disease -...
TRANSCRIPT
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