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All, Like we've seen for cardiovascular disease, eating fish can be a mixed blessing. The omega-3 fatty acids (DHA/EPA) are thought to be beneficial, particularly for brain function. But the mercury, PCBs and other contaminants that bioaccumulate in the fat of fish may also have harmful effects. This new study[1] (thanks to Al Pater!) looks at the association between consumption of fish, plant omega-3s, brain mercury levels and Alzheimer's disease and brain mini-strokes. What they found is a bit nuanced, but worth thinking about. They gave 550 quite elderly but initially dementia-free people in several US nursing homes a yearly dietary questionnaire to measure their weekly intake of fish, DHA/EPA and the plant-derived omega-3 Alpha Linolenic Acid (ALA) until they died. Over an average follow-up of 4.5 years, 286 of the participates died (average age 89!). These folks' brains were autopsied to measure mercury levels and to look for physical signs of Alzheimer's disease (plaques and tangles) as well as brain injuries associated with other forms of dementia, in particular macroinfarctions and microinfarctions (i.e. strokes of various sizes). Here are the highlights of what they found: The more fish meals per week a subject consumed, the higher their brain mercury level (P < 0.02). There was no correlation between intake of ALA or DHA/EPA supplements and brain mercury level. For the majority of people (77%) who weren't carriers of the APOE4 allele that increases one's susceptibility to Alzheimer's disease, neither eating fish, dietary DHA/EPA nor consuming ALA had a significant effect (one way or the other) on the risk of Alzheimer's disease. For the minority (23%) of subjects who were APOE4 carriers, eating more fish and more dietary DHA/EPA was associated with a decreased risk of Alzheimer's disease markers (P < 0.04). Neither DHA/EPA supplements nor dietary ALA impacted Alzheimer's risk in these folks. Dietary ALA, but not fish or DHA/EPA, was associated with reduced prevalence of macroinfarctions (P < 0.03) and microinfarctions (P < 0.04) associated with non-Alzheimer's cognitive impairment, independent of APOE4 status. Those were the major, statistically significant findings. There is one more thing I noticed looking at the table below that appears interesting/suggestive for the majority of us who are lucky enough not have the APOE4 gene. The cells I've highlighted below represent the level of various markers of Alzheimer's disease for APOE4-negative folks. The red cells represent the level of Alzheimer's markers for people who ate the most fish (top red row), or the most dietary DHA/EPA (bottom red row). From the confidence intervals, you can see that none of them are individually significant. But also notice that all of them are positive, meaning there was a trend towards increased markers of Alzheimer's disease in APOE4-negative people who ate the most fish, especially fatty fish. In contrast, now look at the green cells, representing markers for Alzheimer's disease in APOE4-negative people who consumed the most plant-derived ALA. Notice these too are not individually significant, but all of them are negative, pointing towards a reduced risk of Alzheimer's disease with increasing ALA intake. From all this, my summary takeaway message from this study would be the following: For people with the APOE4 gene and therefore increased risk of Alzheimer's disease, eating fish is likely to reduce one's risk of Alzheimer's disease, despite increasing brain mercury levels For people without the APOE4 gene, fish consumption doesn't seem to reduce, and may even increase, one's risk of Alzheimer's disease For people without the APOE4 gene, plant-derived omega-3 ALA (e.g. from walnuts, olive oil, flax, chia) consumption may reduce one's risk of Alzheimer's disease For everyone, dietary ALA appears to reduce one's risk of brain markers for non-Alzheimer's cognitive impairment. Or more succinctly, ALA is likely to be good for everyone's brain health, and fish is likely to be good for the brain health of only the minority of people who carry the APOE4 allele. This seems like an illustration of a benefit of getting one's DNA sequenced with a company like 23andMe to determine whether one is a carrier of the APOE4 allele. --Dean ------------ [1] JAMA. 2016 Feb 2;315(5):489-97. doi: 10.1001/jama.2015.19451. Association of Seafood Consumption, Brain Mercury Level, and APOE e4 Status With Brain Neuropathology in Older Adults. Morris MC, Brockman J, Schneider JA, Wang Y, Bennett DA, Tangney CC, van de Rest O. Full text: http://jama.jamanetwork.com.sci-hub.io/article.aspx?articleID=2484683 Abstract IMPORTANCE: Seafood consumption is promoted for its many health benefits even though its contamination by mercury, a known neurotoxin, is a growing concern. OBJECTIVE: To determine whether seafood consumption is correlated with increased brain mercury levels and also whether seafood consumption or brain mercury levels are correlated with brain neuropathologies. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004-2013. Participants resided in Chicago retirement communities and subsidized housing. The study included 286 autopsied brains of 554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years. EXPOSURES: Seafood intake was first measured by a food frequency questionnaire at a mean of 4.5 years before death. MAIN OUTCOMES AND MEASURES: Dementia-related pathologies assessed were Alzheimer disease, Lewy bodies, and the number of macroinfarcts and microinfarcts. Dietary consumption of seafood and n-3 fatty acids was annually assessed by a food frequency questionnaire in the years before death. Tissue concentrations of mercury and selenium were measured using instrumental neutron activation analyses. RESULTS: Among the 286 autopsied brains of 544 participants, brain mercury levels were positively correlated with the number of seafood meals consumed per week (??=?0.16; P?=?.02). In models adjusted for age, sex, education, and total energy intake, seafood consumption (=?1 meal/week) was significantly correlated with less Alzheimer disease pathology including lower density of neuritic plaques (ß?=?-0.69 score units [95% CI, -1.34 to -0.04]), less severe and widespread neurofibrillary tangles (ß?=?-0.77 score units [95% CI, -1.52 to -0.02]), and lower neuropathologically defined Alzheimer disease (ß?=?-0.53 score units [95% CI, -0.96 to -0.10]) but only among apolipoprotein E (APOE e4) carriers. Higher intake levels of a-linolenic acid (18:3 n-3) were correlated with lower odds of cerebral macroinfarctions (odds ratio for tertiles 3 vs 1, 0.51 [95% CI, 0.27 to 0.94]). Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Higher brain concentrations of mercury were not significantly correlated with increased levels of brain neuropathology. CONCLUSIONS AND RELEVANCE: In cross-sectional analyses, moderate seafood consumption was correlated with lesser Alzheimer disease neuropathology. Although seafood consumption was also correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology. PMID: 26836731

All, As discussed in this thread, evidence suggests ALA may be beneficial for brain health in most people, while DHA/EPA may be a mixed blessing - only helpful for avoid Alzheimer's disease (but not other forms of dementia) in those with the APOE4 allele. And as discussed in this thread, fatty fish high in DHA/EPA may be detrimental for cardiovascular health if contaminated with PCBs, as was the case in several studies of Swedish fish eaters. But this new study [1] shared by Al Pater (thanks Al!) found in another population of fish eaters, this time from Spain, dietary DHA/EPA may in fact be beneficial for avoiding cardiovascular mortality. But dietary DHA/EPA was not significantly beneficial for all-cause mortality. For dietary Alpha Linolenic Acid (ALA) which is an omega-3 from plants (e.g. walnuts, olive oil, flax, chia seeds) the opposite was the case. Namely, dietary ALA reduced all-cause mortality, but not cardiovascular mortality risk. Putting the two together, people who met the dietary recommendations for both DHA/EPA and ALA had the lowest all-cause mortality risk - 37% lower than those who didn't meet either recommendation. Perhaps the fish from Spain have less PCBs than Swedish fish (no - I don't mean the candy :-) ). The full text of the study did not address DHA/EPA supplements - DHA/EPA intake was assessed solely from dietary sources. So it is not clear if a similar beneficial effect could be achieved through a combination of ALA from plant sources and DHA/EPA supplements as fish oil or algae oil, both of which are less likely to be contaminated with mercury or PCBs than the flesh of whole fish. --Dean ------ [1] J Am Heart Assoc. 2016 Jan 26;5(1). pii: e002543. doi: 10.1161/JAHA.115.002543. Dietary Alpha-Linolenic Acid, Marine Omega-3 Fatty Acids, and Mortality in a Population With High Fish Consumption: Findings From the PREvención con DIeta MEDiterránea (PREDIMED) Study. Sala-Vila A, Guasch-Ferré M, Hu FB, et al. http://jaha.ahajournals.org/content/5/1/e002543.long http://jaha.ahajournals.org/content/5/1/e002543.full.pdf+html Abstract BACKGROUND: Epidemiological evidence suggests a cardioprotective role of Alpha-linolenic acid (ALA), a plant-derived Omega-3 fatty acid. It is unclear whether ALA is beneficial in a background of high marine Omega-3 fatty acids (long-chain n-3 polyunsaturated fatty acids) intake. In persons at high cardiovascular risk from Spain, a country in which fish consumption is customarily high, we investigated whether meeting the International Society for the Study of Fatty Acids and Lipids recommendation for dietary ALA (0.7% of total energy) at baseline was related to all-cause and cardiovascular disease mortality. We also examined the effect of meeting the society's recommendation for long-chain n-3 polyunsaturated fatty acids (=/>500 mg/day). METHODS AND RESULTS: We longitudinally evaluated 7202 participants in the PREvención con DIeta MEDiterránea (PREDIMED) trial. Multivariable-adjusted Cox regression models were fitted to estimate hazard ratios. ALA intake correlated to walnut consumption (r=0.94). During a 5.9-y follow-up, 431 deaths occurred (104 cardiovascular disease, 55 coronary heart disease, 32 sudden cardiac death, 25 stroke). The hazard ratios for meeting ALA recommendation (n=1615, 22.4%) were 0.72 (95% CI 0.56-0.92) for all-cause mortality and 0.95 (95% CI 0.58-1.57) for fatal cardiovascular disease. The hazard ratios for meeting the recommendation for long-chain n-3 polyunsaturated fatty acids (n=5452, 75.7%) were 0.84 (95% CI 0.67-1.05) for all-cause mortality, 0.61 (95% CI 0.39-0.96) for fatal cardiovascular disease, 0.54 (95% CI 0.29-0.99) for fatal coronary heart disease, and 0.49 (95% CI 0.22-1.01) for sudden cardiac death. The highest reduction in all-cause mortality occurred in participants meeting both recommendations (hazard ratio 0.63 [95% CI 0.45-0.87]). CONCLUSIONS: In participants without prior cardiovascular disease and high fish consumption, dietary ALA, supplied mainly by walnuts and olive oil, relates inversely to all-cause mortality, whereas protection from cardiac mortality is limited to fish-derived long-chain n-3 polyunsaturated fatty acids. KEYWORDS: fatty acid; nutrition; sudden cardiac death PMID: 26813890

All, One of the initial motivations for studying the possible benefits of the Omega-3s PUFAs DHA & EPA came from observations that the Inuits of Greenland, whose diet contains a very high proportion of polyunsaturated fat from cold-water fish and marine mammals, suffer from relatively low rates of cardiovascular disease. But randomized control trials of the benefits of DHA / EPA supplements for (primary or secondary) prevention of cardiovascular disease have generally been disappointing (e.g. [1]). This new study [2] in Science, might suggest at least part of the explanation for this apparent paradox. That paper used population-genetic analysis of Greenland Inuits to discover regions of two chromosomes that seem to have experienced strong selection in the recent past. Those regions also happen to contain genes involved in fatty acid metabolism; and the variants of the genes that have increased in frequency in Inuits are also associated with small stature and lower weight. From the abstract: By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich in PUFAs. In an accompanying commentary, there is a fascinating map of relatively recent human genetic variations and where they occur around the world (click to enlarge): The one that isn't shown that I find very interesting is the salivary amylase gene (AMY1) for digesting starch. Several studies (e.g. [3]) have found that the number of duplicates of the AMY1 a person has can vary from 2 to about 15 from one individual to the next. The more AMY1 copies you have, the better you are at digesting starch / carbohydrates, and the less prone you are to obesity [3]. Study [4] looked at how the number of AMY1 copies varied between people of different ethnic groups and found a striking correlation between the amount of starch in their ancestral diet and the number of AMY1 copies their genome contained. Here is that result illustrated on a map (click to enlarge): In short, it appears that in cultures whose ancestral diet contained a large fraction of carbohydrates, more copies of the AMY1 gene were selected for since it helped them better process carbs. The bottom line appears to be that there is no "one size fits all" diet that is right for everyone. To some extent at least, the best diet for an individual depends on his/her genes. --Dean -------------------------------- [1] Arch Intern Med. 2012 May 14;172(9):686-94. doi: 10.1001/archinternmed.2012.262. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Kwak SM(1), Myung SK, Lee YJ, Seo HG; Korean Meta-analysis Study Group. Collaborators: Myung SK, Ju W, Oh SW, Bae JH, Kim YK, Park CH, Jeon YJ, Lee EH, Chang YJ, Park SM, Eom CS, Lee YJ, Jung HS, Kwak SM. BACKGROUND: Although previous randomized, double-blind, placebo-controlled trials reported the efficacy of omega-3 fatty acid supplements in the secondary prevention of cardiovascular disease (CVD), the evidence remains inconclusive. Using a meta-analysis, we investigated the efficacy of eicosapentaenoic acid and docosahexaenoic acid in the secondary prevention of CVD. METHODS: We searched PubMed, EMBASE, and the Cochrane Library in April 2011. Two of us independently reviewed and selected eligible randomized controlled trials. RESULTS: Of 1007 articles retrieved, 14 randomized, double-blind, placebo-controlled trials (involving 20 485 patients with a history of CVD) were included in the final analyses. Supplementation with omega-3 fatty acids did not reduce the risk of overall cardiovascular events (relative risk, 0.99; 95% CI, 0.89-1.09), all-cause mortality, sudden cardiac death, myocardial infarction, congestive heart failure, or transient ischemic attack and stroke. There was a small reduction in cardiovascular death (relative risk, 0.91; 95% CI, 0.84-0.99), which disappeared when we excluded a study with major methodological problems. Furthermore, no significant preventive effect was observed in subgroup analyses by the following: country location, inland or coastal geographic area, history of CVD, concomitant medication use, type of placebo material in the trial, methodological quality of the trial, duration of treatment, dosage of eicosapentaenoic acid or docosahexaenoic acid, or use of fish oil supplementation only as treatment. CONCLUSION: Our meta-analysis showed insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease. PMID: 22493407 ----------------- [2] Science. 2015 Sep 18;349(6254):1343-1347. Greenlandic Inuit show genetic signatures of diet and climate adaptation. Fumagalli M(1), Moltke I(2), Grarup N(3), Racimo F(4), Bjerregaard P(5), Jørgensen ME(6), Korneliussen TS(7), Gerbault P(8), Skotte L(2), Linneberg A(9), Christensen C(10), Brandslund I(11), Jørgensen T(12), Huerta-Sánchez E(13), Schmidt EB(14), Pedersen O(3), Hansen T(15), Albrechtsen A(16), Nielsen R(17). The indigenous people of Greenland, the Inuit, have lived for a long time in the extreme conditions of the Arctic, including low annual temperatures, and with a specialized diet rich in protein and fatty acids, particularly omega-3 polyunsaturated fatty acids (PUFAs). A scan of Inuit genomes for signatures of adaptation revealed signals at several loci, with the strongest signal located in a cluster of fatty acid desaturases that determine PUFA levels. The selected alleles are associated with multiple metabolic and anthropometric phenotypes and have large effect sizes for weight and height, with the effect on height replicated in Europeans. By analyzing membrane lipids, we found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, the Inuit have genetic and physiological adaptations to a diet rich in PUFAs. Copyright © 2015, American Association for the Advancement of Science. PMID: 26383953 ----------------- [3] Nat Genet. 2014 May;46(5):492-7. doi: 10.1038/ng.2939. Epub 2014 Mar 30. Low copy number of the salivary amylase gene predisposes to obesity. Falchi M(1), El-Sayed Moustafa JS(2), Takousis P(3), Pesce F(4), Bonnefond A(5), Andersson-Assarsson JC(6), Sudmant PH(7), Dorajoo R(8), Al-Shafai MN(9), Bottolo L(10), Ozdemir E(3), So HC(11), Davies RW(12), Patrice A(13), Dent R(14), Mangino M(15), Hysi PG(15), Dechaume A(16), Huyvaert M(16), Skinner J(17), Pigeyre M(18), Caiazzo R(18), Raverdy V(13), Vaillant E(16), Field S(19), Balkau B(20), Marre M(21), Visvikis-Siest S(22), Weill J(23), Poulain-Godefroy O(16), Jacobson P(24), Sjostrom L(24), Hammond CJ(15), Deloukas P(25), Sham PC(11), McPherson R(26), Lee J(27), Tai ES(28), Sladek R(29), Carlsson LM(24), Walley A(30), Eichler EE(31), Pattou F(18), Spector TD(32), Froguel P(33). Comment in Nat Rev Endocrinol. 2014 Jun;10(6):312. Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10(-14)) and serum enzyme levels (P < 2.20 × 10(-16)), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = -0.15 (0.02) kg/m(2); P = 6.93 × 10(-10)) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13-1.26; P = 1.46 × 10(-10)). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies. PMID: 24686848 ------------------------- [4] Perry, G. H., Dominy, N. J., Claw, K. G., Lee, A. S., Fiegler, H., Redon, R., et al. (2007). Diet and the evolution of human amylase gene copy number variation. [10.1038/ng2123]. Nat Genet, 39(10), 1256-1260.