Key nutrients in the management of synaptic failure a result of Alzheimer s disease

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1 Key nutrients in the management of synaptic failure a result of Alzheimer s disease Patrick Kamphuis, PhD Global Head of Medical and Scientific Affairs Nutricia, Schiphol, The Netherlands

2 Disclosure statement Employee of Nutricia Research No other relevant disclosures

3 Alzheimer s disease: multiple pathologies, multiple approaches T Amyloid Plaques A R G Neurofibrillary tangles AD Synapse loss Synapse loss E T Neurotransmitter deficits

4 Saturated fatty acid Synapses are built from neuronal membranes Opportunity for a dietary approach Choline Phosphate dendritic spine Glycerol neurite Axon

5 Nutritional precursors enhance the synthesis rate of neuronal membranes The Kennedy pathway for biosynthesis of neuronal membrane Synapses consist principally of neuronal membranes dendritic Axon spine terminal neurite Dendritic spine Neurite Axon Kennedy & Weiss (1956) J. Bio. Chem. 222,

6 Nutritional precursors enhance the synthesis rate of neuronal membranes The Kennedy pathway for biosynthesis of neuronal membrane Synapses consist principally of neuronal membranes Kennedy & Weiss (1956) J. Bio. Chem. 222,

Lower nutrient intake due to poor food choices in early AD Lower intake from food sources of DHA vitamin B-6 vitamin B-12 Folate vitamin C vitamin E Lower intake

7 Lower nutrient intake due to poor food choices in early AD Lower intake from food sources of DHA vitamin B-6 vitamin B-12 Folate vitamin C vitamin E Lower intake of Fruits Nuts Seeds Fish Higher intake of Sugars & Snacks Shatenstein et al., J Am Diet Assoc, 2007 Phillips et al., Nutr Neurosci, 2012; Hart et al., Nutr Soc, 2013

8 Nutrition and the brain link with Alzheimer s disease (AD)? Deficiencies in essential nutrients can result in neurological symptoms Diet and nutrient intake may change with age In AD patients, poor nutrition may be related to failure to remember to eat, changes in eating preferences, and/or olfactory changes Epidemiological evidence suggests potential relationship between nutrient intake and dementia B-Vitamins Important nutrients Antioxidants vitamins C and E involved in synaptic Dietary fats membrane synthesis Dietary patterns i.e., Mediterranean diet

9 Relative Risk Incidence (per 100 persons year) Nutrients and risk of AD Rotterdam study Fish consumption AD Dementia < >133 mg/d Vitamin C intake 0 daily > weekly < weekly never Engelhart et al., JAMA 2002 Collaboration in Dementia project Barberger-Gateau et al., BMJ, 2002 Dangour, Vellas et al., J Alz Dis Systematic review on Bvits and Fatty acids

10 But single nutrient intervention doesn t benefit Nutrient Author Journal n3 PUFAs B-vitamins Quinn 2010 Freund-Levi 2006 Smith 2010 Aisen 2008 JAMA Arch Neurol Plos JAMA #Subjects/ Duration months months months months Outcome DHA compared with placebo did not slow the rate of cognitive and functional decline in mild-moderate AD patients. No delay the rate of cognitive decline. However, positive effects were observed in a small group of patients with very mild AD (MMSE>27) Accelerated rate of brain atrophy in mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. No cognitive benefit. Post hoc (Jeneren 2015) links reduced atrophy to high DHA/EPA sub group. 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 months The results of this trial do not support the hypothesis that homocysteine lowering with B vitamins improves cognitive performance. Vitamin E / Antioxidants Vitamin D2 Ginkgo biloba Dysken 2014 Petersen 2005 Galasko 2012 Stein 2011 DeKosky 2008 JAMA N Eng J Med Arch Neurol J Alz Disease JAMA 304 Mean f-up 27 months months weeks 32 8 weeks 3069 median f-up 6.1a Among patients with mild to moderate AD, 2000 IU/d of alpha-tocopherol compared with placebo resulted in slower functional decline. Vitamin E had no benefit in patients with mild cognitive impairment. However, this treatment (vitamin E + vitamin C plus α-lipoic acid) raised the caution of faster cognitive decline 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 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.

11 High adherence to Mediterranean diet reduces risk of cognitive impairment AD MCI MMSE Psaltopoulou et al, Ann Neurol 2013

Epidemiological evidence suggests dietary patterns can reduce AD risk Epidemiological evidence suggests certain dietary patterns can reduce AD risk: Mediterranean Diet 1,2 Based on higher intakes of

and fruit and more green vegetables and berries 1. Scarmeas N, et al. Mediterraneandiet and risk for Alzheimer s disease. AnnNeurol 2006;59:912 21. 2. Martinez-Lapiscina EH, et al.

12 Epidemiological evidence suggests dietary patterns can reduce AD risk Epidemiological evidence suggests certain dietary patterns can reduce AD risk: Mediterranean Diet 1,2 Based on higher intakes of fish, vegetables, fruit DASH diet 3 and monounsaturated fats As above with emphasis on reduced intake of dairy and salt MIND / Nordic / Finnish diet 4,5 As per Mediterranean diet but with less fish and fruit and more green vegetables and berries 1. Scarmeas N, et al. Mediterraneandiet and risk for Alzheimer s disease. AnnNeurol 2006;59: Martinez-Lapiscina EH, et al. Mediterranean diet improves cognition: the PREDIMED-NAVARRA randomised trial. J Neurol Neurosurg Psychiatry 2013;84: Tangney CC, et al. Relation of DASH- and Mediterranean-like dietary patterns on cognitive decline in older persons. Neurology 2014;83: Morris MC, et al. MIND diet associated with reduced incidence of Alzheimer s disease. Alzheimer s & Dementia 11 (2015) Akesson A, et al. Health effects associated with foods characteristic of the Nordic diet. Food Nutr. Res57 ( 2013),

13 Systematic review & meta-analysis: nutrient availability in AD According to Preferred Reporting Items for Systematic Reveiws and Meta-Analysis (PRISMA) guidelines Analyses by independent statistics

14 3 studies 10 studies 11 studies 9 studies 6 studies 37 studies 31 studies 8 studies 20 studies 11 studies Lower blood status in AD of nutrients essential for synaptic membrane synthesis Systematic review and meta-analysis of literature % Cognitive Intact elderly * 1,2,3 * * * *** *** *** *** * :Trushina (2013) PLOS 2:Olde Rikkert (2014) JAD 3: Wang (2014) J Prot Res Meta-analyses De Wilde et al., poster AAIC 2014 Meta-analyses Lopes da Silva (2013) Alz Dement

15 12 studies 31 studies 12 studies 4 studies 9 studies 5 studies 5 studies 7 studies 4 studies 12 studies Lower brain status in AD of nutrients essential for synaptic membrane synthesis Brain nutrient levels in AD versus cognitively healthy elderly 110 % Cognitively Healthy elderly 90 * 1 * 1 ns * 1 * 1 * 1 * 1 1 * 2 ns 3 ns De Wilde, AAIC 2016

16 Increased nutritional need in AD Higher nutrient need due to synaptic membrane loss? Decreased synapse number in AD Nutrient control of membrane and synapse formation Lower nutrients levels in AD? Lower intake, and compromised endogenous synthesis Lower levels in blood Lower levels in the brain

17 Development of a Medical Food containing Dietary precursors and cofactors Stimulating synapse membrane formation requires specific nutrients Uridine (UMP), Omega-3 fatty acids, Phosholipids & Choline, B-Vitamins, Antioxidants Lower Nutrient status Increased nutritional need cannot be met by the regular diet

18 Development of a Medical Food containing Dietary precursors and cofactors 400 mcg Folate 625 mg UMP 300 mg EPA 400 mg Choline 80 mg Vit C 1200 mg DHA 3 mcg Vit B12 40 mg Vit E 60 mcg Selenium 106 mg Phospholipids 1 mg Vit B6

Lower Nutrient status Increased nutritional need cannot be met by the regular diet HYPOTHESIS: Souvenaid

19 Development of a Medical Food containing Dietary precursors and cofactors Stimulating synapse membrane formation requires specific nutrients Uridine (UMP), Omega-3 fatty acids, Phosholipids & Choline, B-Vitamins, Antioxidants Lower Nutrient status Increased nutritional need cannot be met by the regular diet HYPOTHESIS: Souvenaid successfully addresses an unmet nutritional need in people with AD by increasing their intake of these dietary precursors and co-factors

% of patients 2008 - FIRST HUMAN TRIAL SHOWED THAT SOUVENAID

Improved memory in mild and very mild AD Control worsened

20 % of patients FIRST HUMAN TRIAL SHOWED THAT SOUVENAID IMPROVED MEMORY SCORES IN PEOPLE WITH MILD AD Improved memory in mild and very mild AD Control worsened unchanged improved Souvenaid worsened unchanged improved

21 completed & published The Souvenaid clinical trial program amci due to AD Mild AD Moderate AD S-Connect ADAS-cog n=527 (MMSE 14-24); stable on AD drugs; US Souvenir I Souvenir II Souvenir II Open Label WMS-r & ADAS-cog n=225 NL, Ger, Bel, UK, US NTB + EEG n=259 NL, Ger, Bel, Fr, It, Sp Safety + Compliance + NTB This project receives funding from NL STW This project receives funding from the NL Food & Nutrition Delta project, FND N This project receives funding from the NL Food & Nutrition Delta project, FND N 10003

22 Souvenir II: design and methodology Multi-country randomized, controlled trial in drug naive mild AD over 24 weeks, with a further 24 weeks open label phase Primary outcome: Memory Domain NTB (z-score) at 24 weeks RAVLT immediate, delayed, recognition and VPA immediate and delayed Baseline Characteristics Control (n = 129) Souvenaid (n = 130) n=259 Outcome parameters Souvenaid (n=130) Souvenaid Control (n=129) Souvenaid Double blind phase Open Label 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 Values are mean±sd, unless stated otherwise 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)

23 Sustained improvement in memory performance over 24 and 48 weeks Primary: memory domain z-score (p=0.023) Seconday: NTB composite z-score trend (p=0.053) 24 wk vs baseline p = wk vs baseline p = wk vs baseline p = Scheltens et al. J Alzheimers Dis (1):225-36

24 Sustained improvement in memory performance over 24 and 48 weeks Primary: memory domain z-score (p=0.023) Active - Active: p=0.038 Control - Active: p=0.029 Seconday: NTB composite z-score trend (p=0.053) 24 wk vs baseline p = wk vs baseline p = wk vs baseline p = Scheltens et al. J Alzheimers Dis (1): Olde Rikkert et al. J Alzheimers Dis. 2015

25 DHA (% total fatty acids erythrocyte membrane) Souvenaid increases nutrient blood levels - Data from Souvenir II & Open label extension 45 Control Souvenaid Souvenaid Uridine Folate pla DHA 40 Choline B12 pla EPA 35 edha B6 Vit E 30 0 Sample size (N) Double-blind phase 0 24 eepa Open-label phase Hcy Time (weeks) Selenium

26 Souvenaid increases nutrient blood levels - Data from Souvenir II & Open label extension Uridine Folate pla DHA Choline B12 pla EPA edha B6 Vit E eepa Hcy Selenium

27 Souvenaid increases EEG biomarkers for functional connectivity, derivatives of synaptic activity Level 3: network analysis In AD: disruption of optimal organization Stam 2004 Level 2: connectivity analysis In AD: decreased functional connectivity Babiloni et al Level 1: basic signal analysis De Waal et al., PlosOne, 2014; Scheltens et al., J Alz Dis, 2012 In AD: slowing of the oscillations Snaedal et al. 2010

28 Souvenaid increases EEG biomarkers for functional connectivity, derivatives of synaptic activity Level 3: network analysis In AD: disruption of optimal organization p = p = Stam 2004 Level 2: connectivity analysis In AD: decreased functional connectivity p = Babiloni et al Level 1: basic signal analysis De Waal et al., PlosOne, 2014; Scheltens et al., J Alz Dis, 2012 In AD: slowing of the oscillations p = Snaedal et al. 2010

29 Souvenaid increases EEG biomarkers for functional connectivity, derivatives of synaptic activity Level 3: network analysis In AD: disruption of optimal organization p = p = Stam 2004 Level 2: connectivity analysis In AD: decreased functional connectivity p = Babiloni et al Level 1: basic signal analysis De Waal et al., PlosOne, 2014; Scheltens et al., J Alz Dis, 2012 In AD: slowing of the oscillations p = Snaedal et al. 2010

30 Lower levels of multiple key nutrients in early AD (MMSE 25) compared to age-matched healthy controls P = Baseline data from 79 AD patients Data collected at single timepoint for 93 healthy subjects matched for age, gender and country No significant differences B12 (p=0.158), Folate (p=0.309) Olde-Rikkert et al., J Alz Dis, accepted

046 Baseline data from 79 AD patients Data collected at single timepoint for 93

31 Lower levels of multiple key nutrients in early AD (MMSE 25) compared to age-matched healthy controls P = Baseline data from 79 AD patients Data collected at single timepoint for 93 healthy subjects matched for age, gender and country No significant differences B12 (p=0.158), Folate (p=0.309) Olde-Rikkert et al., J Alz Dis, accepted

MRS Study: Design & methodology Goal: A Magnetic

effects of Souvenaid on brain phospholipid

disease dementia (AD) Experimental set up: 4-week,

parallel-group, single-centre, exploratory study

32 MRS Study: Design & methodology Goal: A Magnetic Resonance Spectroscopy (MRS) study to explore the effects of Souvenaid on brain phospholipid metabolites in patients with mild Alzheimer s disease dementia (AD) Experimental set up: 4-week, randomised, controlled, double blind, parallel-group, single-centre, exploratory study in 33 drug naïve mild AD patients Rijpma et al. Neurobiol Aging (S1) S7-8

33 The Souvenaid clinical trial program amci due to AD Mild AD Moderate AD S-Connect ADAS-cog n=527 (MMSE 14-24); stable on AD drugs; US Souvenir I Souvenir II Open Label MRS study WMS-r & ADAS-cog n=225 NL, Ger, Bel, UK, US NTB + EEG n=259 NL, Ger, Bel, Fr, It, Sp Safety + Compliance + NTB 31P and 1H-MRS 30 drug-naïve, NL This project receives funding from NL STW This project receives funding from the NL Food & Nutrition Delta project, FND N This project receives funding from the NL Food & Nutrition Delta project, FND N LipiDiDiet NTB + MRI / CSF n=311(mmse 24); Ger, NL, FI, SW Funded by the EU FP7 project LipiDiDiet, Grant Agreement N FDG-PET MIND-AD FDG-PET 40 drug-naïve, NL Feasibility, tbd This project receives funding by the NL NWO-FCB This project is funding by the Joint Programming Neurodegenerative Disease Research

34 Favorable safety profile across clinical trial program Souvenaid is well tolerated High compliance across all the trials: >95% Trial Total trial n= Total AEs Control AEs Active AEs P-value SI ns SII ns S-Connect ns SII open label LDD ns AE s are consistent with that expected for elderly population with AD No SAE s considered to be related to the study product NNH values for Souvenaid are very high or not calculable, in accordance with its good safety and tolerability profile

Lower vitamin, mineral and omega/3 fatty acid nutrient folate status in folate AD: Meta-analyses n mean sd n mean sd n mean sd n mean sd n mean sd n mean study control control control AD AD AD study

35 Lower vitamin, mineral and omega/3 fatty acid nutrient folate status in folate AD: Meta-analyses n mean sd n mean sd n mean sd n mean sd n mean sd n mean study control control control AD AD AD study control control control study AD AD AD control control control AD AD Folate Agarwal ' Agarwal '10 Anello ' Agarwal ' Anello '04 Asita De Silva ' Anello 180 ' Asita De Silva '05 Cascalheira ' Asita 23 De 15.9 Silva ' Cascalheira '09 Clarke ' Cascalheira ' Clarke '98 Dominguez ' Clarke 164 ' Dominguez '05 Faux ' Dominguez ' Faux '11 Galimberti ' Faux 205 ' Galimberti '08 Galluci ' Galimberti ' Galluci '04 Hogervorst ' Galluci ' Hogervorst '02 Irizarry ' Hogervorst ' Irizarry '05 Joosten ' Irizarry ' Joosten '97 Karimi ' Joosten ' Karimi '09 Koseoglu '07 Koseoglu '07 Lelhuber ' Karimi 51 ' Koseoglu ' Lelhuber '00 Li ' Lelhuber ' Li '04 Linnebank ' Li 30' Linnebank '10 Lovati ' Linnebank ' Lovati '07 Malaguarnera ' Lovati 108 ' Malaguarnera '04 Mizrahi ' Malaguarnera ' Mizrahi '04 Morillas-Ruiz ' Mizrahi ' Morillas-Ruiz '10 Parnetti ' Morillas-Ruiz ' Parnetti '92 Postiglione ' Parnetti ' Postiglione '01 Quadri ' Postiglione ' Quadri '05 Ravaglia ' Quadri ' Ravaglia '04 Regland ' Ravaglia ' Regland '92 Religa ' Regland ' Religa '03 Selley '02 Selley '02 Serot ' Religa 99 ' Selley 27 ' Serot '01 Villa ' Serot 30 ' Villa ' Villa 20 ' Unadjusted Overall (REML, I-squared=88%, P<0.001) Unadjusted Overall (REML, I-squared=88%, P<0.001) Unadjusted Overall (REML, I-squared=88%, P<0.001) Age adjusted Overall (REML meta-regression, P<0.001) Age adjusted Overall (REML meta-regression, P<0.001) Age adjusted Overall (REML meta-regression, P<0.001) vitamin B12vitamin B12 mean weight sd n mean mean sd n mean weight mean sd weight difference (95% CI) (%) AD n mean sd n mean sd study control control difference control (95% CI) AD AD (%) AD difference (95% CI) (%) Vitamin B12 study control control control AD AD AD (-8.03, 6.61) Anello ' (-8.03, 6.61) Anello ' (-8.03, 6.61) Asita De Silva ' (-2.60, ) (-2.60, -0.20) Asita De 4.1Silva ' (-2.60, ) Basun ' (-9.24, ) Basun ' Basun ' (-9.24, ) (-9.24, 1.54) (-4.03, 0.85) Basun ' Basun ' (-4.03, ) (-4.03, 0.85) (-7.80, -2.80) Basun 3.7 ' Basun ' (-7.80, ) (-7.80, -2.80) (-16.51, -6.89) Basun 2.6 ' Basun ' (-16.51, -6.89) Basun 2.6 ' (-16.51, -6.89) Cascalheira ' (-3.12, ) (-3.12, 1.24) Cascalheira 3.8 ' (-3.12, ) Clarke ' (-13.91, ) Clarke ' Dominguez ' (-13.91, ) (-13.91, -8.47) (-6.01, 1.01) Dominguez ' Faux ' (-6.01, ) (-6.01, 1.01) (-12.99, -5.13) Faux ' Galluci ' (-12.99, ) Galluci ' (-12.99, -5.13) (-13.00, 2.40) Glaso ' (-13.00, 2.40) Glaso ' (-13.00, ) Hogervorst ' (-2.14, ) Hogervorst ' Irizarry '05`"' (-2.14, ) (-2.14, 0.78) (-4.37, 1.65) Irizarry '05`"' Joosten ' (-4.37, ) (-4.37, 1.65) (-8.28, -5.08) Joosten 4.0 ' Karimi ' (-8.28, -5.08) (-8.28, -5.08) (-8.75, 0.15) Karimi 2.8 ' Koseoglu ' (-8.75, 0.15) Koseoglu ' (-8.75, 0.15) Kristensen ' (-16.84, ) (-16.84, 0.84) Kristensen 1.4 ' (-16.84, ) Lelhuber ' (-1.08, ) Lelhuber ' Li ' (-1.08, ) (-1.08, 4.22) (-9.41, -5.31) Li ' Linnebank ' (-9.41, ) (-9.41, -5.31) (-4.60, -1.40) Linnebank 4.0 ' Malaguarnera ' (-4.60, -1.40) (-4.60, -1.40) (-1.33, 0.33) Malaguarnera 4.2 ' Mizrahi ' (-1.33, 0.33) Mizrahi 4.2 ' (-1.33, ) Morillas-Ruiz ' (-10.21, ) (-10.21, -3.77) Morillas-Ruiz 3.3 ' Nagga ' (-10.21, -3.77) (-5.11, -4.07) Nagga ' Nilsson ' (-5.11, ) (-5.11, -4.07) (-3.67, -1.93) 4.2 Nilsson ' O'Neill ' (-3.67, -1.93) (-3.67, -1.93) (-5.34, -2.06) O'Neill 4.0 ' Parnetti ' (-5.34, -2.06) Parnetti ' (-5.34, -2.06) (-8.36, -2.58) Postiglione ' (-8.36, -2.58) Postiglione 3.5 ' (-8.36, ) Quadri ' (-10.80, ) Quadri ' Ravaglia ' (-10.80, ) (-10.80, 4.20) (-0.68, 4.98) Ravaglia ' Ravaglia ' (-0.68, ) (-0.68, 4.98) (-12.79, -7.91) Ravaglia 3.7 ' Regland ' (-12.79, -7.91) (-12.79, -7.91) (-3.54, 1.46) Regland 3.7' Religa ' (-3.54, 1.46) Religa ' (-3.54, 1.46) Selley ' (-5.05, ) (-5.05, 0.53) Selley 3.5 ' (-5.05, ) Villa ' (-5.13, ) Villa ' Unadjusted Overall (REML, I-squared=87%, (-5.13, -2.64) P=0.001) (-5.13, -2.64) (-5.83, -2.84) Unadjusted Overall (REML, I-squared=87%, P=0.001) Age adjusted Overall (REML meta-regression, (-5.83, -2.84) P<0.001) (-5.83, -2.84) Age adjusted Overall (REML meta-regression, P<0.001) weight mean difference (95% CI) (%) (-49.58, 39.58) (-67.86, 51.66) ( , -9.12) (-65.54, 73.54) (-34.52, 54.52) (1.72, ) (-27.07, ) ( , ) (-42.49, 8.49) ( , ) (-22.61, 19.81) mean difference (95% CI) (-49.58, 39.58) (-67.86, 51.66) ( , -9.12) 4.00 (-65.54, 73.54) (-34.52, 54.52) (1.72, ) (-27.07, ) ( , ) (-42.49, 8.49) ( , ) (-22.61, 19.81) ( , 17.61) ( , 82.77) ( , ) (-12.78, 90.78) 0.00 (-48.08, 48.08) (-58.11, 96.49) (-86.84, ) ( , ) (-98.58, 52.96) ( , ) (-31.13, 79.13) ( , ) (-68.94, 13.74) (-89.05, ) (-70.60, 4.60) (-41.48, 35.48) (-58.08, ) 1.93 (-58.64, 62.50) ( , ) (-32.19, 26.19) (-83.50, -6.50) (-69.20, 37.20) (-56.02, 35.18) ( , ) ( , ) ( , 71.31) (-57.30, ) (-70.75, ) ( , 17.61) ( , 82.77) 1.1 Similar ( , ) results 3.1 for (-12.78, 90.78) (-48.08, 48.08) (-58.11, 96.49) 2.4 plasma levels of (-86.84, ) ( , ) (-98.58, 52.96) 2.4 vitamins ( , ) 2.3C and E, (-31.13, 79.13) ( , ) (-68.94, 13.74) & DHA (-89.05, ) (-70.60, 4.60) (-41.48, 35.48) (-58.08, ) (-58.64, 62.50) ( , ) (-32.19, 26.19) (-83.50, -6.50) (-69.20, 37.20) (-56.02, 35.18) ( , ) ( , ) ( , 71.31) (-57.30, ) (-70.75, ) AD lower AD higher AD lower AD higher AD lower AD higher AD lower AD higher AD lower AD higher 5.64 ( ); p < Unadjusted overall mean difference (95% CI) ( ); p = ( ); p < Age-adjusted overall mean difference (95% CI) ( ); p < 0.001

36 Summary and conclusions Multiple pathologies associated with AD: synapse loss early hallmark and a valid target for intervention Synapses are composed of neuronal membranes, phospholipids: possibility for nutritional intervention Patients with AD have lower blood and brain levels of key nutrients with an increased need due to accelerated synapse loss Studies of single nutrient supplementation show no benefit Dietary patterns suggests combination of nutrients may be beneficial Several studies have demonstrated that Souvenaid increases levels of key nutrients in plasma Recent evidence from MRS suggests enhanced phospholipid formation

NL-ENIGMA study: Effects of Souvenaid on brain glucose

assessed by 18F-FDG-PET imaging (absolute and relative to a

metabolism in the brain, which is an index of synaptic

Both are known to be correlated and impacted in AD

37 NL-ENIGMA study: Effects of Souvenaid on brain glucose metabolism in early Alzheimer s disease Goal: Exploring the effect of Souvenaid vs. control after 24 weeks on brain glucose metabolism as assessed by 18F-FDG-PET imaging (absolute and relative to a reference region) FDG-PET: 18 F-FDG-PET assesses glucose metabolism in the brain, which is an index of synaptic function. Both are known to be correlated and impacted in AD Population: Subjects with MCI or mild dementia due to AD, stratified for MMSE Design: Timelines: Last patient out expected in 2017 Supported by grant from NWO (Dutch government)

Decreased brain phospholipids in AD indicates

38 Decreased brain phospholipids in AD indicates disrupted membrane integrity 4. Conclusions Phospholipids provide an optimal membrane environment for protein interactions, trafficking and function. There is increasing evidence that phospholipid changes occur during pathogenic processes in Alzheimer s disease...

39 Souvenaid increases levels of the biomarker phospholipids Baseline and 24-week plasma samples from the Souvenir II study Drug-naïve patients with very mild AD Polar lipid profile 5 / 7 measured phospholipids reported by Mapstone significantly increased by Souvenaid By providing nutrients which normally rate-limit phospholipid synthesis Souvenaid can: modify a biomarker profile reflecting disturbed phospholipid metabolism be useful in asymptomatic subjects with plasma lipid biomarker profiles predictive for conversion to AD * P<0.001; Souvenaid vs. Control using ANCOVA Hartmann et al. JAD, 2014

40 Mapstone et al. identified a biomarker panel of 10 plasma lipids that can predict conversion from cognitive healthy to MCI/AD within 2 3 years with >90% accuracy Changes may reflect the breakdown of neuronal membranes Highly publicized findings set of 10 plasma lipids, including 8 phospholipids levels are lower in converters and MCI/AD subjects

41 Phase Lag Index (PLI) in delta band Normalised path length in beta band Peak frequency (Hz) Normalised clustering coefficient in beta band Network parameters suggest preserved synaptic formation, function and network 9,20 9,00 8,80 8,60 8,40 1. Peak Frequency p=0.019 Control Active 3. Brain Network Organization* 1,035 1,030 1,025 1,020 1,015 p=0.009 Control Active 8,20 0,15 0, Time (weeks) Phase Lag Index p=0.011 Control Active 1,010 0,935 0, Time (weeks) 24 p= ,925 0,13 0,920 0, Time (weeks) 24 ITT, MMRM, 2 df contrast, data are mean ±SE 0, Time (weeks) 24 Scheltens et al. J Alzheimers Dis. 2012;31: de Waal et al. Plos One 2014;9:1.

Electrical activity at the synapse EEG: Biomarker for functional connectivity 1.

Clustering & Path Length are measures of Network Organization In AD disrupted

42 Electrical activity at the synapse EEG: Biomarker for functional connectivity 1. Basic Quantitative EEG analysis - Relative power and Peak Frequency In AD disturbed signal strength 1 2. Phase Lag Index (PLI) as Functional Connectivity measure PLI In AD loss of PLI 1 3. Clustering & Path Length are measures of Network Organization In AD disrupted organization 2 Healthy AD 1 Stam CJ et al. Brain. 2009;132: Stam CJ, van Straaten ECW. Clin Neurophysiol doi: /j.clinph

43 Epidemiological evidence suggests dietary patterns can reduce AD risk Adherence to a Mediterranean diet 1,2 - higher intake of fish, vegetables, fruit and monounsaturated fats, can delay cognitive decline Evidence from these and other studies of dietary patterns suggest that nutrient combinations are more effective in reducing AD risk and improving cognitive outcome than single nutrient intervention 1 Scarmeas N, et al. Ann Neurol 2006;59: Martinez-Lapiscina EH, et al. J Neurol Neurosurg Psychiatry 2013;84:

44 Lower nutrient status in AD preceding classic protein energy malnutrition Mi et al, Nutrition, 2013, Adapted from Jack et al. Lancet Neurology, 2010

45 Mean change from baseline in NTB Memory domain z-score SOUVENIR II: SOUVENAID IMPROVES MEMORY IN PATIENTS WITH MILD AD 0,25 Significant* (p=0.023) improved memory Control 0,2 Active 0,15 0,1 0, Time (weeks) 24 Scheltens et al. J Alzheimers Dis (1):

Mean change from baseline in NTB Memory domain z-score 2011- SOUVENIR II: SOUVENAID IMPROVES MEMORY IN PATIENTS WITH MILD AD Significant*

46 Mean change from baseline in NTB Memory domain z-score SOUVENIR II: SOUVENAID IMPROVES MEMORY IN PATIENTS WITH MILD AD Significant* (p=0.023) improved memory 0,25 Control 0,2 Active 0,15 0,1 0, Time (weeks) 24 Scheltens et al. J Alzheimers Dis (1):

2011 Confirmation of improved memory performance in Mild AD (Souvenir II primary) Significant effect on NTB memory domain during 24 weeks (whole period trajectory; p=0.

47 2011 Confirmation of improved memory performance in Mild AD (Souvenir II primary) Significant effect on NTB memory domain during 24 weeks (whole period trajectory; p=0.023) Trend on NTB composite score during 24 weeks (whole period trajectory; p=0.053) Statistical analysis re-run by Rush Alzheimer s Disease Center ITT, Mixed Model for Repeated Measures (trajectory, mean ± SE) Scheltens et al, J Alzheimers Dis. 2012

48 2012- Souvenir II open label study Change between 24 an 48 weeks (paired t-tes p=0.025 active-activ p=0.008 control-acti

Nutritional intervention in early Alzheimer s disease. Sasha Newsam, PhD Global Medical Affairs Manager Nutricia

Nutritional intervention in early Alzheimer s disease Sasha Newsam, PhD Global Medical Affairs Manager Nutricia Agenda Nutrition and brain function Single nutrient intervention Diet and risk of Alzheimer