1. Treatment AD in the earliest stage: The role of medical nutrition
Prof. Dr. Philip Scheltens

2. Disclosures The Alzheimer Center has received funding from:
AEGON, ZONMW, Alzheimer Nederland, Heineken Nederland, ING, Stichting VUmc Fonds, AHAF, ISOA, ISAO, Pfizer, Jansen, Novartis, KLM Royal Dutch Airlines, KPN, KPMG, Twentse Kabel Holding, Stichting Zabawas, RABO Bank
Image analysis research and clinical trials are carried out with Nutricia Advanced Medical Nutrition, Jansen Research Foundation, Novartis, Roche, Merck, Lundbeck, Pfizer
Dr Scheltens receives no personal compensation from any of the above or others except from the VUmc

4. Alzheimer: de getallen
Nu: ~ patiënten in Nederland
Belangrijkste risicofactor: Leeftijd
Dubbele vergrijzing:
méér ouderen
worden ouder
 snelle toename!
Schatting 2040:
Aantal jong dementerende
(<65) neemt toe

5. De impact van Alzheimer
1 op de 10 > 65 heeft Alzheimer 
1 op de 3 > 80 heeft Alzheimer 

6. De impact van Alzheimer
1 op de 10 > 65 heeft Alzheimer 
1 op de 3 > 80 heeft Alzheimer 
Iedere 15 minuten krijgt iemand Alzheimer

7. De impact van Alzheimer
1 op de 10 > 65 heeft Alzheimer 
1 op de 3 > 80 heeft Alzheimer 
Iedere 15 minuten krijgt iemand Alzheimer
Aangenomen dat per patiënt 3 zorgverleners (part time) betrokken zijn; zijn er 1.5 miljoen zorgverleners nodig in 2040.
Terwijl de beroepsbevolking in aantal afneemt…
...neemt de belasting voor de maatschappij toe! 
Conclusie: er ligt een grote uitdaging voor ons. Oplossingen moeten snel gevonden worden.    7

8. ‘Dementia’ and ‘Neuronutrients’
> 10 Years of Research
‘98
‘99
’00
’01
’02
’03
’04
’05
’06
’07
‘08
‘09
’10
’11
‘12
Various national and international preclinical research consortia including
‘Dementia’ and ‘Neuronutrients’
Prof Wurtman, MIT
Prof. Scheltens VUMc, NL
Prof. Bennett
Rush, USA
Prof. Scheltens
VUMc, NL
Collaboration
BTS project “Dementie” ( )
Prof Monique Breteler, Erasmus Medical Center, The Netherlands
Prof Paul Luiten, Rijksuniversiteit Groningen, The Netherlands
BIT project “Neuronutrients” ( )
Prof Richard Wurtman, MIT / Harvard Medical school, Cambridge, USA …
Prof. Soininen
UEF, Finland
Souvenir I received funding from Stichting Technische Wetenschappen, Souvenir II received funding from the NL Food & Nutrition Delta project, FND #10003, LipiDiDiet: Funded by the EU FP7 project LipiDiDiet, Grant Agreement #211696 8

9. Alzheimer: 3 fundamentele processen
Neurofibrillaire
kluwens
Synapsverlies
Seniele plaques

10. Synaptic Failure in Alzheimer’s disease
Control
MCI AD 5 10 *
-13%
-44%
# Synapses dentate gyrus (x1010)
Synapse loss is an early event in the disease process
Synaptic loss is strongest structural correlate with cognitive decline
Failure to replace the loss of synaptic contacts leads to the decline in memory
Scheff et al., Neurobiol Aging, 2006

11. Sperling et al., Alz & Dement, 2011
Synapse Loss in AD is an early event
Synapse loss is an early event in the AD continuum
Synaps loss happens early
Current thinking illustrated by AD model, most shown picture on AD conferences, changes in biomarkers preceed functional decline
More later re memory loss early symptom in AD, this study illustrates that loss of synapses is associated with memory decline
So synapses are important, already early in disease
Fig. 3. Hypothetical model of dynamic biomarkers of the AD expanded to explicate the preclinical phase: Ab as identified by cerebrospinal fluid Ab42 assay or
PET amyloid imaging. Synaptic dysfunction evidenced by fluorodeoxyglucose (F18) positron emission tomography (FDG-PET) or functional magnetic
resonance imaging (fMRI), with a dashed line to indicate that synaptic dysfunction may be detectable in carriers of the 34 allele of the apolipoprotein E
gene before detectable Ab deposition. Neuronal injury is evidenced by cerebrospinal fluid tau or phospho-tau, brain structure is evidenced by structural magnetic
resonance imaging. Biomarkers change from normal to maximally abnormal (y-axis) as a function of disease stage (x-axis). The temporal trajectory of two key
indicators used to stage the disease clinically, cognitive and behavioral measures, and clinical function are also illustrated. Figure adapted with permission from
Jack et al [22].
Sperling et al., Alz & Dement, 2011 11

12. Nutritional precursor control of neuronal membrane synthesis
Saturated fatty acid
Glycerol
Phosphate
Choline
PUFA
Axon
neurite
dendritic
spine

13. Phospholipids are synthesized by the Kennedy Pathway
Saturated fatty acid
Glycerol
Phosphate
Choline
PUFA
e.g.
DHA
One way to do that might be to try to increase the formation of neuronal membranes, as membranes are the main constituents of synapses. Already in 1954 prof kennedy discoved this pathway for the synsthesis of neuralnal membrane, showing that it takes 3 precursors that are normally present in the diet to form Pl and neural membranes via several steps.
More recently Prof Wurtman discovered that this pathway is controlled by low affinity enzymes, which implies that if you provide more of the substrates you will end up with more end prpoduct. For instance the notion that UMP is rate liminint in this pathway is illustrated by this experiment where it was showen that increased dietary intake of UMP increased the level of CDP chioline in the brain
KENNEDY EP, WEISS SB (1956). J. Biol. Chem. 222 (1): 193–214 13

14. Different nutritional status in patients with mild AD
No significant differences were observed for plasma folate, vitamins B6 and B12, choline,
vitamins A and E, plasma fatty acids, BMI, and calf circumference.
J.W. Sijben, M.G.M Olde Rikkert et al. Poster EFNS 2012 Stockhom

15. Verzadigde vetzuren
Onverzadigde vetzuren

17. Increase the formation of neuronal membranes
Providing the Nutritional Precursors and Co-Factors
for Neuronal Membrane Formation
UMP DHA, EPA Choline Phospholipids B vitamins Anti-oxidants
Hypothesized to:
Increase the formation of neuronal membranes
Much of early developmental work was conducted
By Professor Richard Wurtman at MIT, Boston, USA

18. Nutritional precursors increase membrane dependent structures: Neurite outgrowth
Control
Uridine 50 µM
Pooler et al (2005) Neuroscience
B-vitamins, choline and omega-3 fatty acids also stimulate neurite outgrowth in vitro
plaatje: NGF-DIFFERENTIATED PHEOCHROMOCYTOMA CELLS
4 dagen behandeld in vitro
Darios et al. (2006) Nature;
Wang et al. (2000) Neurosci Lett;
Calderon et al. (2004) J Neurochem

19. Spine Density hippocampus (for 50µM)
Nutritional precursors increase membrane dependent structures
(dendritic spines in gerbil hippocampus)
Spine Density hippocampus (for 50µM)
Control (choline)
UMP
UMP DHA
DHA ** * 20 40 60 80
100
We used gerbils (Meriones unguiculatus) for these studies because the metabolism of pyrimidines in this species more closely resembles that in humans than does pyrimidine metabolism in rats: plasma levels of uridine are higher than those of cytidine, both basally and after giving a uridine
(Cansev et al., 2005) or cytidine (Wurtman et al., 2000; Cansev and Wurtman, 2005) source, in humans and gerbils but not in rats (Lopez-Coviella et al., 1995).
Dendritic spines are small membranous protrusions extending from post synaptic dendrites in neurons, most of which eventually form synapses with presynaptic axon terminals
Same picture, , number of DSP per length of dendrite
Effect fast
Did not affect length of width of indivdual spines
Sakamoto et al. (2007) Brain Res 19 19

20. & Cognition (ADAS-cog)
Clinical Trials
Prodromal
Mild
Moderate
Memory (WMS-r)
& Cognition (ADAS-cog)
Memory (NTB)
Biomarker EEG & MEG
Cognition (ADAS-cog)
Cognition (NTB)
Biomarker MRI & CSF
Trials are registered in the ICMJE compliant

21. Souvenir I: Proof of Concept Study in Drug-Naive mild AD
Multi-country (NL, Bel, Ger, UK, US), randomized, controlled trial
Intervention 12 weeks (+ optional 12 wk extension)
Co-primary outcomes:
WMS-r delayed verbal recall
ADAS-cog-13
Baseline Characteristics
Control
(n = 106)
Active
Sex (male/female; counts)
52 / 54
54 / 52
Age (y)
73.3 ± 7.8
74.1 ± 7.2
BMI (kg/m2)
26.2 ± 3.5
26.2 ± 4.8
Years of education on top of primary school
6.0 ± 4.0
5.5 ± 3.9
Days since AD diagnosis (median)
31.5 (0 – )
30.0 (0 – )
Total MMSE score
24.0 ± 2.5
23.8 ± 2.7
t ≤-3 t= wks
n=212
Souvenaid (n=106)
Control (n=106)
Outcome parameters
Values are mean ±SD, unless stated otherwise

22. Blood Nutritional Parameters
Significant changes (p<0.001) in vitamin E and EPA
P-values for changes from Baseline to Week 24, control vs active AND changes from Week 24 to Week 48, control-active vs active-active.
ITT, data are mean ± SE

23. No difference in AEs and Compliance
Safety
No significant differences in the number of (Serious) Adverse Events (S)AEs
No clinically relevant differences in blood safety parameters
No difference in dropouts (# patients) due to (S)AEs
Tolerance
No difference in product appreciation (taste and amount) between the Control and Active group
Overall product compliance was very high at 95% with no difference between the groups
SAEs
Control: 14 SAEs in 11 patients, one possibly related (panic attack / hyperventilation)
Active: 13 SAEs in 7 patients

24. Wechsler Memory Score
Logisch geheugen  b) Uitgestelde herinnering (na 30 minuten)
Verhaal A
Anna / Jansen / uit Amsterdam / Zuid / die werkte/ als werkster / op een kantoorgebouw / deed aangifte / op het politiebureau / Singel, / dat zij de vorige avond/ in de Spuistraat / was aangehouden / en van 115 € /
was beroofd. / Zij had vier / kleine kinderen / de huur /
was nog niet betaald / en ze hadden reeds twee dagen / niet gegeten. / De agenten waren zeer getroffen /
door dit verhaal / en hielden een geldinzameling / voor haar.
Max. = 25
Totaal verhaal A

25. Co-Primary Outcome: WMS-r Delayed Verbal Recall Score
mild AD after 12 weeks
Very Mild AD
after 12 weeks
(p=0.021)
(p=0.019)
At baseline, approximately 40% of patients scored 0 [lowest score] on the WMS-r delayed verbal recall scale of 0–25. Given this skewed distribution, it was necessary to substitute the planned mixed-model analysis of 12-week data with nonparametric analyses. Both noncategorical (Mann–Whitney
U Wilcoxon W test) and categorical nonparametric analyses (c2 test) gave similar results.
ITT, Chi-square
*At baseline 40% scored 0 [lowest score], planned MMRM substituted by nonparametric analyses, MWU and Chi-square gave similar results
Pre-defined subgroup MMSE , Chi-square
Scheltens et al. Alzheimers Dement (1):1-10.

26. No significant (p=0.826) effect1
Co-Primary Outcome: ADAS-cog
Primary analysis:
No significant (p=0.826) effect1
ITT, MMRM, data are mean ± SE
1Scheltens et al. Alzheimers Dement (1):1-10.
2Kamphuis et al. J Nutr Health Aging (8):720-4.

27. & Cognition (ADAS-cog)
Clinical Trials
Prodromal
Mild
Moderate
Memory (WMS-r)
& Cognition (ADAS-cog)
Memory (NTB)
Biomarker EEG & MEG
Cognition (ADAS-cog)
Cognition (NTB)
Biomarker MRI & CSF
Trials are registered in the ICMJE compliant

28. Baseline Characteristics
S-Connect study: Mild to Moderate AD
using AD medication
Principle investigators: David Bennett and Raj Shah, Rush, Chicago
Multi-centre (48 sites in the US), randomized, controlled trial
Intervention 24 weeks
Primary outcome:
ADAS-cog-11
Baseline Characteristics
Control
(n = 262)
Active
(n = 265)
Age (y)
76.9 (8.2)
76.6 (8.2)
Sex: males (n[%])
127 (48.5%)
126 (47.5%)
Years of education on top of primary school
6.4 (3.5)
6.7 (3.6)
Total MMSE score
19.3 (3.0)
19.5 (3.2)
Duration AD since diagnosis (months)
34.9 (29.6)
32.7 (25.0)
Acetylcholinesterase inhibitors
243 (92.7%)
251 (94.7%)
NMDA antagonist
170 (64.9%)
177 (66.8%)
BMI (kg/m2)
26.64 (4.56)
26.19 (4.51)
n=527
n=265 Active
t ≤ wk
Outcome parameters
n=262 Control
Values are mean±SD, unless stated otherwise

29. No difference in Adverse Events
Body System
Control (n=262)
Active (n=265)
p-value
Any AE
165 (60.1)
150 (56.8)
0.130
Body as a whole
33 (12.7)
24 (9.1)
0.208
Nervous system
21 (8.1)
27 (10.2)
0.450
Gastro-intestinal
38 (14.6)
41 (15.5)
0.808
Metabolic & nutritional
19 (7.3)
19 (7.2)
1.000
Musculo-skeletal
15 (5.8)
0.183
Psychiatric
43 (16.5)
32 (12.1)
0.170
Respiratory system
42 (16.2)
50 (18.9)
0.423
Skin and appendages
18 (6.9)
8 (3.0)
0.045
Urinary system
25 (9.5)
0.432
Other
27 (10.4)
20 (7.6)
0.287
Occurrence of > 5% in total subjects
Overall compliance during 24 weeks was 94% and not different between the groups

30. No significant effect* (p=0.513) during 24 weeks
Primary Outcome: ADAS-cog
No significant effect* (p=0.513) during 24 weeks
ITT, MMRM, data are mean ±SE
*Statistical analysis run by Rush Alzheimer’s Disease Centre, Rush University Medical Centre
Shah et al., J Nutr Health Aging, 2011;15; Suppl 1:S30, Manuscript in preparation

31. & Cognition (ADAS-cog)
Clinical Trials
Prodromal
Mild
Moderate
Memory (WMS-r)
& Cognition (ADAS-cog)
Memory (NTB)
Biomarker EEG & MEG
Cognition (ADAS-cog)
Cognition (NTB)
Biomarker MRI & CSF
Trials are registered in the ICMJE compliant

32. Baseline Characteristics
Souvenir II study: Drug-Naive Mild AD
Multi-country (NL, Ger, Bel, Fr, It, Sp), randomized, controlled trial
Intervention 24 weeks
Primary outcome: Memory Domain NTB (z-score):
RAVLT immediate, delayed, recognition and VPA immediate and delayed
Baseline Characteristics
Control
(n = 129)
Active
(n = 130)
Age (y)
73.2 (8.4)
74.4 (6.9)
Sex: males (n[%])
64 (49.6)
68 (52.3)
Years of education on top of primary school
6.6 (4.6)
6.5 (4.8)
Total MMSE score
25.1 (2.9)
25.1 (2.8)
Duration AD since diagnosis (months) (median[range])
2.0 ( )
1.0 ( )
BMI (kg/m2)
26.7 (4.2)
26.1 (4.1)
n=259
n=130 Active
t ≤ wk
n=129 Control
Outcome parameters
Values are mean±SD, unless stated otherwise

33. No Difference in Adverse Events
Body system
Examples
Control
(n=129)
Active
(n=130)
p-value
Body as a whole
Fatigue, influenza-like symptoms
20 (15.5%)
11 (8.5%)
p=0.125
Central and peripheral nervous system disorders
Dizziness, headache
18 (14.0%)
p=0.237
Gastro-intestinal system disorders
Constipation, diarrhoea, flatulence, nausea
30 (23.3%)
22 (17.1%)
p=0.277
Metabolic and nutritional disorders
Hyperglycaeemia, weight increase
9 (7.0%)
13 (10.1%)
p=0.505
Musculo-skeletal system disorders
Arthralgia, ischial neuralgia
10 (7.8%)
p=1.000
Psychiatric disorders
Anxiety, depression, insomnia
16 (12.4%)
15 (11.6%)
Respiratory system disorders
Pharyngitis, bronchitis
p=0.400
Skin and appendages disorders
Rash, skin dry
4 (3.1%)
p=0.168
Other
Fall, surgical intervention
8 (6.2%)
Occurrence of > 5% in total subjects
Overall compliance during 24 weeks was 97% and not different between the groups

34. Primary Efficacy: Memory Domain Score (z-score) of the NTB
ITT, MMRM 2df contrast, data are mean ±SE
*Statistical analysis re-run by Rush Alzheimer’s Disease Center
Scheltens et al. J Alzheimers Dis (1):

35. Secondary Efficacy: NTB Total and NTB Executive Domain (z-score)
NTB composite score trend (p=0.053)
NTB executive domain score no significant effect (p=0.686)
ITT, MMRM, 2 df contrast, data are mean ±SE
Scheltens et al. J Alzheimers Dis (1):

36. Exploratory – Memory domain z-score
Double-blind treatment
Open-label extension
Overall Open Label ITT population. This includes ALL subjects. Key point of this result is that active continues to increase and control catches up after starting on Souvenaid.
Week 0, 12, 24 -> SII ITT;
Week 36, 48 -> OLE ITT, all subjects
Raw means and SE; change from baseline 12 24 36 48
Control (N) -
100
103 85 83
Active (N)
107

37. Electrical Activity at the Synapse – EEG: Biomarker for Functional Connectivity
Basic quantitative EEG analysis -
Relative power and Peak Frequency
In AD disturbed signal strength1
PLI
Phase Leg Index (PLI) as Functional Connectivity measure
In AD loss of PLI1
Healthy AD
Clustering & Path length are measures of Network Organization
In AD disrupted Organization2
1Stam CJ et al. Brain ,
2Stam CJ, van Straaten ECW. Clin Neurophysiol 2012 doi: /j.clinph

38. 3. Brain Network organization*
Network Parameters suggest Preserved
Synaptic Formation, Function and Network
1. Peak Frequency
3. Brain Network organization*
p=0.019
p=0.009
2. Phase Leg Index
p=0.053
p=0.011
Scheltens et al. J Alzheimers Dis (1):
*Manuscript in preparation, Developing topics P4-363
ITT, MMRM, 2 df contrast, data are mean ±SE

39. & Cognition (ADAS-cog)
Clinical Trials
Prodromal
Mild
Moderate
Memory (WMS-r)
& Cognition (ADAS-cog)
Memory (NTB)
Biomarker EEG & MEG
Cognition (ADAS-cog)
Cognition (NTB)
Biomarker MRI & CSF
Trials are registered in the ICMJE compliant

40. EU – Funded* LipiDiDiet: Proof of Concept Study in Prodromal AD
Principle investigator: H. Soininen (UEF, Kuopio, Finland)
24-Month randomized, controlled, multicenter (11 sites in Fin, Swe, Ger, NL)
Drug-naive prodromal AD patients (Dubois et al., 2007) (recruited 240 / 300)
Primary Outcome: Neuropsychological Test Battery (NTB)
Secondary Outcomes:
Progression to AD
Functional Abilities
CSF and MRI
A randomised, controlled, double-blind, parallel group, multicentre study to assess the effect of a Medical Food in prodromal AD subjects
Prodromal AD as defined by episodic memory disorder (Pieter Jelle Vissers version B)with -1SD on 2 out of 8 tests including at least 1 memory teest (cut-off?) and evidence for underlying AD pathology either 1. CSF beta-amyloid 1-42/1-40 ratio <1, T-tau >350 pg/ml and phospho tau >60 pg/ml or 2. MRI evidence for hippocampal atrophy greater than normal for age (Lars-Olof, Hilkka)
New research criterea for the diagnosis of alzheimer’s, revised criterea to caputre the earlies stages before full-blown dementia as well as memory impairment
Must be at least one or more abnormal biomarkers among
Structural neuroimaging with mri (medial temperol lobe atrophy)
Molecular neuroimaging with PET (reudced glucose or pib)
- cerebrospinal fluid analysis of amylod or tau proteins
- episodic memory impairment (gradually decline)
* Funded by the EU FP7 project LipiDiDiet, Grant Agreement #211696

41. Mild AD is a New Target
Very limited intervention studies in an exclusively mild AD population have been reported1
Van Gool WA et al., Lancet 2001; 358: 455–60. (hydroxychloroquine)
Seltzer B et al., Arch Neurol 2004; 61: 1852–6. (Donepezil)
Lannfelt L et al., Lancet Neurol 2008; 7: 779–86. (PBT2)
Kessler H et al., J Neural Transm 2008; 115: 1181–7. (copper)
Green RC et al., J Am Med Assoc 2009; 302: 2557–64. (Tarenflurbil)
Hampel H et al., J Clin Psych 2009; 70: 922–31. (lithium)
Scheltens P et al., Alzheimers Dement 2010; 6: 1–10. (Souvenaid)
Souvenir II is the first study to suggest memory improvement as a predefined primary outcome measure
Scheltens P et al., J Alzheimers Dis 2012; 31(1): (Souvenaid)
1Medline search string: English up to June 2012, Searches were restricted to randomized controlled clinical
trials performed in an exclusively mild AD study population. "mild/early Alzheimer's" or "very mild Alzheimer's" or
"cognition testing and outcome and Alzheimer’s" and randomized/controlled/single blind/double blind/intervention
study/trial" including nutritional intervention studies.

42. The AD Continuum Abnormal Normal Time Presymptomatic Dementia
CSF Aβ42
Amyloid imaging
FDG-PET
MRI hippocampal volume CSF Tau
Cognitive performance
Function (ADL)
FDG-PET (Synaptic Dysfunction)
MRI hippocampal volume
CSF Tau
Prodromal
Modified from Aisen PS Alzheimers Dement. 2010 42

43. Multi Level Approach: no single magic bullit for AD
IMMUNISATION ?
LOWERING AMYLOID ?
MEDICAL FOOD
SYMPTOMATIC APPROACH
CARE

44. VUmc Alzheimer Center