D R D A V I D W I L K I N S O N

C O N S U L T A N T I N O L D A G E P S Y C H I A T R Y

Nutrition and Alzheimer’s Disease

Agenda

Rethinking Alzheimer’s disease

Emerging specific nutritional needs for AD patients

Interpretation of evidence

A multi modal approach

What does the future hold?

Rethinking Alzheimer’s disease

“Since a cure for dementia is not yet available, finding effective preventive strategies is essential

for a sustainable society in an aging world”

“As dementia, cardiovascular diseases, stroke, and diabetes mellitus – all major public health problems –

share several risk factors, public health efforts promoting a healthier lifestyle have the potential to

enhance health status in advanced age”

Mangialasche et al. Alzheimers Res Ther 2012; 4 (1): 6

2014 2024

Memantine, AChEIs, combination

Improved and earlier diagnosis

Patient segmentation (genetics…)

Other cognitive enhancers

Disease-modifying therapies

Community-wide prevention initiatives (diet, exercise…)

AD treatment 2014 and beyond

The brain requires nutrients to function

The brain needs specific nutrients to build and maintain its structure1

The brain is 60% fat2 - the type of fat influences the physical properties of cell membranes3

Nutritional deficiencies are associated with impaired brain function, for example: Omega 3 fatty acid levels affect mood, behaviour, stress, depression and dementia1,4,5

Vitamin B deficiency is linked to neurologic disorders and psychological disturbances1

The need to supply specific nutrients to the brain may be increased in neurological disease, such as AD6

Enzymatic reactions in the brain are controlled by the local concentrations of their substrates, often nutrients that cross the BBB7

1. Bourre. J Nutr Health Aging 2006a,b; 2. Nolte's The Human Brain, 6th Edition 2009 3. Youdim et al 2000 4. Bourre. J Nutr Health Aging 2005; 5. Phillips et al. Nutr Neurosci 2012; 6. van Wijk et al. J Alzheimers Dis. 2013 ; 7. Wurtmann 2008 .

Similar results for

plasma levels

of vitamins B12 and C

Lower nutrient status in AD Independent of nourishment status

Unadjusted Overall (REML, I-squared=90%, P<0.001)

Baldeiras '08

Polidori '02

Mangialasche '11

Zaman '92

Sinclair '98

study

Ciabattoni '07

Polidori '04

Age adjusted Overall (REML meta-regression, P<0.001)

Ahlskog '95

Bourdel-Marchasson '01

Feillet-Coudray '99

Glaso '04

37

40

187

20

41

n

control

44

55

15

23

14

17

36.8

33.0

38.9

30.0

36.0

mean

control

52.0

50.2

24.6

42.3

34.3

37.6

13.4

5.2

5.5

12.0

1.5

sd

control

13.0

10.2

7.8

8.3

9.2

9.2

42

35

168

10

25

n

AD

44

63

12

20

25

20

28.7

21.3

33.0

18.6

31.1

mean

AD

33.0

37.8

20.8

34.8

36.0

25.2

11.0

4.0

2.7

3.6

1.5

sd

AD

15.0

5.8

5.7

8.1

8.8

11.5

-8.56 (-11.59, -5.52)

-8.10 (-13.55, -2.65)

-11.70 (-13.79, -9.61)

-5.81 (-6.70, -4.92)

-11.38 (-17.11, -5.65)

-4.90 (-5.63, -4.17)

mean

difference (95% CI)

-19.00 (-24.87, -13.13)

-12.40 (-15.45, -9.35)

-9.71 (-13.27, -6.15)

-3.84 (-8.91, 1.23)

-7.50 (-12.41, -2.59)

1.73 (-4.21, 7.67)

-12.40 (-19.07, -5.73)

8.3

10.7

11.2

8.1

11.2

weight

(%)

7.9

10.1

8.6

8.7

7.9

7.3

-8.56 (-11.59, -5.52)

-8.10 (-13.55, -2.65)

-11.70 (-13.79, -9.61)

-5.81 (-6.70, -4.92)

-11.38 (-17.11, -5.65)

-4.90 (-5.63, -4.17)

mean

difference (95% CI)

-19.00 (-24.87, -13.13)

-12.40 (-15.45, -9.35)

-9.71 (-13.27, -6.15)

-3.84 (-8.91, 1.23)

-7.50 (-12.41, -2.59)

1.73 (-4.21, 7.67)

-12.40 (-19.07, -5.73)

8.3

10.7

11.2

8.1

11.2

weight

(%)

7.9

10.1

8.6

8.7

7.9

7.3

AD lower AD higher

0-20 -15 -10 -5 0 5 10

vitamin E

Unadjusted Overall (REML, I-squared=90%, P<0.001)

Baldeiras '08

Polidori '02

Mangialasche '11

Zaman '92

Sinclair '98

study

Ciabattoni '07

Polidori '04

Age adjusted Overall (REML meta-regression, P<0.001)

Ahlskog '95

Bourdel-Marchasson '01

Feillet-Coudray '99

Glaso '04

37

40

187

20

41

n

control

44

55

15

23

14

17

36.8

33.0

38.9

30.0

36.0

mean

control

52.0

50.2

24.6

42.3

34.3

37.6

13.4

5.2

5.5

12.0

1.5

sd

control

13.0

10.2

7.8

8.3

9.2

9.2

42

35

168

10

25

n

AD

44

63

12

20

25

20

28.7

21.3

33.0

18.6

31.1

mean

AD

33.0

37.8

20.8

34.8

36.0

25.2

11.0

4.0

2.7

3.6

1.5

sd

AD

15.0

5.8

5.7

8.1

8.8

11.5

-8.56 (-11.59, -5.52)

-8.10 (-13.55, -2.65)

-11.70 (-13.79, -9.61)

-5.81 (-6.70, -4.92)

-11.38 (-17.11, -5.65)

-4.90 (-5.63, -4.17)

mean

difference (95% CI)

-19.00 (-24.87, -13.13)

-12.40 (-15.45, -9.35)

-9.71 (-13.27, -6.15)

-3.84 (-8.91, 1.23)

-7.50 (-12.41, -2.59)

1.73 (-4.21, 7.67)

-12.40 (-19.07, -5.73)

8.3

10.7

11.2

8.1

11.2

weight

(%)

7.9

10.1

8.6

8.7

7.9

7.3

-8.56 (-11.59, -5.52)

-8.10 (-13.55, -2.65)

-11.70 (-13.79, -9.61)

-5.81 (-6.70, -4.92)

-11.38 (-17.11, -5.65)

-4.90 (-5.63, -4.17)

mean

difference (95% CI)

-19.00 (-24.87, -13.13)

-12.40 (-15.45, -9.35)

-9.71 (-13.27, -6.15)

-3.84 (-8.91, 1.23)

-7.50 (-12.41, -2.59)

1.73 (-4.21, 7.67)

-12.40 (-19.07, -5.73)

8.3

10.7

11.2

8.1

11.2

weight

(%)

7.9

10.1

8.6

8.7

7.9

7.3

AD lower AD higher

0-20 -15 -10 -5 0 5 10

vitamin E

AD lower AD higher

4.35 (2.27-6.42); P < 0.001

4.64 (2.02-7.26); P = 0.001

8.56 (5.52-11.59); P < 0.001

9.71 (6.15-13.27); P = 0.001

Unadjusted overall mean difference (95% CI)

Age-adjusted overall mean difference (95% CI)

Vitamin E Folate

Unadjusted Overall (REML, I-squared=87%, P<0.001)

Hogervorst '02

Anello '04

Irizarry '05

Joosten '97

Koseoglu '07

Clarke '98

Age adjusted Overall (REML meta-regression, P=0.001)

Asita De Silva '05

Galimberti '08

Dominguez '05

Cascalheira '09

study

Galluci '04

Faux '11

Agarwal '10

Karimi '09

62

181

88

49

40

108

21

23

19

36

control

n

42

760

127

49

24.9

15.7

35.2

8.6

28.1

22.9

19.7

19.8

29.6

20.4

control

mean

14.1

30.3

15.7

15.9

11.3

5.9

32.9

3.2

3.4

10.0

9.7

6.2

9.0

1.7

control

sd

11.1

12.7

30.1

8.6

66

180

145

52

51

164

23

29

29

19

AD

n

137

205

32

51

15.9

14.3

29.9

7.9

21.4

17.6

15.9

8.6

17.9

18.8

AD

mean

11.6

29.4

15.0

14.5

11.3

5.7

21.3

4.2

4.4

10.7

8.4

2.8

7.2

5.3

AD

sd

6.1

14.5

14.7

6.6

-4.35 (-6.42, -2.27)

-9.06 (-12.99, -5.13)

-1.40 (-2.60, -0.20)

-5.30 (-13.00, 2.40)

-0.68 (-2.14, 0.78)

-6.68 (-8.28, -5.08)

-5.30 (-7.80, -2.80)

-4.64 (-7.26, -2.02)

-3.85 (-9.24, 1.54)

-11.19 (-13.91, -8.47)

-11.70 (-16.51, -6.89)

-1.59 (-4.03, 0.85)

difference (95% CI)

mean

-2.50 (-6.01, 1.01)

-0.94 (-3.12, 1.24)

-0.71 (-8.03, 6.61)

-1.36 (-4.37, 1.65)

6.8

8.8

4.0

8.7

8.6

8.0

5.6

7.9

6.1

8.1

(%)

weight

7.2

8.3

4.3

7.6

-4.35 (-6.42, -2.27)

-9.06 (-12.99, -5.13)

-1.40 (-2.60, -0.20)

-5.30 (-13.00, 2.40)

-0.68 (-2.14, 0.78)

-6.68 (-8.28, -5.08)

-5.30 (-7.80, -2.80)

-4.64 (-7.26, -2.02)

-3.85 (-9.24, 1.54)

-11.19 (-13.91, -8.47)

-11.70 (-16.51, -6.89)

-1.59 (-4.03, 0.85)

difference (95% CI)

mean

-2.50 (-6.01, 1.01)

-0.94 (-3.12, 1.24)

-0.71 (-8.03, 6.61)

-1.36 (-4.37, 1.65)

6.8

8.8

4.0

8.7

8.6

8.0

5.6

7.9

6.1

8.1

(%)

weight

7.2

8.3

4.3

7.6

AD lower AD higher

0-20 -15 -10 -5 0 5 10

folate

AD higher AD lower

Unadjusted Overall (REML, I-squared=87%, P<0.001)

Hogervorst '02

Anello '04

Irizarry '05

Joosten '97

Koseoglu '07

Clarke '98

Age adjusted Overall (REML meta-regression, P=0.001)

Asita De Silva '05

Galimberti '08

Dominguez '05

Cascalheira '09

study

Galluci '04

Faux '11

Agarwal '10

Karimi '09

62

181

88

49

40

108

21

23

19

36

control

n

42

760

127

49

24.9

15.7

35.2

8.6

28.1

22.9

19.7

19.8

29.6

20.4

control

mean

14.1

30.3

15.7

15.9

11.3

5.9

32.9

3.2

3.4

10.0

9.7

6.2

9.0

1.7

control

sd

11.1

12.7

30.1

8.6

66

180

145

52

51

164

23

29

29

19

AD

n

137

205

32

51

15.9

14.3

29.9

7.9

21.4

17.6

15.9

8.6

17.9

18.8

AD

mean

11.6

29.4

15.0

14.5

11.3

5.7

21.3

4.2

4.4

10.7

8.4

2.8

7.2

5.3

AD

sd

6.1

14.5

14.7

6.6

-4.35 (-6.42, -2.27)

-9.06 (-12.99, -5.13)

-1.40 (-2.60, -0.20)

-5.30 (-13.00, 2.40)

-0.68 (-2.14, 0.78)

-6.68 (-8.28, -5.08)

-5.30 (-7.80, -2.80)

-4.64 (-7.26, -2.02)

-3.85 (-9.24, 1.54)

-11.19 (-13.91, -8.47)

-11.70 (-16.51, -6.89)

-1.59 (-4.03, 0.85)

difference (95% CI)

mean

-2.50 (-6.01, 1.01)

-0.94 (-3.12, 1.24)

-0.71 (-8.03, 6.61)

-1.36 (-4.37, 1.65)

6.8

8.8

4.0

8.7

8.6

8.0

5.6

7.9

6.1

8.1

(%)

weight

7.2

8.3

4.3

7.6

-4.35 (-6.42, -2.27)

-9.06 (-12.99, -5.13)

-1.40 (-2.60, -0.20)

-5.30 (-13.00, 2.40)

-0.68 (-2.14, 0.78)

-6.68 (-8.28, -5.08)

-5.30 (-7.80, -2.80)

-4.64 (-7.26, -2.02)

-3.85 (-9.24, 1.54)

-11.19 (-13.91, -8.47)

-11.70 (-16.51, -6.89)

-1.59 (-4.03, 0.85)

difference (95% CI)

mean

-2.50 (-6.01, 1.01)

-0.94 (-3.12, 1.24)

-0.71 (-8.03, 6.61)

-1.36 (-4.37, 1.65)

6.8

8.8

4.0

8.7

8.6

8.0

5.6

7.9

6.1

8.1

(%)

weight

7.2

8.3

4.3

7.6

AD lower AD higher

0-20 -15 -10 -5 0 5 10

folate

Lopes da Silva et al, Alzheimers Dement, 2013

Impaired liver conversion of ALA1 to DHA2 in AD

Astarita et al. PLoSOne. 2010

Reduced liver biosynthesis of DHA

Reduced peroxisomal D-bifunctional

protein expression

Control AD

Tota

l mR

NA

p = 0.048

Control AD

DH

A (

nm

ol/

g)

p = 0.0077

1α-linolenic acid 2docosahexaenoic acid

-0.2

0.2

0.6

20 40 60 80 100

Ch

oli

ne

– C

rea

tin

e R

ati

o C

ha

ng

e

Aft

er C

ho

lin

e In

tak

e

Age (y)

Brain Uptake of Choline Decreases With Aging

p < 0.001 for younger vs older subjects

Older men

Older women

Younger men

Younger women

Impaired nutrient uptake and absorption: choline

1. Cohen et al. JAMA. 1995

• Choline intake increases plasma levels similarly in younger and older adults • Brain choline shows lower increase after choline intake in older compared with younger adults

PHOSPHATIDYLETHANOLAMINE(enriched in DHA)

PHOSPHATIDYLCHOLINE (enriched in DHA)

PEMT

HCy

Met

CYSTEINE

PEMT PATHWAY

liver-derived lipoproteins DHA

Choline

B6

B12 FO

High Homocysteine levels reduce availability of DHA and choline

High HCy levels in AD inhibit the activity of methyltransferases like PEMT involved in DHA and choline production

Via PEMT, high homocysteine levels negatively impact DHA and choline availability

Normal levels of HCy

Lower nutrient levels in AD brain/CSF compared to healthy controls

Nutrient

Number of studies

Significant lower Lower Higher Significant

higher

DHA 9 5 1 2

EPA 1 2

Choline 2 3 3

Folate 4 3 1

Vitamin B12 1 2

Vitamin C 3 1

Vitamin E 2 1 2

Selenium 3 5 3

Lower nutrient intakes due to poor food choices in early AD

DHA

vitamin B-6

vitamin B-12

Folate

vitamin C

vitamin E

Shatenstein et al., J Am Diet Assoc, 2007

Lower intake from food sources of

Phillips et al., Nutr Neurosci, 2012; Hart et al., Nutr Soc, 2013

Lower intake of

Fruits

Nuts

Seeds

Fish Higher intake of

Sugars & Snacks

• Changes in regulation of appetite

• Hypometabolism of hypothalamus, • Hippocampal atrophy, impairment of olfaction and taste • Genetic predisposition • Metabolic changes: increase TNF-alpha levels

Preclinical stage

• Memory and attentional deficits • Reduced intake, unbalanced nutrient choice

• Increased energy requirements • Restless, wandering • Co-morbid medical illness

Early stage of AD

• Reduced food intake • Apraxia, dependency • Dysphagia • Medication side effects

Late stage of AD

Altered nutrient intake in AD: potential causes

12

1. adapted from Wirth 2012

• Multiple pathologies occur in AD, including neuroinflammation, neurovascular pathology and neurodegeneration

• Approaches that have targeted single pathologies, such as amyloid aggregation or inflammatory responses, or individual nutrients have had limited success

• A multi-modal approach may therefore be required, as has been effective in other conditions such as heart failure1

• The Finger study

AD is a multi-faceted disease requiring a multi-domain approach

1. Gillete-Guyonnet et al. Br J Clin Pharmacol. 2013;75:738–755.

Kivipelto et al., Lancet Neurology 2006

0

2

4

6

8

10

12

14

16

18

0-5 6-7 8-9 10-11 12-15

SCORE

2 %

CAIDE Dementia Risk Score

Age, years < 47

47-53

>53

0

3

4

Education,

years

≥10

7-9

0-6

0

2

3

Sex Women

Men

0

1

Systolic BP,

mmHg

140

> 140

0

2

BMI, kg/m2 30

> 30

0

2

Cholesterol,

mmol/l

6.5

> 6.5

0

2

Physical

activity

Active

Inactive

0

1

Midlife AD risk profile,

20 years prediction

Diet and AD risk

Epidemiological data has shown an association between certain dietary patterns and a lower risk of AD, e.g.1

Regular intake of fish (providing PUFAs)2,3

Mediterranean diet 4,5

Adherence to nutritional recommendations in middle-age adults is associated with future memory performance6

BUT we do not eat specific foods or nutrients in isolation, so supplementation of single nutrients is likely to yield mixed results.

These data suggest that supplementation with specific combinations of nutrients is more effective in improving cognitive performance than single nutrient supplementation

1.Salerno-Kennedy et al. Int J Vitam Nutr Res. 2005 2. Kalmijn . J Nutr Health Aging 2000 3. Barberger-Gateau et al. BMJ 2002 4. Solfrizzi et al. Expert Rev. Neurother. 2011 5. Martínez-Lapiscina et al JNNP 2013 6. Kesse-Guyot et al. Am J Clin Nutr 2011

Single nutrient interventions in AD/MCI: in general no beneficial effects on cognition

Nutrient Author Journal #Subjects/

Duration Outcome

n3 PUFAs

Quinn

2010 JAMA

402

18 months

DHA compared with placebo did not slow the rate of cognitive and

functional decline in mild-moderate AD patients.

Freund-Levi

2006 Arch Neurol

174

6 months

Administration of n3PUFA in mild -moderate AD patients did

not delay the rate of cognitive decline according to the MMSE or the

cognitive portion of the ADAS. However, positive effects were observed in

a small group of patients with very mild AD (MMSE>27)

B-vitamins

Aisen

2008 JAMA

409

18 months

This regimen of high-dose B vitamin supplements does

not slow cognitive decline in individuals with mild to moderate AD.

McMahon

2006 N Eng J Med

276

24 months

The results of this trial do not support the hypothesis that homocysteine

lowering with B vitamins improves cognitive performance.

Vitamin E /

Antioxidants

Dysken

2014 JAMA

304

Mean f-up

27 months

Among patients with mild to moderate AD, 2000 IU/d of alpha-tocopherol

compared with placebo resulted in slower functional decline.

Petersen

2005 N Eng J Med

769

36 months Vitamin E had no benefit in patients with mild cognitive impairment.

Galasko

2012 Arch Neurol

52

16 weeks

However, this treatment (vitamin E + vitamin C plus α-lipoic acid) raised the

caution of faster cognitive decline

Vitamin D2 Stein

2011 J Alz Disease

32

8 weeks

We conclude that high-dose vitamin D provides

no benefit for cognition or disability over low-dose vitamin D

in mild-moderate AD

Ginkgo biloba DeKosky

2008 JAMA

3069

median f-up

6.1 Y

Ginkgo biloba at 120 mg twice a day was not effective in reducing either

the overall incidence rate of dementia or AD incidence in elderly

individuals with normal cognition or those with MCI.

Why have single nutrient supplements failed?

Cognition poorly assessed or assessed post hoc

Populations too heterogenous

Level of supplementation is very variable1

Variable dietary intake confounds total nutrient levels

May be that multiple nutrient combinations are more effective by being more physiological

1. Barnes et al. Nutr Rev 2014

What correlates best with severity of dementia?

Synapse loss/neurone loss

Neurotransmitter loss –

acetylcholine

Neurofibrillary tangles

Amyloid plaques

Reduced

plasma levels

folate, Vit B12,

Vit C, Vit E

Reduced CSF and

brain levels of

omega-3

(DHA/EPA)

Age-related reduced

uptake of choline by brain

Reduced synthesis

of uridine

monophosphate

Increased

homocysteine

Alzheimer’s disease is not primarily a nutritional disorder –

but age-related nutritional deficiencies occur

Methodologies in nutrition studies

Assumptions are dangerous…

Digestion

Absorption

Metabolism

Transport across BBB

Choline uptake across BBB decreases with age

Metabolism of long chain fats in liver decreases in AD

Vitamin B12 digestion and absorption decreases with age

Microbiome?

The need to take a broad view of the evidence

Take preclinical studies into consideration for likely MOA

Look at trends, doses, comparators, intakes in:

• Epidemiology

• Prospective cohorts

• Observational studies

• Population based studies

RCTs but interpret results with caution1 as nutrition trials do not lend easily to RCT formats

1. Blumberg et al 2010

So where is there good evidence?

Nutrition for optimal brain health1

Vitamin E DHA Folate & B12 Ratio of saturated to unsaturated fats Some aspects of Alzheimer’s disease2 Neuroinflammation Glucose dysregulation Homocysteine Neuronal loss

These disease elements can be influenced with nutrition

1. Morriss JAMA 2010 2. Ferreira et al Alz Dem 2014

Advice from Royal College of Psychiatry

RCGP website

Depression Bipolar Schizophrenia ADHA Epilepsy

Eat diet rich in omega 3

Eat diet rich in omega 3

Eat diet rich in omega 3

No clear advice

Eat ketogenic diet

Selenium Selenium Calcium

Folate Folate

Tryptophan Tryptophan

Vitamin D Vitamin D

S-adenosyl- methionine

S-adenosyl-methionine

St John’s Wort St John’s Word

No advice on AD or dementia yet advice on nutrition for other major organ failures like heart, kidney and liver are common place and accepted.

Dietary guidelines for AD prevention

A Special Report, Physicians Committee for Responsible Medicine, July 2013

The seven guidelines to reduce risk of Alzheimer’s disease

1 Minimise your intake of saturated and trans fats

2 Eat plant-based foods –vegetables, legumes, fruits & wholegrains should replace meat and dairy products as primary staples of the diet

3 Consume 15 mg of vitamin E from foods daily. Healthful food sources incl nuts, seeds, green leafy veg and wholegrains

4 Take a vitamin B12 supplement : 2.4 micrograms per day for adults

5 Avoid multivitamins with iron and copper

6 Choose aluminium free products (?)

7 Exercise for 120 minutes each week

Whats the future for nutrition in AD

Dietary correction earlier in disease course

Nutrient combinations preferable to single nutrient supplementation

Dietary pattern adoption instead of single food recommendations

Better trial development to what works best for nutrition

Nutrition in combination with other lifestyle factors

Higher doses may be needed in diseased populations

D R D A V I D W I L K I N S O N

C O N S U L T A N T I N O L D A G E P S Y C H I A T R Y

Nutrition and Alzheimer’s Disease