APOE-ε4 +, N (%) 311 (26)

Moderate alcohol

intake, N (%) 408 (34)

Hispanic, N (%) 454 (38)

Others, N (%) 13 (1)

White, N (%) 356 (30)

Black, N (%) 385 (32)

Female, N (%) 823 (68)

Ethnicity

Education (years),

mean(SD) 10.0 ( 4.8 )

Caloric intake

(Kcal/day), mean(SD) 1433 ( 525 )

Aβ42 (pg/mL),

mean(SD) 38.7 ( 27 )

range 5-272

Age (years), mean(SD) 75.3 (6.0)

Aβ42 tertiles

Total

N 1208


Diet

Metabolic Insulin

Adiponectin

Vascular Clinical,

Homocysteine MRI SCI, WMH


IL-6 IL-1 CRP


Diet

Metabolic Insulin

Adiponectin

Vascular Clinical,

Homocysteine


IL-6 IL-1 CRP



!!! Choose this slide or the next one. I think this one is good enough.


White LR et al. Journal of the American College of Nutrition, 2000;19(2): 242–255

NIKOS SCARMEAS MD, MSc · •Vitamin B12 •Crystal, Ortof et al. 1994, Seshadri, Baser et al. ... step of analysis Nutrients : SFA, MUFA, -3 PUFA, -6 PUFA, Vit E, Vit B12, Folate

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