Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial

Isabella C Arellanes, Nicholas Choe, Victoria Solomon, Xulei He, Brian Kavin, Ashley E Martinez, Naoko Kono, David P Buennagel, Nalini Hazra, Giselle Kim, Lina M D'Orazio, Carol McCleary, Abhay Sagare, Berislav V Zlokovic, Howard N Hodis, Wendy J Mack, Helena C Chui, Michael G Harrington, Meredith N Braskie, Lon S Schneider, Hussein N Yassine, Isabella C Arellanes, Nicholas Choe, Victoria Solomon, Xulei He, Brian Kavin, Ashley E Martinez, Naoko Kono, David P Buennagel, Nalini Hazra, Giselle Kim, Lina M D'Orazio, Carol McCleary, Abhay Sagare, Berislav V Zlokovic, Howard N Hodis, Wendy J Mack, Helena C Chui, Michael G Harrington, Meredith N Braskie, Lon S Schneider, Hussein N Yassine

Abstract

Background: Past clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment.

Methods: 33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition.

Findings: A 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups.

Interpretation: Dementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers.

Trial registration: NCT02541929.

Funding: HNY was supported by R01AG055770, R01AG054434, R01AG067063 from the National Institute of Aging and NIRG-15-361854 from the Alzheimer's Association, and MGH by the L. K. Whittier Foundation. This work was also supported by P50AG05142 (HCC) from the National Institutes of Health. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Keywords: APOE; Alzheimer's disease; DHA; Dementia; Omega-3; RCT.

Conflict of interest statement

Declaration of Competing Interest The authors have no conflict of interest.

Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Consort diagram. From 117 participants screened for eligibility, 33 were randomized into placebo (n = 15, APOE4=7, non-APOE4=8) and DHA (n = 18, APOE4=8, non-APOE4=10) treatment arms.
Fig. 2
Fig. 2
Comparison of post-intervention difference in CSF DHA and EPA levels at baseline and 6-months based on treatment arm and APOE4 status. Comparison of a) change in CSF DHA between DHA and placebo treatments arms separated by APOE4 status, b) change in CSF EPA between treatment arms separated by APOE4 status, c) change in plasma DHA between treatments arms separated by APOE4 status, and d) change in plasma EPA between treatment arms separated by APOE4 status, e) mean DHA% change compared to baseline in CSF and plasma, f) mean% change in EPA compared to baseline in CSF and plasma. The p values were derived from a linear model ANCOVA.

References

    1. Zhang Y., Chen J., Qiu J., Li Y., Wang J., Jiao J. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. Am J Clin Nutr. 2016;103(2):330–340.
    1. Yassine H.N., Feng Q., Azizkhanian I., Rawat V., Castor K., Fonteh A.N. Association of serum docosahexaenoic acid with cerebral amyloidosis. JAMA Neurol. 2016;73(10):1208–1216.
    1. Calon F.L., GP, Yang F., Morihara T., Teter B., Ubeda O., Rostaing P., Triller A., Salem N., Jr., Ashe K.H., Frautschy S.A., Cole G.M. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 2004;43(5):633–645.
    1. Bouwens MvdR O., Dellschaft N., Bromhaar M.G., de Groot L.C., Geleijnse J.M., Muller M., Afman L.A. Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells. Am J Clin Nutr. 2009;90:415–424.
    1. Hooijmans C., Rutters F., Dederen P., Gambarota G., Veltien A., Van Groen T. Changes in cerebral blood volume and amyloid pathology in aged Alzheimer APP/PS1 mice on a docosahexaenoic acid (DHA) diet or cholesterol enriched Typical Western Diet (TWD) Neurobiol Dis. 2007;28(1):16–29.
    1. de Magalhães J., Muller M., Rainger G.Ed., Steegenga W. Fish oil supplements, longevity, and aging. Aging. 2016;8(8):1578–1582.
    1. Swanson D., R. Block, Mousa S.A. Omega-3 fatty acids EPA and DHA: health benefits throughout life. Adv Nutr. 2012;3(1):1–7.
    1. Funk C. Prostaglandins and leukotrienes advances in eicosanoid biology. Science. 2001;294(5548):1871–1875.
    1. Thomas J., Thomas C., Radcliffe J., Itsiopoulos C. Omega-3 fatty acids in early prevention of inflammatory neurodegenerative disease: a focus on Alzheimer's disease. Biomed Res Int. 2015;2015:172801.
    1. Itakura H., Yokoyama M., Matsuzaki M., Saito Y., Origasa H., Ishikawa Y. Relationships between plasma fatty acid composition and coronary artery disease. J Atheroscler Thromb. 2011;18(2):99–107.
    1. Yassine H.N., Braskie M.N., Mack W.J., Castor K.J., Fonteh A.N., Schneider L.S. Association of docosahexaenoic acid supplementation with alzheimer disease stage in apolipoprotein E epsilon4 carriers: a review. JAMA Neurol. 2017
    1. Sydenham E., Dangour A.D., Lim W.S. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev. 2013 doi: 10.1002/14651858.CD005379.pub3.
    1. Yi D., Lee Y., Byun M.S., Lee J.H., Ko K., Sohn B.K. Synergistic interaction between APOE and family history of Alzheimer's disease on cerebral amyloid deposition and glucose metabolism. Alzheimers Res Ther. 2018;10(1):84.
    1. Head D., Bugg J.M., Goate A.M., Fagan A.M., Mintun M.A., Benzinger T. Exercise engagement as a moderator of the effects of APOE genotype on amyloid deposition. Arch Neurol. 2012;69(5):636–643.
    1. Chouinard-Watkins R., Rioux-Perreault C., Fortier M., Tremblay-Mercier J., Zhang Y., Lawrence P. Disturbance in uniformly 13C-labelled DHA metabolism in elderly human subjects carrying the apoE epsilon4 allele. Br J Nutr. 2013;110(10):1751–1759.
    1. Chouinard-Watkins R., Plourde M. Fatty acid metabolism in carriers of apolipoprotein E epsilon 4 allele: is it contributing to higher risk of cognitive decline and coronary heart disease? Nutrients. 2014;6(10):4452–4471.
    1. Yassine H.N., Croteau E., Rawat V., Hibbeln J.R., Rapoport S.I., Cunnane S.C. DHA brain uptake and APOE4 status: a PET study with [1-11 C]-DHA. Alzheimers Res Ther. 2017;9(1):23.
    1. Freund Levi Y., Vedin I., Cederholm T., Basun H., Faxen Irving G., Eriksdotter M. 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):428–436.
    1. Khot V., Kale A., Joshi A., Chavan-Gautam P., Joshi S. Expression of genes encoding enzymes involved in the one carbon cycle in rat placenta is determined by maternal micronutrients (folic acid, vitamin B12) and omega-3 fatty acids. Biomed Res Int. 2014;2014
    1. Albert M.S., DeKosky S.T., Dickson D., Dubois B., Feldman H.H., Fox N.C. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's Dement: J Alzheimer's Assoc. 2011;7(3):270–279.
    1. Jimenez E.Y., Mangani C., Ashorn P., Harris W.S., Maleta K., Dewey K.G. Breast milk from women living near Lake Malawi is high in docosahexaenoic acid and arachidonic acid. Prostaglandins Leukot Essent Fatty Acids. 2015;95:71–78.
    1. Rawat V., Wang S., Sima J., Bar R., Liraz O., Gundimeda U. ApoE4 alters ABCA1 membrane trafficking in astrocytes. J Neurosci. 2019;39(48):9611–9622.
    1. Nation D.A., Sweeney M.D., Montagne A., Sagare A.P., D'Orazio L.M., Pachicano M. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270–276.
    1. Yassine H.N., Rawat V., Mack W.J., Quinn J.F., Yurko-Mauro K., Bailey-Hall E. The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer's disease. Alzheimers Res Ther. 2016;8(1):25.
    1. Bazinet R.P., Metherel A.H., Chen C.T., Shaikh S.R., Nadjar A., Joffre C. Brain eicosapentaenoic acid metabolism as a lead for novel therapeutics in major depression. Brain Behav Immun. 2020;85:21–28.
    1. Dyall S.C. Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Front Aging Neurosci. 2015;7:52.
    1. Dong Y., Pu K., Duan W., Chen H., Chen L., Wang Y. Involvement of Akt/CREB signaling pathways in the protective effect of EPA against interleukin-1β-induced cytotoxicity and BDNF down-regulation in cultured rat hippocampal neurons. BMC Neurosci. 2018;19(1):52.
    1. Kohli P., Levy B.D. Resolvins and protectins: mediating solutions to inflammation. Br J Pharmacol. 2009;158(4):960–971.
    1. Tassoni D., Kaur G., Weisinger R.S., Sinclair A.J. The role of eicosanoids in the brain. Asia Pac J Clin Nutr. 2008;17(Suppl 1):220–228.
    1. Tao Q., Ang T.F.A., DeCarli C., Auerbach S.H., Devine S., Stein T.D. Association of chronic low-grade inflammation with risk of Alzheimer Disease in ApoE4 carriers. JAMA Netw Open. 2018;1(6)
    1. Arterburn L., Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am. J. Clin. Nutr. 2006;83(6 Suppl):1467S–1476S.
    1. Umhau J.C., Zhou W., Carson R.E., Rapoport S.I., Polozova A., Demar J. Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography. J Lipid Res. 2009;50(7):1259–1268.
    1. Yassine H.N., Rawat V, Mack W.J., Quinn J.F., Yurko-Mauro K., Bailey-Hall E., Aisen P.S., Chui H.C., Schneider L.S. The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer's disease. Alzheimer's Rea Therapy. 2016;8:25.
    1. Jernerén F., Elshorbagy A.K., Oulhaj A., Smith S.M., Refsum H., Smith A.D. Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr. 2015;102(1):215–221.
    1. Jernerén F., Cederholm T., Refsum H., Smith A.D., Turner C., Palmblad J. Homocysteine status modifies the treatment effect of omega-3 fatty acids on cognition in a randomized clinical trial in mild to moderate Alzheimer's disease: the OmegAD study. J Alzheimers Dis. 2019;69(1):189–197.
    1. Flock M.R., Skulas-Ray A.C., Harris W.S., Etherton T.D., Fleming J.A., Kris-Etherton P.M. Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial. J Am Heart Assoc. 2013;2(6)
    1. Bhatt D.L., Steg P.G., Miller M., Brinton E.A., Jacobson T.A., Ketchum S.B. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22.
    1. Bhatt D.L., Steg P.G., Brinton E.A., Jacobson T.A., Miller M., Tardif J.C. Rationale and design of REDUCE-IT: reduction of cardiovascular events with icosapent ethyl-intervention trial. Clin Cardiol. 2017;40(3):138–148.
    1. Andrieu S., Guyonnet S., Coley N., Cantet C., Bonnefoy M., Bordes S. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 2017;16(5):377–389.
    1. Cukierman-Yaffe T., Bosch J., Diaz R., Dyal L., Hancu N., Hildebrandt P., et al. Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. Lancet Diabetes Endocrinol 2014;2(7):562–72.
    1. Manson J.E., Cook N.R., Lee I.-.M., Christen W., Bassuk S.S., Mora S. Marine n−3 fatty acids and prevention of cardiovascular disease and cancer. N Engl J Med. 2018;380(1):23–32.
    1. Chocano-Bedoya P.O., Bischoff-Ferrari H.A. DO-HEALTH: vitamin D3-omega-3-home exercise-healthy aging and longevity trial—dietary patterns in five European countries. In: Weaver CM, Bischoff-Ferrari H, Daly RM, Wong M-S, editors. Proceedings of the 10th international symposium on nutritional influences on bone health. Springer International Publishing; Cham: 2019. pp. 3–10.
    1. Sydenham E., Dangour A.D., Lim W.-.S. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Sao Paulo Med J. 2012;130(6):419.
    1. Yurko-Mauro K., Alexander D.D., Van Elswyk M.E. Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One. 2015;10(3)
    1. Eriksdotter M., Vedin I., Falahati F., Freund-Levi Y., Hjorth E., Faxen-Irving G. Plasma fatty acid profiles in relation to cognition and gender in Alzheimer's disease patients during oral omega-3 fatty acid supplementation: the OmegAD study. J Alzheimers Dis. 2015;48(3):805–812.
    1. Soininen H., Solomon A., Visser P.J., Hendrix S.B., Blennow K., Kivipelto M., et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial. Lancet Neurol 2017;16(12):965–75.
    1. Hooijmans C.R., Pasker-de Jong P., de Vries R., Ritskes-Hoitinga M. The effects of long-term omega-3 fatty acid supplementation on cognition and Alzheimer's pathology in animal models of Alzheimer's disease: a systematic review and meta-analysis. J Alzheimer's Dis. 2012;28(1):191–209.
    1. Schuchardt J.P., Hahn A. Bioavailability of long-chain omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids. 2013;89(1):1–8.
    1. Liu L., Bartke N., Van Daele H., Lawrence P., Qin X., Park H.G. Higher efficacy of dietary DHA provided as a phospholipid than as a triglyceride for brain DHA accretion in neonatal piglets. J Lipid Res. 2014;55(3):531–539.
    1. Liu J.J., Green P., John Mann J., Rapoport S.I., Sublette M.E. Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease. Brain Res. 2015;1597:220–246.
    1. Nguyen L.N., Ma D., Shui G., Wong P., Cazenave-Gassiot A., Zhang X. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. 2014;509(7501):503–506.
    1. Patrick R.P. Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease. Faseb J. 2019;33(2):1554–1564.
    1. Metherel A.H., Chouinard-Watkins R., Trépanier M.-.O., Lacombe R.J.S., Bazinet R.P. Retroconversion is a minor contributor to increases in eicosapentaenoic acid following docosahexaenoic acid feeding as determined by compound specific isotope analysis in rat liver. Nutr Metab. 2017;14:75.
    1. Conquer J.A., Holub B.J. Dietary docosahexaenoic acid as a source of eicosapentaenoic acid in vegetarians and omnivores. Lipids. 1997;32(3):341–345.
    1. Grønn M., Christensen E., Hagve T.-.A., Christophersen B.O. Peroxisomal retroconversion of docosahexaenoic acid (22:6(n−3)) to eicosapentaenoic acid (20:5(n−3)) studied in isolated rat liver cells. Biochim Biophys Acta (BBA) – Lipids Lipid Metab. 1991;1081(1):85–91.
    1. Champeil-Potokar G., Hennebelle M., Latour A., Vancassel S., Denis I. Docosahexaenoic acid (DHA) prevents corticosterone-induced changes in astrocyte morphology and function. J Neurochem. 2016;136(6):1155–1167.
    1. Chouinard-Watkins R., Plourde M. Fatty acid metabolism in carriers of apolipoprotein E epsilon 4 allele: is it contributing to higher risk of cognitive decline and coronary heart disease? Nutrients. 2014;6(10):4452–4471.
    1. Fanelli F., Sepe S., D'Amelio M., Bernardi C., Cristiano L., Cimini A. Age-dependent roles of peroxisomes in the hippocampus of a transgenic mouse model of Alzheimer's disease. Mol Neurodegener. 2013;8(1):8.
    1. Yassine H.N., FQ, Azizkhanian I., Rawat V., Castor K., Fonteh A.N., Harrington M.G., Zheng L., Reed B.R., DeCarli C., Jagust W.J., Chui H.C. Association of serum docosahexaenoic acid with cerebral amyloidosis. JAMA Neurol. 2016;73(10):1208–1216.
    1. Eckert G.P., Chang S., Eckmann J., Copanaki E., Hagl S., Hener U. Liposome-incorporated DHA increases neuronal survival by enhancing non-amyloidogenic APP processing. Biochim Biophys Acta. 2011;1808(1):236–243.
    1. Grimm M.O., Kuchenbecker J., Grösgen S., Burg V.K., Hundsdörfer B., Rothhaar T.L. Docosahexaenoic acid reduces amyloid beta production via multiple pleiotropic mechanisms. J Biol Chem. 2011;286(16):14028–14039.

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