Do Apolipoprotein E Polymorphisms Influence Risk of Cognitive Decline by Modulating Omega-3 Fatty Acid Metabolism?

BACKGROUND: Compared to the epsilon 2 or epsilon 3 alleles, the epsilon 4 allele of apolipoprotein E (ApoE4) is associated with twice the prevalence of late-onset Alzheimer's disease (AD). Epidemiological studies show that risk of AD varies inversely with consumption of omega-3 fatty acids from fish and seafood. Despite apparently lower fish intake in AD, pooled analysis of the literature shows that plasma and brain docosahexaenoic acid (DHA) is actually the same in AD as in healthy age-matched controls. Fish oil trials in AD are also not convincing. We recently shown that ApoE4 carriers have 41% higher fasting plasma EPA and DHA compared to non-carriers, but the plasma EPA and DHA response to fish oil in ApoE4 carriers was half that seen in non-carriers.

HYPOTHESES: (i) Carriers of ApoE4 have altered metabolism of carbon-13 (13C)-DHA as well as EPA and DHA provided in a dietary supplement. (ii) A dietary supplement of EPA+DHA will improve cognitive performance but only in non-carriers of ApoE4.

OBJECTIVES: In both carriers and non-carriers of ApoE4, to compare whether- i) ApoE4 alters incorporation of 13C-DHA into plasma lipids or its beta-oxidation.

ii) 13C-DHA metabolism changes while on a dietary supplement of EPA+DHA; iii) Better cognitive performance occurs while on EPA+DHA and is linked to raising plasma EPA and/or DHA.

EXPERIMENTAL METHODS: Participants older than 50 y old and not demented were enrolled. DHA metabolism was evaluated using both 13C-DHA and an EPA+DHA supplement (2.4 g/d for 5 mo; n = 20/gp). Before and in the last month of supplementation, plasma uptake and beta-oxidation of 50 mg of 13C-DHA was followed during one month. Blood omega-3 fatty acids was evaluated monthly during the supplementation period. Cognitive testing was performed before and 4 months after starting the omega-3 fatty acid supplement.

IMPLICATIONS: This project will help explain the apparent link that is newly emerging between ApoE polymorphisms, altered omega-3 fatty acid metabolism and risk of cognitive decline, and should help in the development of nutraceutical-based clinical trials using fish oil for the elderly.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Dietary supplement: omega-3 fatty acid

Detailed Description

To come

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H4C4
      • Melanie Plourde

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• MCI will be defined by Winblad et al. (33), with diagnosis confirmed by a geriatrician through neuropsychological evaluation done within the last 6 months.
• if diagnosis was done more than 6 months ago, the subject will be re-evaluated before inclusion to confirm MCI rather than conversion to AD.

Exclusion Criteria:

• tobacco
• malnutrition (assessed from blood albumin, haemoglobin and lipids)
• subjects already taking an EPA+DHA supplements
• swallowing problems, uncontrolled diabetes (raised fasting glucose, haemoglobin A1c)
• uncontrolled thyroid disease
• severe renal failure
• chronic immune condition or inflammation (raised C-reactive protein, white cell count)
• cancer
• recent major surgery or cardiac event
• uncorrected visual or hearing problems
• dementia
• ongoing or past severe drug or alcohol abuse
• psychiatric difficulties or depression as evaluated by the geriatric depression scale test (34)
• use of psychotropic medications except for short-acting benzodiazepines taken before sleep.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Omega-3 fatty acid supplement; Data obtained after the intervention was compared to baseline data	Dietary supplement: omega-3 fatty acid; Subjects will be given four 1 g capsules of fish oil providing 1.4 g/d of EPA and 1.0 g/d of DHA as ethyl esters (Ocean Nutrition, Dartmouth, NS), which is similar to the dose used in previous studies with MCI and AD (20, 21).; Other Names: Ocean Nutrition, Dartmouth, NS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
13C-DHA incorporation into plasma lipids or beta-oxidation.	Before and in the last month of supplementation, plasma incorporation and beta-oxidation of 50 mg of 13C-DHA will be followed during one month. Blood and breath samples will be collected at time 0 h, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 7 d, 14 d, 21 d, and 28 d.	one month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive performance compared to baseline	Cognitive testing was done before and 4 months after starting the omega-3 fatty acid supplement.	5 month

Collaborators and Investigators

• Sponsor: Université de Sherbrooke

Publications and helpful links

General Publications

• Plourde M, Chouinard-Watkins R, Rioux-Perreault C, Fortier M, Dang MT, Allard MJ, Tremblay-Mercier J, Zhang Y, Lawrence P, Vohl MC, Perron P, Lorrain D, Brenna JT, Cunnane SC. Kinetics of 13C-DHA before and during fish-oil supplementation in healthy older individuals. Am J Clin Nutr. 2014 Jul;100(1):105-12. doi: 10.3945/ajcn.113.074708. Epub 2014 May 14.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: February 24, 2012
• First Submitted That Met QC Criteria: April 11, 2012
• First Posted (Estimate): April 13, 2012

Study Record Updates

• Last Update Posted (Estimate): April 13, 2012
• Last Update Submitted That Met QC Criteria: April 11, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction
• Other Study ID Numbers: AFMNet-1; Discovery grant (Other Grant/Funding Number: Advanced Foods and Materials Network)