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Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 1/2016

Open Access 01-12-2016 | Research

The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease

Authors: Hussein N. Yassine, Varun Rawat, Wendy J. Mack, Joseph F. Quinn, Karin Yurko-Mauro, Eileen Bailey-Hall, Paul S. Aisen, Helena C. Chui, Lon S. Schneider

Published in: Alzheimer's Research & Therapy | Issue 1/2016

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Abstract

Background

Apolipoprotein E (APOE) ɛ4 and low cerebrospinal fluid (CSF) amyloid-β42 (Aβ42) levels are predictors for developing Alzheimer’s disease (AD). The results of several studies indicate an interaction between docosahexaenoic acid (DHA) consumption and cognitive outcomes by APOE genotype. Our objective in the present study was to examine whether APOE ɛ4 genotype and low CSF Aβ42 levels were associated with reduced delivery of DHA to CSF in the Alzheimer’s Disease Cooperative Study-sponsored DHA clinical trial.

Methods

Phospholipid DHA was assayed in the plasma of 384 participants and CSF of 70 participants at baseline. Forty-four of the 70 participants completed the 18-month follow-up visit after allocation to placebo (n = 15) or DHA (n = 29). Plasma and CSF DHA levels, CSF Aβ42, Tau, and phosphorylated Tau were measured at baseline and after the 18-month intervention. Participants were divided into tertiles based on baseline Aβ42 CSF levels. To assess DHA delivery across the blood-brain barrier, the ratio of CSF to plasma DHA levels was calculated.

Results

At baseline, there were no significant differences between CSF or plasma phospholipid DHA levels by CSF Aβ42 tertiles or ɛ4 status. After 18 months of DHA supplementation, participants at the lowest Aβ42 tertile had significantly lower CSF DHA levels (p = 0.01) and lower CSF-to-plasma DHA ratios (p = 0.05) compared to the other tertiles. Baseline CSF Aβ42 levels were significantly lower in ɛ4 carriers than in ɛ4 noncarriers (p = 0.01). Participants carrying the ɛ4 allele (n = 25) demonstrated a less pronounced increase in CSF DHA level compared with noncarriers (n = 4), with a possible interaction effect between treatment and APOE genotype (p = 0.07).

Conclusions

APOE ɛ4 allele and lower CSF Aβ42 levels were associated with less transport of DHA to CSF. Brain amyloid pathology may limit the delivery of DHA to the brain in AD.

Trial Registration

Clinicaltrials.gov identifier: NCT00440050. Registered on 22 Feb 2007.
Literature
1.
Lambert JC et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452–8.CrossRefPubMedPubMedCentral
2.
Corder EH et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3.CrossRefPubMed
3.
4.
Cunnane SC et al. Fish, docosahexaenoic acid and Alzheimer’s disease. Prog Lipid Res. 2009;48(5):239–56.CrossRefPubMed
5.
Cunnane SC et al. Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2012;29(3):691–7.PubMedPubMedCentral
6.
Söderberg M et al. Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids. 1991;26(6):421–5.CrossRefPubMed
7.
Corrigan F et al. Abnormal content of n-6 and n-3 long-chain unsaturated fatty acids in the phosphoglycerides and cholesterol esters of parahippocampal cortex from Alzheimer’s disease patients and its relationship to acetyl CoA content. Int J Biochem Cell Biol. 1998;30(2):197–207.CrossRefPubMed
8.
Prasad MR et al. Regional membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res. 1998;23(1):81–8.CrossRefPubMed
9.
Freund-Levi Y et al. ω-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD Study: a randomized double-blind trial. Arch Neurol. 2006;63(10):1402–8.CrossRefPubMed
10.
Chiu CC et al. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(6):1538–44.CrossRefPubMed
11.
Johnson EJ et al. Cognitive findings of an exploratory trial of docosahexaenoic acid and lutein supplementation in older women. Nutr Neurosci. 2008;11(2):75–83.CrossRefPubMed
12.
13.
Yurko-Mauro K et al. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010;6(6):456–64.CrossRefPubMed
14.
Vellas B et al. MAPT study: a multidomain approach for preventing Alzheimer’s disease: design and baseline data. J Prev Alzheimers Dis. 2014;1:13–22.PubMedPubMedCentral
15.
van de Rest O et al. Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology. 2008;71(6):430–8.CrossRefPubMed
16.
Daiello LA et al. Association of fish oil supplement use with preservation of brain volume and cognitive function. Alzheimers Dement. 2015;11(2):226–35.CrossRefPubMed
17.
Huang TL et al. Benefits of fatty fish on dementia risk are stronger for those without APOE ε4. Neurology. 2005;65(9):1409–14.CrossRefPubMed
18.
Whalley LJ et al. n-3 Fatty acid erythrocyte membrane content, APOE ε4, and cognitive variation: an observational follow-up study in late adulthood. Am J Clin Nutr. 2008;87(2):449–54.PubMed
19.
Bazinet RP, Layé S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci. 2014;15(12):771–85.CrossRefPubMed
20.
Vandal M et al. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2. J Neurochem. 2014;129(3):516–26.CrossRefPubMed
21.
Calon F. Omega-3 polyunsaturated fatty acids in Alzheimer’s disease: key questions and partial answers. Curr Alzheimer Res. 2011;8(5):470–8.CrossRefPubMed
22.
Freund-Levi Y et al. Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer’s disease: the OmegAD study. J Intern Med. 2014;275(4):428–36.CrossRefPubMed
23.
Kuratko CN et al. The relationship of docosahexaenoic acid (DHA) with learning and behavior in healthy children: a review. Nutrients. 2013;5(7):2777–810.CrossRefPubMedPubMedCentral
24.
Arterburn LM et al. Bioequivalence of docosahexaenoic acid from different algal oils in capsules and in a DHA-fortified food. Lipids. 2007;42(11):1011–24.CrossRefPubMed
25.
Folch J, Lees M, Sloane-Stanley G. A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem. 1957;226(1):497–509.PubMed
26.
Morrison WR, Smith LM. Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride-methanol. J Lipid Res. 1964;5(4):600–8.PubMed
27.
28.
29.
Bazan NG, Colangelo V, Lukiw WJ. Prostaglandins and other lipid mediators in Alzheimer’s disease. Prostaglandins Other Lipid Mediat. 2002;68:197–210.CrossRefPubMed
30.
Mashek DG, Coleman RA. Cellular fatty acid uptake: the contribution of metabolism. Curr Opin Lipidol. 2006;17(3):274–8.CrossRefPubMed
31.
Kuipers RS et al. Fetal intrauterine whole body linoleic, arachidonic and docosahexaenoic acid contents and accretion rates. Prostaglandins Leukot Essent Fatty Acids. 2012;86(1):13–20.CrossRefPubMed
32.
Carver JD et al. The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects. Brain Res Bull. 2001;56(2):79–85.CrossRefPubMed
33.
Purdon A et al. Energy consumption by phospholipid metabolism in mammalian brain. Neurochem Res. 2002;27(12):1641–7.CrossRefPubMed
34.
Fonteh AN et al. Human cerebrospinal fluid fatty acid levels differ between supernatant fluid and brain-derived nanoparticle fractions, and are altered in Alzheimer’s disease. PLoS One. 2014;9(6):e100519.CrossRefPubMedPubMedCentral
35.
Palop JJ et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron. 2007;55(5):697–711.CrossRefPubMed
36.
Sanchez-Mejia RO et al. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer’s disease. Nat Neurosci. 2008;11(11):1311–8.CrossRefPubMedPubMedCentral
37.
Lehtonen JY, Holopainen JM, Kinnunen PK. Activation of phospholipase A2 by amyloid β-peptides in vitro. Biochemistry. 1996;35(29):9407–14.CrossRefPubMed
38.
Rapoport SI. Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo. Prostaglandins Leukot Essent Fatty Acids. 2013;88(1):79–85.CrossRefPubMed
39.
40.
Plourde M et al. Plasma n-3 fatty acid response to an n-3 fatty acid supplement is modulated by apoE ε4 but not by the common PPAR-α L162V polymorphism in men. Br J Nutr. 2009;102(8):1121–4.CrossRefPubMed
41.
Conway V et al. Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype? Lipids Health Dis. 2014;13:148.CrossRefPubMedPubMedCentral
42.
Samieri C et al. Relationship between diet and plasma long-chain n-3 PUFAs in older people: impact of apolipoprotein E genotype. J Lipid Res. 2013;54(9):2559–67.CrossRefPubMedPubMedCentral
43.
Samieri C et al. ω-3 fatty acids and cognitive decline: modulation by ApoEε4 allele and depression. Neurobiol Aging. 2011;32(12):2317. e13–e22.CrossRefPubMed
44.
Morris MC et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60(7):940–6.CrossRefPubMed
45.
Morris MC et al. Association of seafood consumption, brain mercury level, and APOE ε4 status with brain neuropathology in older adults. JAMA. 2016;315(5):489–97.CrossRefPubMed
Metadata
Title
The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease
Authors
Hussein N. Yassine
Varun Rawat
Wendy J. Mack
Joseph F. Quinn
Karin Yurko-Mauro
Eileen Bailey-Hall
Paul S. Aisen
Helena C. Chui
Lon S. Schneider
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2016
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-016-0194-x

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