Role of DHA in Cognitive Aging and Alzheimer s Disease

January 14, 2019 | Author: Phoebe McLaughlin | Category: N/A
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1 Role of DHA in Cognitive Aging and Alzheimer s Disease Michelle Keske PhD 10 November, 20082 Conflict of Interest Mart...


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

Conflict of Interest

Martek Biosciences Corporation

Microalgae versus Fish Oil Fish oil with DHA+EPA

Algal DHA Oil

Fish eat algae

Fermentation Process

Algae make DHA

Docosahexaenoic acid (DHA) • Omega-3 fatty acid • Important component of all cell membranes


• 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

22:6 3

• Important in infant visual and mental development • Maintains cardiovascular, visual and neural function throughout the lifespan

Long-chain Omega-3 Intakes

LCPUFA’s in various tissues Brain

20 15 10 5 0





Retina 20 15 10 5 0













Adipose 20

weight % total fatty acids

weight % total fatty acids

n-3 n-6


weight % total fatty acids

weight % total fatty acids


15 10 5 0





Lauritzen et al (2001) Prog Lipid Res




15 10 5



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)

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

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)

Evidence Reviews • Several evidence reviews have been conducted – – – –

AHRQ Report, 2005 Cochrane Report, 2006 ISSA, A. 2006 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.”

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

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.

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.

Pre-clinical Studies (Aged mice) • Dietary supplementation of DHA in mice (Lim et al., 2002)

– supplemented 0. 5 – 2 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)

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

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

Pre-clinical Studies (AD models) (Green, et al, Journal of Neuroscience, 2007)

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 1200



800 600




control DHA-T DHA-S DHA-T + ARA


control DHA-T DHA-S DHA-T + ARA







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

Results 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 No difference in CDR Global or CDR-SOB Benefit was reported in a post hoc analysis of subjects with MMSE>27 (n=32)

MIDAS (Memory Improvement with Docosahexaenoic Acid Study) 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 Registered on

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

Other Clinical Trials In-progress • OPAL Study -Older people and n-3 PUFAs (UK), RCT, n=798, 24 mths,700mg/d (500mgDHA, 200mgEPA), 70-79 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, 71:430-438 • Older People, Omega-3 and Cognitive Health (Australia), RCT, n=400, 18 mths, 585mg/d (450mgDHA, 135mg EPA), 65-90 yrs, ongoing • Montauban Study -Omega-3 prevention of dementia study (long-term) (France), RCT, n=1200, 3 yrs, 800mg/d, >70 yrs

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