Fatty Acid Metabolism in Carriers of Apolipoprotein E Epsilon 4 Allele: Determining the Blood-to-brain Link

Study Overview
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Brief Summary
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In Canada,  17 millions of adults between 30-64 y old could benefit from a prevention strategy to lower the risk of Alzheimer's disease (AD). Although a lot of epidemiological studies reported positive cognitive outcomes in populations eating fish, there is skepticism about the link between docosahexaenoic acid (DHA), an omega-3 (OM3) fatty acid in fish and prevention of cognitive decline. This is largely because there is a disconnect between epidemiological, molecular and animal studies which generally favor a link between higher DHA intake and cognition whereas clinical DHA and fish oil trial seem not to support such as link. There are several knowledge gaps in this field that might explain why clinical trials were not successful. This project will focus on two major gaps : OM3 fatty acid metabolism and the blood-to-brain DHA link. OM3 supplements in cardiovascular disease have faced the same issues for decades but the more recent trials have now generated the clinical evidence supporting primary and secondary cardiovascular events reduction and a better risk to benefit balance of OM3 drugs compared to statins, for instance. What if, for cognitive decline, the target was missed because the supplement/drug formulations were not appropriately designed to target the brain? The investigators hypothesize that (i) E4 carriers display a faulty packaging of circulating OM3, leading to reduced bioavailability for brain cells, (ii) The use of new OM3 formulation can direct plasma DHA into brain compartments more readily available for the brain, thereby increasing brain DHA concentrations and improving cognition. Studies in mice and humans will be performed to test OM3 metabolism and the blood-to-brain DHA link. Ultimately the information generated in this research project will help to better design clinical trials in term of fatty acid formulation, expected level to reach in the plasma and the brain.

Official Title
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Fatty Acid Metabolism in Carriers of Apolipoprotein E Epsilon 4 Allele: Determining the Blood-to-brain Link

Conditions
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Healthy

Intervention / Treatment
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* Dietary Supplement: omega-3 phospholipids
* Dietary Supplement: omega-3 Triglycerides


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Men and women aged between 30-50 years old. Exclusion Criteria: Tobacco use, Malnutrition (assessed from blood albumin, hemoglobin and lipids), Diabetes, Participants taking an EPA+DHA supplement or consuming more than 2 fish meals per week, Uncontrolled thyroid, renal and endocrine disorder disease, Chronic immune condition or inflammation (CRP > 10 mg/l, white cell count), Cancer, Recent major surgery or cardiac event, Pregnant or lactating women, Pre-menopause or menopause, Dementia, Ongoing or past severe drug or alcohol abuse, Psychiatric difficulties or major depression Ongoing or past intensive physical training.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind controlled randomized study with a parallel study design (40 men and 40 women, ApoE4 carriers and non carriers)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ApoE4 carriers<br>The results obtained for APOE4 carriers will be compared to the one obtained from APOE4 non-carriers. Carriers are defined as being at least carrier of one APOE4 allele. | Dietary Supplement: omega-3 phospholipids<br>* The intervention is a randomized double blind parallel design testing the metabolism of a krill oil omega-3 phospholipid supplement compared to fish oil omega-3 triglycerides in carriers and non-carriers of the ApoE4 allele. Half of the carriers and non-carriers will receive phospholipids and the other half will receive triglycerides. The intervention choice will be randomized and double blind. Participants will be instructed to take 4 supplements every day (2 in the morning and 2 in the evening) (4 g/ day of phospholipids), providing 1.8 g/day of omega-3 fatty acids. They will come back fasted to the research center on weeks 0, 1, 2, 3, 4, 8 and 12 of the study for blood draws. The omega-3 fatty acids metabolism will be compared between the carriers and non carriers of the ApoE4 allele.<br>Dietary Supplement: omega-3 Triglycerides<br>* The intervention is a randomized double blind parallel design testing the metabolism of a krill oil omega-3 phospholipid supplement compared to fish oil omega-3 triglycerides in carriers and non-carriers of the ApoE4 allele. Half of the carriers and non-carriers will receive phospholipids and the other half will receive triglycerides. The intervention choice will be randomized and double blind. Participants will be instructed to take 4 supplements every day (2 in the morning and 2 in the evening), providing 1.8 g/day of omega-3 fatty acids. They will come back fasted to the research center on weeks 0, 1, 2, 3, 4, 8 and 12 of the study for blood draws. The omega-3 fatty acids metabolism will be compared between the carriers and non carriers of the ApoE4 allele.<br>|
| Experimental: ApoE4 non carriers<br>The results obtained for APOE4 carriers will be compared to the one obtained from APOE4 non-carriers. Carriers are defined as being at least carrier of one APOE4 allele. | Dietary Supplement: omega-3 phospholipids<br>* The intervention is a randomized double blind parallel design testing the metabolism of a krill oil omega-3 phospholipid supplement compared to fish oil omega-3 triglycerides in carriers and non-carriers of the ApoE4 allele. Half of the carriers and non-carriers will receive phospholipids and the other half will receive triglycerides. The intervention choice will be randomized and double blind. Participants will be instructed to take 4 supplements every day (2 in the morning and 2 in the evening) (4 g/ day of phospholipids), providing 1.8 g/day of omega-3 fatty acids. They will come back fasted to the research center on weeks 0, 1, 2, 3, 4, 8 and 12 of the study for blood draws. The omega-3 fatty acids metabolism will be compared between the carriers and non carriers of the ApoE4 allele.<br>Dietary Supplement: omega-3 Triglycerides<br>* The intervention is a randomized double blind parallel design testing the metabolism of a krill oil omega-3 phospholipid supplement compared to fish oil omega-3 triglycerides in carriers and non-carriers of the ApoE4 allele. Half of the carriers and non-carriers will receive phospholipids and the other half will receive triglycerides. The intervention choice will be randomized and double blind. Participants will be instructed to take 4 supplements every day (2 in the morning and 2 in the evening), providing 1.8 g/day of omega-3 fatty acids. They will come back fasted to the research center on weeks 0, 1, 2, 3, 4, 8 and 12 of the study for blood draws. The omega-3 fatty acids metabolism will be compared between the carriers and non carriers of the ApoE4 allele.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DHA levels in LPC and FFA | To evaluate plasma DHA levels in lysophosphatidylcholine and free fatty acids by ApoE genotype and treatment intervention. | baseline, 1, 2, 3, 4, 8 and 12 weeks after baseline | 
| EPA levels in LPC and FFA | To evaluate plasma EPA levels in lysophosphatidylcholine and free fatty acids by ApoE genotype and treatment intervention. | baseline, 1, 2, 3, 4, 8 and 12 weeks after baseline |