The benefit to cardiovascular health offers one reason to chow down on foods loaded with omega-3 fatty acids. A paper in the July 14 JAMA Neurology online adds another: The same chemicals pare down a person’s risk of developing amyotrophic lateral sclerosis. Researchers at the Harvard School of Public Health determined that among a massive sample of one million people, those who ate the most omega-3-rich foods—such as salmon, flaxseed, and walnuts—had two-thirds the risk of developing ALS later on than those who ate the least. This retrospective, observational study cannot determine cause and effect, cautioned first author Kathryn Fitzgerald. She suspects that these unsaturated fatty acids, which form part of cell membranes in the brain, could protect neurons against oxidative stress or inflammation.

“The result is persuasive and consistent with earlier studies,” commented Michael Swash of the Royal London Hospital in an editorial accompanying the publication (Veldink et al., 2007; Okamoto et al., 2007). Unlike that previous work, which examined people’s diets after they were diagnosed with ALS, the current study analyzed data collected before any subject came down with the disease. 

Despite finding that diet helps, eating more omega-3s would be unlikely to make much difference for people at high risk for ALS due to familial mutations, said Joseph Quinn of the Oregon Health and Science University in Portland, who was not involved in the study. Anne-Marie Wills of Massachusetts General Hospital in Boston suggested that since the incidence of  ALS is so low compared with cardiovascular disease, healthy people should focus more on eating a heart-healthy diet (see full comment below).

Alzheimer’s researchers have been researching these fats for a long time. In a randomized, placebo-controlled clinical trial, introducing omega-3 fatty acids after diagnosis failed to improve symptoms in people Alzheimer’s disease (see Nov 2010 news story), and this "should make us skeptical about using omega-3 fatty acids to treat ALS," Wills said. Quinn said the picture for AD prevention remains incomplete. One study found people who dined on fish weekly were less likely to develop Alzheimer’s (see Jul 2003 news story). 

Because inflammation and oxidative stress have been implicated in ALS, Fitzgerald, senior author Alberto Ascherio, and colleagues suspected that omega-3s might do some good. Fortunately, the data to answer their question was available. They obtained dietary and disease information from five longitudinal, prospective studies: the National Institutes of Health-American Association of Retired Persons Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Health Professionals Follow-Up Study, the Multiethnic Cohort Study, and the Nurses’ Health Study. Together, these cohorts included more than one million participants. Of those, nearly 1,000 developed ALS over the data collection periods of eight to 24 years, depending on the cohort.

The studies provided Fitzgerald with data on omega-3 fatty acid intake, based on food questionnaires the subjects filled out. She divided the participants into five quintiles, from those who savored the most omega-3s to those who ate the least. Those in the highest quintile had a 34 percent lower risk of developing ALS than those in the lowest. Intake of other kinds of fats did not influence ALS risk. While a thin physique has been associated with ALS (see May 2011 news story and O’Reilly et al., 2013), Fitzgerald found the omega-3 benefit held true even if she controlled for body mass index. 

Mouse studies would be the obvious next step, Quinn said, and in fact one such experiment has already been done. Researchers attempted to treat ALS model mice with omega-3 fatty acids and found the disease course sped up, instead of slowing down (Yip et al., 2013). That might be because the researchers used seafood-derived fatty acids, while Fitzgerald observed plant-made versions were most beneficial, Wills speculated.

“This big-data study suggests that at least 20 percent of the U.S. population may be at risk for ALS due to inadequate omega-3 intake … It seems doubtful that any protection involves an ALS-specific mechanism, but more likely a general neuroprotective or anti-inflammatory mechanism,” Greg Cole of the University of California, Los Angeles, commented in an email to Alzforum. Cole was not part of the study group, but he has studied the role of such fatty acids in AD. “The study lacks measurement of blood levels of omega-3 but dietary questionnaires are reasonably well-validated,” he said. Fitzgerald said she hopes to examine how blood biomarkers for fatty acids correlate to ALS incidence in a follow-up study. Wills said that proving the fatty acid benefit experimentally would be difficult. “Unfortunately, deciding whether it would be helpful to increase [omega-3 fatty acid] intake if you carry an ALS mutation would require a very large and long clinical trial,” she wrote.—Amber Dance.

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  1. This is the first large, prospective study of dietary fatty acid intake in ALS and a much more robust confirmation of the association seen in two prior retrospective case-control studies (Veldink et al., 2007; Okamoto et al., 2007). The authors also commented on the recent, apparently contradictory finding by Yip et al. (Yip et al., 2013) that showed that dietary eicosapentaenoic acid (EPA), a marine-derived fatty acid, did not improve survival in the SOD1 ALS mouse model. One possible explanation for this discrepancy is the different kinds of fatty acids used. The marine-derived omega-3 fatty acids (like EPA) used in the Yip paper were only marginally significant in the Fitzgerald JAMA Neurology study; Fitzgerald and colleagues found that plant-derived fatty acids like alpha-linolenic acid were more effective. However, as we have learned from the Alzheimer's experience with omega-3 supplementation, even a strong epidemiological association may not translate into an effective treatment.

    References:

    . Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2007 Apr;78(4):367-71. Epub 2006 Apr 28 PubMed.

    . Lifestyle factors and risk of amyotrophic lateral sclerosis: a case-control study in Japan. Ann Epidemiol. 2009 Jun;19(6):359-64. PubMed.

    . The omega-3 fatty acid eicosapentaenoic acid accelerates disease progression in a model of amyotrophic lateral sclerosis. PLoS One. 2013;8(4):e61626. Print 2013 PubMed.

  2. This study has large enough subject numbers in prospective cohorts with long follow-up (eight to 24 years) to be able to detect reduced ALS diagnosed at death in those with higher total dietary omega-3. This long follow-up is extremely important if you want to see primary prevention in late-onset diseases. The study lacks measurements of blood levels of omega-3, but dietary questionnaires are reasonably well-validated and should be valid with the large numbers of participants examined. Long-term consumption of dietary alpha-linolenic acid (ALA) is certainly relevant to chronic brain uptake of omega-3 in the lower quintiles of intake, and there is a reasonable spread with upper quintiles reporting 2.35 times more ALA intake.

    This big-data study suggests that at least 20 percent of the U.S. population may be at risk for one neurodegenerative disease (ALS) due to inadequate omega-3 intake. They report ALA intake at only 0.83 gms/day in the lowest quintile group, which turned out to have the highest risk of ALS. 0.83 grams is roughly half that recommended by the Institute of Medicine in their Dietary Reference Intakes (DRI) tables. The study reports only 40 mg/day of marine omega-3 intake in the lowest quintile (high risk group) versus 300 mg/day in the highest quintile, protected group. 

    It seems doubtful that any protection from ALS involves an ALS-specific mechanism. It is more likely that a general neuroprotective or anti-inflammatory mechanism is involved. The authors speculate on several such possibilities. Their result is reminiscent of the dementia risk reduction (10 years later) in the highest quintile vs. lowest quintiles of docosahexaenoic acid (DHA) consumption in the Framingham Heart Study. That study found that in the highest quintile of DHA consumption, 180 mg/day, protection from dementia associated with plasma phosphatidylcholine (PC). A more recent plasma lipidomics study reports a 10-member blood panel that includes PCs that associated with risk of cognitive decline in two large cohorts, and half the panel are omega-3 responsive (Mapstone et al., 2014). 

    The recent epidemiology of brain MRI changes reported in the Framingham, Women's Health Initiative Memory, and ADNI studies, where benefits appear only in ApoE4 non-carriers, also point to some neuroprotective role for higher blood marine omega-3. This relatively consistent epi data point to the need for a long clinical trial in subjects with low quintiles of intake that has sufficient power to show an effect in ApoE3 carriers. 

    The Institute of Medicine has failed to set DRIs for marine omega-3 intake which has led some researchers to conclude that American intakes are adequate. The IOM recommended eating fatty fish to get more marine omega-3 to reduce cardiovascular disease (CVD) risk, but it also recommended avoiding fatty fish with high mercury leading to a somewhat confusing Seafood Choices pamphlet. Because IOM never developed a marine omega-3 DRI, the FDA has now limited label claims on marine omega-3 supplements, effectively discouraging more consumption. Worse, there have been several recent meta-analyses on marine omega-3 that claim no benefit for cardiovascular risk—but those studies included study populations with extensive statin use, often nearly 50 percent. In fact, those with the highest known CVD risk factors are almost all on statins these days. The meta-analysis is really showing that adding omega-3 on top of statins didn’t help reduce infarcts, but the public now gets the message that omega-3s are not protective when the real message is that omega-3s don’t add significant reduction to infarct risk on top of the most widely used statins. It would be interesting if the investigators looked at the impact of statins in the same data sets as there is some literature suggesting they may actually increase risk of ALS (see January 20, 2011, story in the Pacific Standard).—Gregory M. Cole

     

    References:

    . Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014 Apr;20(4):415-8. Epub 2014 Mar 9 PubMed.

    View all comments by Gregory Cole

References

News Citations

  1. Paper Alert: Negative DHA Trial Fuels Soul-Searching in AD Field
  2. Talking Fish Fat And Cholesterol
  3. Being Pleasantly Plump: Way to Live Longest with ALS?

Paper Citations

  1. . Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2007 Apr;78(4):367-71. Epub 2006 Apr 28 PubMed.
  2. . Lifestyle factors and risk of amyotrophic lateral sclerosis: a case-control study in Japan. Ann Epidemiol. 2009 Jun;19(6):359-64. PubMed.
  3. . Premorbid body mass index and risk of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Apr;14(3):205-11. Epub 2012 Oct 29 PubMed.
  4. . The omega-3 fatty acid eicosapentaenoic acid accelerates disease progression in a model of amyotrophic lateral sclerosis. PLoS One. 2013;8(4):e61626. Print 2013 PubMed.

Further Reading

Papers

  1. . Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2014 Jun 14;383(9934):2065-72. Epub 2014 Feb 28 PubMed.
  2. . Omega-3 polyunsaturated fatty acids in the brain: metabolism and neuroprotection. Front Biosci. 2012;17:2653-70. PubMed.
  3. . Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. II. Diet. Am J Epidemiol. 2000 Jan 15;151(2):164-73. PubMed.
  4. . A nutritional approach to ameliorate altered phospholipid metabolism in Alzheimer's disease. J Alzheimers Dis. 2014;41(3):715-7. PubMed.
  5. . The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER): Study design and progress. Alzheimers Dement. 2013 Jan 16; PubMed.

Primary Papers

  1. . Dietary ω-3 polyunsaturated fatty acid intake and risk for amyotrophic lateral sclerosis. JAMA Neurol. 2014 Sep;71(9):1102-10. PubMed.
  2. . Diet and Risk of Amyotrophic Lateral Sclerosis: Is Lifestyle Important?. JAMA Neurol. 2014 Jul 14; PubMed.