Less Salmon, More Plaques? Link Between Omega-3s and Aβ Reinvigorates Fish Oil Debate
Omega-3 fatty acids as an intervention for Alzheimer’s disease may not be dead in the water just yet. A new study may reinvigorate interest in the fish oils. Researchers led by Helena Chui at the University of Southern California have used PET and MRI scans to correlate markers of Alzheimer’s disease with blood levels of the essential fatty acid docosahexaenoic acid (DHA). They report that people with the least amount of DHA have the most amyloid and atrophy in brain regions associated with AD. The findings, published August 8 in JAMA Neurology, do not prove that DHA blocks AD pathology, however they do mesh well with animal studies suggesting the fatty acid thwarts Aβ accumulation. “The … study has the potential to rekindle interest in the therapeutic potential of DHA,” wrote Joseph Quinn of Oregon Health & Sciences University in Portland in an editorial that accompanied the paper. Quinn headed a previous DHA clinical trial, but was not involved in the current 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,” commented Frédéric Calon of the University of Laval in Quebec (see full comment below).
DHA is the most abundant fatty acid in the brain, and must be obtained in the diet. Nuts, leafy greens, and meats contain some DHA or its precursor, alpha-linolenic acid, but seafood—especially fatty fish such as salmon—comes loaded with it. According to epidemiological studies, fish consumption and/or elevated levels of DHA in the blood correlate with a lower incidence of AD (see Tully et al., 2003; Cunnane et al., 2012). Preclinical work using animal models indicates that DHA treatment reduces amyloid burden, tau tangles, and damage to synapses (see Lim et al., 2005; Green et al., 2007; and Sep 2004 news). However, clinical trials of DHA supplementation in people with mild to moderate AD fell flat, despite some indication that DHA bestows cognitive benefits to healthy elders (see Oct 2006 news; Nov 2010 news; Yurko-Mauro et al., 2010; and Nov 2015 conference news). If DHA works as an anti-amyloid agent in people as it does in animals, then perhaps trials failed because they started too late, reasoned first author Hussein Yassine.
Against this backdrop, Yassine and colleagues wanted to home in on the potential link between DHA, amyloid, and neurodegeneration. They assessed amyloid deposition via PiB-PET imaging, brain volume via MRI, and DHA levels in serum of 61 participants in the Aging Brain Study in California, which measures vascular contributions to cognitive impairment. Many of the participants, ranging in age from 67 to 88, had risk factors for vascular disease including diabetes or obesity. Nearly half (30) of the participants were cognitively healthy, 29 had a Clinical Dementia Rating (CDR) score of 0.5, on par with mild cognitive impairment, and two had higher CDR scores. Based on a PiB standard uptake value ratio cut-off of 1.08, 23 people in the study tested positive for cerebral amyloid.
The researchers found that brain amyloid inversely correlated with serum DHA. Compared with people who tested negative for cerebral amyloidosis, people in the PiB-positive group had 23 percent lower serum DHA. This was measured as a proportion of their total serum fatty acids. Of all of the risk factors considered in the study, only two—serum DHA and ApoE4 genotype—independently predicted whether a person would have cerebral amyloid. The correlation between DHA and amyloid deposition was strongest in people lacking the ApoE4 allele.
On closer analysis, the amyloid-DHA correlation only held in people whose serum DHA fell into the bottom quartile. This extrapolates to a very low DHA intake—corresponding to less than one serving of fish per month, Yassine told Alzforum.
What about brain volume? The researchers found that serum DHA across all quartiles correlated with a larger hippocampus, especially in the left subiculum, right and left CA4, and presubicular areas. The association extended to the cortex as well, because higher DHA correlated with greater total cortical gray matter, and with larger left entorhinal, left inferior temporal, and precuneus regions. No association emerged with white-matter volume or lesions, or the size of the primary motor cortex, suggesting that DHA levels correlated with the volume of regions most affected by AD.
Finally, the researchers compared DHA levels to performance on cognitive tests. They found that higher DHA associated with better nonverbal memory scores, but this association disappeared after accounting for ApoE4 status.
Yassine and other researchers stressed the correlative nature of the findings. Yassine said the field needs to further test the effects of DHA on readily measurable biomarkers, such as brain glucose metabolism and neuronal activity. “These are the kinds of studies that will be most useful at figuring out whether intervention could be useful at the preclinical stage,” he said.
Hilkka Soininen of the University of Eastern Finland in Kuopio found Yassine’s results encouraging, despite the obvious caveats of the study, such as its small size and the substantial burden of vascular disease among its participants. Yvonne Freund-Levi of the Karolinska Institute in Sweden wrote that any conclusions about the effects of limited seafood intake on amyloid deposition would be premature, especially given the lack of healthy aged people unburdened by vascular risk factors in the study, and the absence of controls for body mass index, weight, and gender in some of the statistical analyses. “The recommendation for the future is to design randomized controlled trials with inquiries about diet and omega 3 supplementation, where healthy elderly and prodromal AD patients will be followed longitudinally every six months for as long as possible using amyloid-PET and structural MRI,” she wrote to Alzforum.
Calon pointed out that measuring DHA as a proportion of the total serum fatty acids may produce different results than measuring the absolute concentration of DHA, or DHA in erythrocyte membranes, which is a more accurate predictor of dietary DHA intake. Researchers conducting the Multidomain Alzheimer Preventive Trial (MAPT), in which erythrocyte DHA is measured, will soon report results that jibe with Yassine’s, according to MAPT investigator Bruno Vellas of University of Toulouse in France (see Carrié et al., 2012). In the placebo arm of the three-year DHA intervention trial, cognition deteriorated in normal older people in the lowest quartile of erythrocyte DHA, but not in those in the other three quartiles, Vellas wrote to Alzforum. Vellas presented some of the MAPT’s data at the CTAD meeting last November (Nov 2015 conference news), but many researchers have refrained from commenting until the full data has been published.
Yassine and colleagues are currently recruiting cognitively normal ApoE4 carriers to measure potential benefits of DHA on neuronal connectivity via functional MRI. Although DHA more strongly associated with amyloid in ApoE4 non-carriers in the Aging Brain Study, Yassine said ApoE4 carriers make a better test group, since they are most likely to develop AD. One caveat is that Yassine and colleagues recently reported that ApoE4 and amyloid accumulation prevent uptake of DHA into the brain (see Yassine et al., 2016). While this could potentially diminish the effectiveness of DHA treatment in ApoE4 carriers, Yassine hopes that high enough doses will compensate. The researchers will measure the amount of DHA that makes it into the brain via CSF sampling.—Jessica Shugart
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- Tully AM, Roche HM, Doyle R, Fallon C, Bruce I, Lawlor B, Coakley D, Gibney MJ. Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study. Br J Nutr. 2003 Apr;89(4):483-9. PubMed.
- Cunnane SC, Schneider JA, Tangney C, Tremblay-Mercier J, Fortier M, Bennett DA, Morris MC. Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2012;29(3):691-7. 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.
- 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.
- Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N, Stedman M, . Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010 Nov;6(6):456-64. PubMed.
- Carrié I, van Kan GA, Gillette-Guyonnet S, Andrieu S, Dartigues JF, Touchon J, Dantoine T, Rouaud O, Bonnefoy M, Robert P, Cuffi MN, Bories L, Bordes S, Gasnier Y, Desclaux F, Sudres K, Pesce A, Vellas B. Recruitment strategies for preventive trials. The MAPT study (MultiDomain Alzheimer Preventive Trial). J Nutr Health Aging. 2012 Apr;16(4):355-9. 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.
- Fotuhi M, Mohassel P, Yaffe K. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat Clin Pract Neurol. 2009 Mar;5(3):140-52. PubMed.
- Hashimoto M, Hossain S, Al Mamun A, Matsuzaki K, Arai H. Docosahexaenoic acid: one molecule diverse functions. Crit Rev Biotechnol. 2016 Jul 17;:1-19. PubMed.
- Yassine HN, Feng Q, Azizkhanian I, Rawat V, Castor K, Fonteh AN, Harrington MG, Zheng L, Reed BR, DeCarli C, Jagust WJ, Chui HC. Association of Serum Docosahexaenoic Acid With Cerebral Amyloidosis. JAMA Neurol. 2016 Oct 1;73(10):1208-1216. PubMed.
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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.
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.
University 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.
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