Causal Relationships Between LC-omega-3-enriched Diet and Cognition

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:

• 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.

Inclusion criteria

• male and female subjects aged between 20-80 years old

Exclusion criteria

• tobacco use,
• malnutrition (assessed from blood albumin, hemoglobin and lipids),
• subjects taking an EPA+DHA supplement for more than one month,
• swallowing problems,
• severe gastro-intestinal problems,
• diabetes,
• uncontrolled thyroid disease,
• severe renal failure,
• liver disease or any other endocrine disorder,
• medication that would affect lipoprotein metabolism,
• chronic immune condition or inflammation (CRP > 10 mg/l, white cell count),
• cancer,
• recent major surgery or cardiac event,
• pregnant or lactating women,
• uncorrected visual or hearing problems,
• dementia,
• ongoing or past severe drug or alcohol abuse,
• psychiatric difficulties or depression, and
• ongoing or past intensive physical training