Causal Relationships Between LC-omega-3-enriched Diet and Cognition
Condition: Healthy
Study type: Interventional

Summary: 
      Nutrition is key to healthy aging for a number of diseases but the investigators have
      reported imbalances in the distribution of long chain omega-3 fatty acids (LC-omega-3) in the
      elderly and in the carriers of apolipoprotein E epsilon 4 (APOE4) isoform. Carrying APOE4
      isoform is currently recognized as being the most important genetic risk factor of cognitive
      decline. The investigators believe that dysregulation of LC-omega-3 metabolism is intimately
      link with higher risk of cognitive decline. The current project will investigate whether
      there is a causal relationship between LC-omega-3-enriched diet and cognition using, on the
      one hand, a randomized double-blind placebo-controlled design and on the other hand,
      transgenic mice carrying human APOE4. In both study, the investigators will focus
      specifically on the distribution (level) of LC-omega-3 into lipoproteins with age and/or
      APOE4 isoform to evaluate whether dysfunctional transport of LC-omega-3 is associated with
      lower cognitive scores on visuospatial capacity, verbal fluency or working memory. In APOE4
      mice, the investigators will evaluate LC-omega-3 brain uptake together with the level of
      LC-omega-3 in the brain membranes and the level of APOE protein within the brain. The present
      investigation will provide key basis for understanding how to develop nutritional strategies
      for healthy aging and the preservation of cognitive function.
    

Detailed description: 
      OVERALL AIM: In human and animal models, to investigate imbalances in the distribution of
      long chain omega-3 fatty acids (LC-omega-3) in plasma lipids and lipoproteins brought about
      by age and APOE4 genotype and to evaluate whether these imbalances are linked with cognitive
      functions. BACKGROUND: Risk of cognitive decline increases with age. Epidemiological studies
      strongly support a link between lower risk of cognitive decline and higher intake of fatty
      fish containing LC-omega-3. However, our clinical studies show that there are imbalances in
      the distribution of LC-omega-3 in plasma lipids that occur during aging and in the carriers
      of apolipoprotein E epsilon4 (APOE4) genotype, the most important genetic risk for cognitive
      decline. As a consequence, these imbalances appear to contribute to dysregulation of
      LC-omega-3 metabolism and to higher risk of cognitive decline. Our preliminary results in
      elderly humans show that visuospatial, verbal fluency and working memory scores are improved
      after 4 months supplementation with 3 g/d LC-omega-3, supporting a beneficial role of
      LC-omega-3 in cognition in the elderly. How this beneficial effect occurs is unknown but is
      potentially because the supplementation reverses or overrides imbalances in brain LC-omega-3
      uptake and tissue content occurring during aging and in APOE4 carriers. Molecular mechanisms
      will be evaluated in 4-month and 15-month old transgenic mice expressing human APOE4. OVERALL
      HYPOTHESIS: Higher LC-omega-3 levels in lipoproteins are associated with higher LC-omega-3
      brain uptake and membrane levels in APOE4 carriers leading to better cognitive scores on
      visuospatial, verbal fluency and working memory tests.

      RESEARCH PLAN: Specific questions to be addressed are:

      1) What is the role of APOE4 and blood lipoproteins on the causal relationship between a
      LC-omega-3-enriched diet and cognition? Three hundred participants aged between 20-80 y old
      will be recruited and randomized into a placebo (corn oil) or 3 g/d omega-3 fatty acid
      supplement for 6 months (150 subjects/group). LC-omega-3 use mostly VLDL and LDL to travel in
      the blood. Hence, we will collect blood samples once monthly for quantification of LC-omega-3
      levels into VLDL, LDL and HDL, with longitudinal follow-up of LC-omega-3 throughout the
      supplementation period. This will provide key information regarding differences lipoprotein
      content of LC-omega-3 over the supplementation. We will perform cognitive tests with a focus
      on visuospatial, verbal fluency and working memory in the placebo and in the LC-omega-3
      treated groups before and after the supplement. Age, sex and APOE4 genotype will be the
      interaction variables of interest. Statistical association test between cognitive scores and
      LC-omega-3 distribution in lipoproteins will also be performed to find the best LC-omega-3
      marker associated with cognition.
    

Intervention name(s): omega-3 fatty acid supplementation; corn/soybean oil placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): This study will use a randomized placebo-controlled double-blind design and the intervention period will be 6 months. Participants will be instructed to consume 4 x 1285 mg fish oil capsules/d, two capsules with each of the main daily meals. The placebo will be composed of corn/soybean oil as used in other randomized placebo-controlled trials. The daily treatment will provide 1.2 g/d of DHA and 2.4 g/d of EPA (Ocean Nutrition Canada, Dartmouth, NS). All capsules will contain citrus flavor to mask the fishy taste and odor of the LC-omega-3 oil and will be provided to the participants monthly.; This study will use a randomized placebo-controlled double-blind design and the intervention period will be 6 months. Participants will be instructed to consume 4x 1285 mg capsules/d, two capsulesat breackfast and two capsules at dinner. The placebo will be composed of corn/soybean oil as used in other randomized placebo-controlled trials.
Other intervention name(s): MEG-3; 40/20 (EPA/DHA)ethyl esters fish oil capsules; Meg-3 40:20 EPA:DHA ethyl esters
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Prevention