Role of DHA in Cognitive Aging and Alzheimer s Disease

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1 Role of DHA in Cognitive Aging and Alzheimer s Disease Michelle Keske PhD 10 November, 2008

2 Conflict of Interest Martek Biosciences Corporation

3 Microalgae versus Fish Oil Algal DHA Oil Fish oil with DHA+EPA Fermentation Process Fish eat algae Algae make DHA

4 Docosahexaenoic acid (DHA) Omega-3 fatty acid Important component of all cell membranes DHA 22:6 3 Found in all tissues; most abundant in neural and retinal tissue Brain: 97% of n-3 is DHA Retina: 93% of n-3 is DHA Important in infant visual and mental development Maintains cardiovascular, visual and neural function throughout the lifespan

5 Long-chain Omega-3 Intakes

6 weight % total fatty acids weight % total fatty acids weight % total fatty acids weight % total fatty acids LCPUFA s in various tissues Brain Retina n-3 n ALA EPA DHA LA ARA 0 ALA EPA DHA LA ARA Adipose Liver ALA EPA DHA LA ARA 0 ALA EPA DHA LA ARA Lauritzen et al (2001) Prog Lipid Res

7 DHA Distribution in the Brain DHA represents 10 to 15% of brain total fatty acids Of brain n-3 fatty acids, DHA represents 97% DHA preferentially represented in cell membranes frontal cortex executive function working memory - sustained attention, - problem solving hippocampus spatial learning declarative memory formation (ability to recall facts and events)

8 Role of DHA in Brain Structure and Function Structural Role Integrated into brain phospholipids Modulates function of signal transduction molecules, G-protein coupled receptors (e.g. rhodopsin) Functional Roles Converted to anti-inflammatory docosanoids recently, neuroprotectin D1 (protection from stroke) Serves as second messenger in synaptic signal transduction and synaptic function Neuronal differentiation Myelination Synaptogenesis

9 Human Studies on Aging and Dementia Epidemiology Risk of Dementia: Fish consumption > 1x/week or higher serum DHA, 40-60% risk reduction of dementia (Kalmijn, 1997; Barberger-Gateau, 2002, 2007; Morris, 2003; Schaefer, 2006; ) Greater proportion of RBC membrane or plasma n-3 Fatty Acids are significantly associated with lower risk of cognitive decline (Heude, 2003; Beydoun, 2007) Cognitive Performance in Elderly: Greater fish consumption better cognitive scores (Nurk, 2007); or less cognitive decline (van Gelder, 2007; Dullemeijer, 2007) Brain MRI scan: greater Omega-3 intake associated with greater grey matter volume in the anterior cingulate cortex, hippocampus and amygdala (Conklin, 2007) DHA Deficiency Brain phospholipid fatty acids are significantly reduced in AD frontal cortex & hippocampus vs. age-matched controls (Soderburg, 1991) Plasma levels n-3 fatty acids are significantly lower in AD (Conquer, 2000)

10 Evidence Reviews Several evidence reviews have been conducted AHRQ Report, 2005 Cochrane Report, 2006 ISSA, A Noel,K et al Research & Practice in Alzheimer s Disease, 2006 AHRQ Report, March 2005 states Total omega-3 fatty acid consumption and consumption of DHA (but not ALA or EPA) were associated with a significant reduction in the incidence of Alzheimer s however due to small number of studies further research is necessary before a strong conclusion can be drawn.

11 Omega-3 Centre Consensus Report Oct 08 Level of Evidence: Cognition : - Ranking +1 - Weak evidence to date, important to follow up - Dose difficult to define Dementia, Alzheimer s disease: - Ranking +1 - Weak evidence to date, important to follow up - Dose difficult to define

12 Pathology of Alzheimer s Disease Amyloid Plaques: Deposits of beta-amyloid. Plaques found in the spaces between the brain s nerve cells. Neurofibrillary Tangles: Twisted threads of a protein called tau. Tau is a protein found inside nerve cells. In AD, Tau changes so that it becomes threads wound around each other.

13 In vitro studies DHA Neuroprotective effects in aging human neural cells (Lukiw, 2005) DHA attenuates Amyloid Beta secretion biosynthesis of neuroprotectin D1 neuroprotective gene expression DHA increases neuron survival (Florent, 2006) DHA prevents neuronal apoptosis induced by soluble amyloid-β oligomers.

14 Pre-clinical Studies (Aged mice) Dietary supplementation of DHA in mice (Lim et al., 2002) supplemented g DHA / 100g diet increased brain DHA content by 4 wt. % (absolute) Improved maze-learning ability after 4 months decreased latency and reduced errors Chronic DHA (300mg/kg/d, 10 wks) decreased reference and working spatial memory errors in Aged rats (Gamoh, 2001)

15 Pre-clinical Studies (AD models) Chronic Administration of DHA in Amyloid β-infused Rats (Hashimoto, 2002; 2005) Dietary DHA (300mg/kg/d) supplementation of β-amyloid infused rats for 12 weeks DHA group had greater avoidance responses (conditioned avoidance task) vs. control or Aβ groups DHA group had reduced reference and working memory errors (8-arm radial maze) vs. control or Aβ groups

16 Pre-clinical Studies (AD models) (Calon, et al. Neuron, 2004; Lim et al. J. Neuroscience, 2005) Martek DHA supplementation of transgenic Alzheimer s mice: 70% reduction in insoluble total amyloid Beta 40% reduction in amyloid plaque burden improvement in learning and memory task

17 control DHA-T DHA-S DHA-T + ARA control DHA-T DHA-S DHA-T + ARA pg/ml (Green, et al, Journal of Neuroscience, 2007) Pre-clinical Studies (AD models) Martek DHA supplementation of triple transgenic Alzheimer s mice: significantly reduced soluble Ab (amyloid plaque precursor) reduced tau protein (neurofibrillary tangle precursor) and phosphorylated tau significantly decreased presenilin PS1 (catalytic core of γ-secretase) levels no effect on Amyloid Precursor processing Soluble Ab / 9 Months Ab40 * Ab42 Control DHA-T DHA-S DHA-T+ARA

18 Clinical Studies The OmegaAD study 204 subjects with AD and MMSE>15 Randomized to omega 3 s vs placebo Dose:1.7 g DHA and 0.6 g EPA per day Placebo-controlled for 6 months

19 In all subjects at 6 months or 12 months (open-label of omega-3s) (n=91 omega-3; n=87 placebo) No difference in ADAS-cog No difference in MMSE Results No difference in CDR Global or CDR-SOB Benefit was reported in a post hoc analysis of subjects with MMSE>27 (n=32)

20 MIDAS (Memory Improvement with Docosahexaenoic Acid Study) Registered on Goal: Evaluate the effects of Martek DHA on cognitive outcomes in healthy elderly (>55 yrs.) with a mild memory complaint (Martek-sponsored study) Trial Design: Randomized, double-blind, placebo-controlled, parallel, multi-center Oral Dose: 900 mg DHA/day or placebo (corn/soy) Study treatment: 6 mos. Sample size: 465 subjects Primary Endpoint: cognitive test of memory, attention & learning (CANTAB) Secondary Endpoints: cognitive tests of executive function, Activity of Daily Living skills, visual acuity, plasma phospholipid fatty acid levels, safety and tolerability

21 NIH trial: Effect of DHA in Alzheimer s Disease Hypothesis: DHA supplementation will slow the rate of cognitive decline in patients with mild-to-moderate Alzheimer s Disease (AD) by a combination of antioxidant, anti-amyloid, and neuroprotectant effects. Trial Design: Randomized, double-blind, placebo-controlled, parallel, multi-center study Doses: 2,000 mg DHA/day vs. placebo Study treatment: 18 months Sample size: 400 patients Sites: 50 (U.S.) ADCS centers Primary Endpoints: changes in Cognitive measures: ADAS-Cog and CDR-SOB Secondary Endpoints: biomarkers, fatty acid levels, MRI, safety measures Registered on

22 Other Clinical Trials In-progress OPAL Study -Older people and n-3 PUFAs (UK), RCT, n=798, 24 mths,700mg/d (500mgDHA, 200mgEPA), yrs old, Results projected in 2008 MEMO Study -Omega-3 and mental health in elderly (Netherlands), RCT, n=300, 6 mths, 3 arms: 400mg, 1.8 mg/d (EPA/DHA), placebo; 65+ yrs, Results recently published in Neurology, 2008, 71: Older People, Omega-3 and Cognitive Health (Australia), RCT, n=400, 18 mths, 585mg/d (450mgDHA, 135mg EPA), yrs, ongoing Montauban Study -Omega-3 prevention of dementia study (long-term) (France), RCT, n=1200, 3 yrs, 800mg/d, >70 yrs

23 Thank You

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