Fitzgerald KC, O'Reilly EJ, Falcone GJ, McCullough ML, Park Y, Kolonel LN, Ascherio A.
Dietary ω-3 Polyunsaturated Fatty Acid Intake and Risk for Amyotrophic Lateral Sclerosis.
JAMA Neurol. 2014 Sep 1;71(9):1102-10.
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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.
Veldink JH, Kalmijn S, Groeneveld GJ, Wunderink W, Koster A, de Vries JH, van der Luyt J, Wokke JH, Van den Berg LH.
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
Okamoto K, Kihira T, Kondo T, Kobashi G, Washio M, Sasaki S, Yokoyama T, Miyake Y, Sakamoto N, Inaba Y, Nagai M.
Lifestyle factors and risk of amyotrophic lateral sclerosis: a case-control study in Japan.
Ann Epidemiol. 2009 Jun;19(6):359-64.
Yip PK, Pizzasegola C, Gladman S, Biggio ML, Marino M, Jayasinghe M, Ullah F, Dyall SC, Malaspina A, Bendotti C, Michael-Titus A.
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
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
Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH, Hall WJ, Fisher SG, Peterson DR, Haley JM, Nazar MD, Rich SA, Berlau DJ, Peltz CB, Tan MT, Kawas CH, Federoff HJ.
Plasma phospholipids identify antecedent memory impairment in older adults.
Nat Med. 2014 Apr;20(4):415-8. Epub 2014 Mar 9