This is a very nice new paper from Yassine et al. revealing significant associations between low serum docosahexaenoic acid (DHA) concentrations and (i) brain amyloid load (PiB PET), (ii) smaller brain volume (MRI), and (iii) impaired nonverbal memory in volunteers with no or mild cognitive impairment recruited in the Aging Brain Study.
The unique value of this study stems in great part from the scarcity of published evaluations of the effect of omega-3 fatty acids on brain pathology. Most such evidence comes from preclinical studies (Joffre et al., 2014; Calon, 2011), as decreases in brain Aβ levels after DHA treatment in APP transgenic mice have been reported by at least four groups (Lim et al., 2005; Oksman et al., 2006; Hooijmans et al., 2009; Perez et al., 2010) and in the 3xTg-AD model, albeit to a lesser extent, by two others (Green et al., 2007; Arsenault et al., 2011). No comparable clinical evidence is available. To my knowledge, only one small intervention study has reported decreased gray-matter volume after treatment with a DHA/EPA combo (Witte et al., 2013).
The association between high blood DHA levels and higher memory performance is also interesting, but this information supplements a more numerous literature well-reviewed in Table 3 by the authors. It also agrees well with novel results presented by Cornelia van Duijn at the AAIC in Toronto, who reported that blood DHA was significantly associated with better general cognitive ability in two large population-based studies, totaling more than 5000 individuals.
APOE ε4 carriage appears to strongly influence the response to DHA as suggested by data from randomized controlled trials (Quinn et al., 2009, #31101), epidemiological analysis (Samieri et al., 2011; Barberger-Gateau et al., 2007), CSF measurements (Yassine et al., 2016), and DHA brain transport studies in animal models (Vandal et al., 2014; Salem et al., 2015). However, although the strongest associations shown by Yassine et al. were independent of APOE genotype, the number of APOE ε4 carriers included in their study was probably too limited to draw definitive conclusions.
DHA can be found in different blood components, most being bound to carriers such as albumin and/or in esterified forms (cholesteryl esters, phospholipids and triacylglycerides). Here, the authors have based their analysis on total serum DHA expressed as a percentage of the total fatty acid drawn and extracted after a fasting period, thereby excluding DHA molecules incorporated in erythrocyte membranes. This pool of DHA is possibly more readily accessible for brain tissue (Chen et al., 2015), but erythrocyte content might better reflect long-term dietary intake (Sun et al., 2007). Thus, DHA from erythrocyte membranes and serum DHA expressed as absolute values or obtained in different experimental conditions might give different results. One must also consider that serum DHA levels result from the balance between dietary intake, metabolism, and exchange rate with tissue, and thus may not simply reflect brain concentrations (Vandal et al., 2014; Salem et al., 2015).
As mentioned in the editorial from Dr. Quinn, we must avoid drawing conclusions on possible causative links from such a cross-sectional study. Nevertheless, this paper provides new key information, which, combined with various previous evidence, will hopefully bring a resurgence of interest in the therapeutic potential of omega-3 fatty acids in the AD research field.
References:
Arsenault D, Julien C, Tremblay C, Calon F.
DHA improves cognition and prevents dysfunction of entorhinal cortex neurons in 3xTg-AD mice.
PLoS One. 2011 Feb 23;6(2):e17397.
PubMed.
Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alpérovitch A.
Dietary patterns and risk of dementia: the Three-City cohort study.
Neurology. 2007 Nov 13;69(20):1921-30.
PubMed.
Calon F.
Omega-3 polyunsaturated fatty acids in Alzheimer's disease: key questions and partial answers.
Curr Alzheimer Res. 2011 Aug;8(5):470-8.
PubMed.
Chen CT, Kitson AP, Hopperton KE, Domenichiello AF, Trépanier MO, Lin LE, Ermini L, Post M, Thies F, Bazinet RP.
Plasma non-esterified docosahexaenoic acid is the major pool supplying the brain.
Sci Rep. 2015 Oct 29;5:15791.
PubMed.
Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko-Mauro KA, Ellis L, LaFerla FM.
Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels.
J Neurosci. 2007 Apr 18;27(16):4385-95.
PubMed.
Hooijmans CR, Van der Zee CE, Dederen PJ, Brouwer KM, Reijmer YD, van Groen T, Broersen LM, Lütjohann D, Heerschap A, Kiliaan AJ.
DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice.
Neurobiol Dis. 2009 Mar;33(3):482-98. Epub 2008 Dec 16
PubMed.
Joffre C, Nadjar A, Lebbadi M, Calon F, Laye S.
n-3 LCPUFA improves cognition: the young, the old and the sick.
Prostaglandins Leukot Essent Fatty Acids. 2014 Jul-Aug;91(1-2):1-20. Epub 2014 May 14
PubMed.
Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM.
A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model.
J Neurosci. 2005 Mar 23;25(12):3032-40.
PubMed.
Oksman M, Iivonen H, Hogyes E, Amtul Z, Penke B, Leenders I, Broersen L, Lütjohann D, Hartmann T, Tanila H.
Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on beta-amyloid accumulation in APP/PS1 transgenic mice.
Neurobiol Dis. 2006 Sep;23(3):563-72. Epub 2006 Jun 12
PubMed.
Perez SE, Berg BM, Moore KA, He B, Counts SE, Fritz JJ, Hu YS, Lazarov O, Lah JJ, Mufson EJ.
DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects.
J Neurosci Res. 2010 Apr;88(5):1026-40.
PubMed.
Salem N Jr, Vandal M, Calon F.
The benefit of docosahexaenoic acid for the adult brain in aging and dementia.
Prostaglandins Leukot Essent Fatty Acids. 2015 Jan;92:15-22. Epub 2014 Oct 24
PubMed.
Samieri C, Féart C, Proust-Lima C, Peuchant E, Dartigues JF, Amieva H, Barberger-Gateau P.
ω-3 fatty acids and cognitive decline: modulation by ApoEε4 allele and depression.
Neurobiol Aging. 2011 Dec;32(12):2317.e13-22. Epub 2010 Jun 8
PubMed.
Sun Q, Ma J, Campos H, Hankinson SE, Hu FB.
Comparison between plasma and erythrocyte fatty acid content as biomarkers of fatty acid intake in US women.
Am J Clin Nutr. 2007 Jul;86(1):74-81.
PubMed.
Vandal M, Alata W, Tremblay C, Rioux-Perreault C, Salem N Jr, Calon F, Plourde M.
Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2.
J Neurochem. 2014 May;129(3):516-26. Epub 2014 Jan 29
PubMed.
Witte AV, Kerti L, Hermannstädter HM, Fiebach JB, Schreiber SJ, Schuchardt JP, Hahn A, Flöel A.
Long-chain omega-3 fatty acids improve brain function and structure in older adults.
Cereb Cortex. 2014 Nov;24(11):3059-68. Epub 2013 Jun 24
PubMed.
Yassine HN, Rawat V, Mack WJ, Quinn JF, Yurko-Mauro K, Bailey-Hall E, Aisen PS, Chui HC, Schneider LS.
The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer's disease.
Alzheimers Res Ther. 2016 Jun 30;8:25.
PubMed.
Hussein N. Yassine et al. report an association between greater serum DHA levels and less cerebral amyloidosis as well as higher volumes of several subregions of the brain affected in AD in cognitively healthy older adults. These data underline MAPT data where we observed that older participants at the lowest quartile of red blood cell (RBC) DHA/EPA have a three-year cognitive decline similar to those with CDR 0.5/early MCI no while those with DHA in the other quartiles had no decline (paper in review, presented at the CTAD). Moreover, in the MAPT trial, as cited in the Yassine paper, we observed cognitive benefit on the CDR-SB in participants at the lowest quartile of red blood cell DHA who received 800 mg/day of DHA supplementation over three years. Dr Yassine’s results and our MAPT results build a good rational for the LO MAPT Trial (Low Omega 3 Alzheimer Preventive Trial). The primary objective of LO MAPT is to demonstrate the efficacy of an 18-month intervention with a supplementation of omega-3s (DHA+EPA) on cognitive decline as measured by a composite score of neuropsychological assessments in older adults with low DHA/EPA status (RBC DHA/EPA index ≤ 4.83 percent) and subjective memory complaints or a family history of Alzheimer’s disease. Recruitment (N=400) will start before the end of 2016. LO MAPT is funded by the Toulouse Gerontpopole, French Ministry of HEALTH PHRC with additional funding by the Alzheimer’s Association (Chicago) and the Alzheimer’s Drug Discovery Foundation. The products and placebo are provided by DSM, Switzerland. Results are expected late 2020. DHA is an alternative to current anti-amyloid drug development and must definitively be evaluated in a targeted trial.
Comments
Laval University Research Center
This is a very nice new paper from Yassine et al. revealing significant associations between low serum docosahexaenoic acid (DHA) concentrations and (i) brain amyloid load (PiB PET), (ii) smaller brain volume (MRI), and (iii) impaired nonverbal memory in volunteers with no or mild cognitive impairment recruited in the Aging Brain Study.
The unique value of this study stems in great part from the scarcity of published evaluations of the effect of omega-3 fatty acids on brain pathology. Most such evidence comes from preclinical studies (Joffre et al., 2014; Calon, 2011), as decreases in brain Aβ levels after DHA treatment in APP transgenic mice have been reported by at least four groups (Lim et al., 2005; Oksman et al., 2006; Hooijmans et al., 2009; Perez et al., 2010) and in the 3xTg-AD model, albeit to a lesser extent, by two others (Green et al., 2007; Arsenault et al., 2011). No comparable clinical evidence is available. To my knowledge, only one small intervention study has reported decreased gray-matter volume after treatment with a DHA/EPA combo (Witte et al., 2013).
The association between high blood DHA levels and higher memory performance is also interesting, but this information supplements a more numerous literature well-reviewed in Table 3 by the authors. It also agrees well with novel results presented by Cornelia van Duijn at the AAIC in Toronto, who reported that blood DHA was significantly associated with better general cognitive ability in two large population-based studies, totaling more than 5000 individuals.
APOE ε4 carriage appears to strongly influence the response to DHA as suggested by data from randomized controlled trials (Quinn et al., 2009, #31101), epidemiological analysis (Samieri et al., 2011; Barberger-Gateau et al., 2007), CSF measurements (Yassine et al., 2016), and DHA brain transport studies in animal models (Vandal et al., 2014; Salem et al., 2015). However, although the strongest associations shown by Yassine et al. were independent of APOE genotype, the number of APOE ε4 carriers included in their study was probably too limited to draw definitive conclusions.
DHA can be found in different blood components, most being bound to carriers such as albumin and/or in esterified forms (cholesteryl esters, phospholipids and triacylglycerides). Here, the authors have based their analysis on total serum DHA expressed as a percentage of the total fatty acid drawn and extracted after a fasting period, thereby excluding DHA molecules incorporated in erythrocyte membranes. This pool of DHA is possibly more readily accessible for brain tissue (Chen et al., 2015), but erythrocyte content might better reflect long-term dietary intake (Sun et al., 2007). Thus, DHA from erythrocyte membranes and serum DHA expressed as absolute values or obtained in different experimental conditions might give different results. One must also consider that serum DHA levels result from the balance between dietary intake, metabolism, and exchange rate with tissue, and thus may not simply reflect brain concentrations (Vandal et al., 2014; Salem et al., 2015).
As mentioned in the editorial from Dr. Quinn, we must avoid drawing conclusions on possible causative links from such a cross-sectional study. Nevertheless, this paper provides new key information, which, combined with various previous evidence, will hopefully bring a resurgence of interest in the therapeutic potential of omega-3 fatty acids in the AD research field.
References:
Arsenault D, Julien C, Tremblay C, Calon F. DHA improves cognition and prevents dysfunction of entorhinal cortex neurons in 3xTg-AD mice. PLoS One. 2011 Feb 23;6(2):e17397. PubMed.
Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alpérovitch A. Dietary patterns and risk of dementia: the Three-City cohort study. Neurology. 2007 Nov 13;69(20):1921-30. PubMed.
Calon F. Omega-3 polyunsaturated fatty acids in Alzheimer's disease: key questions and partial answers. Curr Alzheimer Res. 2011 Aug;8(5):470-8. PubMed.
Chen CT, Kitson AP, Hopperton KE, Domenichiello AF, Trépanier MO, Lin LE, Ermini L, Post M, Thies F, Bazinet RP. Plasma non-esterified docosahexaenoic acid is the major pool supplying the brain. Sci Rep. 2015 Oct 29;5:15791. PubMed.
Green KN, Martinez-Coria H, Khashwji H, Hall EB, Yurko-Mauro KA, Ellis L, LaFerla FM. Dietary docosahexaenoic acid and docosapentaenoic acid ameliorate amyloid-beta and tau pathology via a mechanism involving presenilin 1 levels. J Neurosci. 2007 Apr 18;27(16):4385-95. PubMed.
Hooijmans CR, Van der Zee CE, Dederen PJ, Brouwer KM, Reijmer YD, van Groen T, Broersen LM, Lütjohann D, Heerschap A, Kiliaan AJ. DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APPswe/PS1dE9 mice. Neurobiol Dis. 2009 Mar;33(3):482-98. Epub 2008 Dec 16 PubMed.
Joffre C, Nadjar A, Lebbadi M, Calon F, Laye S. n-3 LCPUFA improves cognition: the young, the old and the sick. Prostaglandins Leukot Essent Fatty Acids. 2014 Jul-Aug;91(1-2):1-20. Epub 2014 May 14 PubMed.
Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N Jr, Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005 Mar 23;25(12):3032-40. PubMed.
Oksman M, Iivonen H, Hogyes E, Amtul Z, Penke B, Leenders I, Broersen L, Lütjohann D, Hartmann T, Tanila H. Impact of different saturated fatty acid, polyunsaturated fatty acid and cholesterol containing diets on beta-amyloid accumulation in APP/PS1 transgenic mice. Neurobiol Dis. 2006 Sep;23(3):563-72. Epub 2006 Jun 12 PubMed.
Perez SE, Berg BM, Moore KA, He B, Counts SE, Fritz JJ, Hu YS, Lazarov O, Lah JJ, Mufson EJ. DHA diet reduces AD pathology in young APPswe/PS1 Delta E9 transgenic mice: possible gender effects. J Neurosci Res. 2010 Apr;88(5):1026-40. PubMed.
Salem N Jr, Vandal M, Calon F. The benefit of docosahexaenoic acid for the adult brain in aging and dementia. Prostaglandins Leukot Essent Fatty Acids. 2015 Jan;92:15-22. Epub 2014 Oct 24 PubMed.
Samieri C, Féart C, Proust-Lima C, Peuchant E, Dartigues JF, Amieva H, Barberger-Gateau P. ω-3 fatty acids and cognitive decline: modulation by ApoEε4 allele and depression. Neurobiol Aging. 2011 Dec;32(12):2317.e13-22. Epub 2010 Jun 8 PubMed.
Sun Q, Ma J, Campos H, Hankinson SE, Hu FB. Comparison between plasma and erythrocyte fatty acid content as biomarkers of fatty acid intake in US women. Am J Clin Nutr. 2007 Jul;86(1):74-81. PubMed.
Vandal M, Alata W, Tremblay C, Rioux-Perreault C, Salem N Jr, Calon F, Plourde M. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2. J Neurochem. 2014 May;129(3):516-26. Epub 2014 Jan 29 PubMed.
Witte AV, Kerti L, Hermannstädter HM, Fiebach JB, Schreiber SJ, Schuchardt JP, Hahn A, Flöel A. Long-chain omega-3 fatty acids improve brain function and structure in older adults. Cereb Cortex. 2014 Nov;24(11):3059-68. Epub 2013 Jun 24 PubMed.
Yassine HN, Rawat V, Mack WJ, Quinn JF, Yurko-Mauro K, Bailey-Hall E, Aisen PS, Chui HC, Schneider LS. The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer's disease. Alzheimers Res Ther. 2016 Jun 30;8:25. PubMed.
View all comments by Frederic CalonUniversity of Toulouse
Hussein N. Yassine et al. report an association between greater serum DHA levels and less cerebral amyloidosis as well as higher volumes of several subregions of the brain affected in AD in cognitively healthy older adults. These data underline MAPT data where we observed that older participants at the lowest quartile of red blood cell (RBC) DHA/EPA have a three-year cognitive decline similar to those with CDR 0.5/early MCI no while those with DHA in the other quartiles had no decline (paper in review, presented at the CTAD). Moreover, in the MAPT trial, as cited in the Yassine paper, we observed cognitive benefit on the CDR-SB in participants at the lowest quartile of red blood cell DHA who received 800 mg/day of DHA supplementation over three years. Dr Yassine’s results and our MAPT results build a good rational for the LO MAPT Trial (Low Omega 3 Alzheimer Preventive Trial). The primary objective of LO MAPT is to demonstrate the efficacy of an 18-month intervention with a supplementation of omega-3s (DHA+EPA) on cognitive decline as measured by a composite score of neuropsychological assessments in older adults with low DHA/EPA status (RBC DHA/EPA index ≤ 4.83 percent) and subjective memory complaints or a family history of Alzheimer’s disease. Recruitment (N=400) will start before the end of 2016. LO MAPT is funded by the Toulouse Gerontpopole, French Ministry of HEALTH PHRC with additional funding by the Alzheimer’s Association (Chicago) and the Alzheimer’s Drug Discovery Foundation. The products and placebo are provided by DSM, Switzerland. Results are expected late 2020. DHA is an alternative to current anti-amyloid drug development and must definitively be evaluated in a targeted trial.
View all comments by Bruno VellasMake a Comment
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