First Trial of Fish Fats Shows Promise for Early AD

The results of the first randomized, double-blind, placebo-controlled clinical trial of omega-3 fatty acid supplements for the treatment of Alzheimer disease show no effect on the mental decline in patients with mild to moderate AD. The disappointing results cast a glimmer of hope, however, for the small number of subjects with very mild AD who showed a significant slowing of disease progression during 6 months of treatment. The work, from Jan Palmblad and colleagues at the Karolinska Institute in Stockholm, is published in the October Archives of Neurology.

Epidemiological evidence ties intake of fish, rich in the omega-3 polyunsaturated fatty acids docosohexaenoic acid (DHA) and eicosapentaenoic acid (EPA), to a lower risk of Alzheimer disease (see ARF related news story). DHA helps maintain synapses and reduce amyloid burden in mice (see ARF related news story; Calon et al., 2005; and Lim et al., 2005), and influences the activation of AKT, an important survival pathway for neurons (see ARF related news story). More importantly, people with lower serum levels of this fatty acid may have an increased risk for AD (see Kyle et al., 1999).

To look for a therapeutic effect of omega-3 fats, the researchers, led by first author Yvonne Freund-Levi, randomized 204 AD patients to receive DHA/EPA capsules (for a total dose of 1,720 mg DHA/600 mg EPA) or placebo for 6 months. After the treatment period, all the subjects received open label omega-3 for another 6 months. The treatment was well tolerated, and 174 people finished the trial. The researchers found no difference in cognitive decline between the treated and placebo groups over the 6 or 12 months as measured by the Mini-Mental State Exam and the cognitive portion of the Alzheimer Disease Assessment Scale (ADAS-Cog).

Thinking that omega-3 fats might selectively affect early events in AD, the researchers performed a post hoc analysis of subgroups of patients, dividing them according to MMSE scores. In the group of 32 patients with the most mild AD (MMSE >27, Clinical Dementia Rating Score 0.5-1), omega-3 supplementation stopped the decline in MMSE scores. Even with the small number of subjects, the results reach statistical significance. In addition, the very mild cases in the placebo group also showed a statistically significant slowing of decline when they were switched to treatment for second half of the study.

These results support the idea that omega-3 fatty acids, particularly DHA, might be useful in preventing AD. This would be consistent with epidemiological studies, which show that fish consumption lowers the risk of developing dementia. But the current findings are based on very few patients treated for a short time; longer, larger trials will be necessary to confirm the findings. Likewise, more studies will be needed to find out if DHA acts mainly as an anti-inflammatory agent, or has a different, perhaps direct effect on neurons.

“These findings cannot serve as a basis for general recommendations for treatment of AD with dietary DHA-rich fish oil preparations,” the authors write. “However, studies in larger cohorts with mild cognitive impairment, including those at risk for AD, are needed to further explore the possibility that omega-3 fatty acids might be beneficial in halting initial progression of the disease.” Given that the treatment appears safe and was well tolerated, that may be a pill some folks are willing to swallow.—Pat McCaffrey

Comments

  1. This new study from Freund-Levi et al. has solid data to show the negative result that at the dose used, DHA-enriched omega-3 fatty acid (fish oil base) supplementation does not produce cognitive benefits in the overall group of AD patients tested. However, it also contains post hoc analysis suggesting that patients at the earliest stages of disease had significant benefits—notably, a possible slowing or arrest in decline. The authors conclude that their results support possible efficacy for prevention, but not treatment. Since prevention is a major public health goal, and unlike current available options this particular intervention is both very safe and very cheap, we are excited and optimistic about the results.

    It is not surprising that fish oil looks better for prevention than treatment. The argument for using fish oil stems largely from epidemiology and animal model data, both likely to pertain more to prevention than treatment. Epidemiology is clearly most relevant to early intervention and prevention, while the animal models used to support DHA’s use have lacked major neuron loss and tangle pathology and are better models for very early stages of AD or MCI than fully developed AD. For example, our group observed that the APP Tg2576 model did not show significant synaptophysin loss—based on Western blots—even when placed on a DHA-depleted diet, but that a marker for dendritic spines in excitatory neurons, drebrin, showed massive APP transgene- and DHA-dependent loss in cortex and hippocampus (Calon et al., 2004). Drebrin was the most DHA-sensitive marker we could find. Several reports had shown massive drebrin loss in AD temporal cortex and hippocampus, but none had related this to the MMSE or cognitive decline. Recent data from the religious orders study show that the massive drebrin loss in AD superior temporal cortex is not progressive throughout the disease, but begins with MCI and falls off like a cliff as incipient AD develops (Counts et al., 2006). The drebrin loss has occurred by MMSE 25, and there is no further loss with progression, unlike synaptophysin, which continues to decline as MMSE scores drop.

    We hypothesized that we did not see synaptophysin loss because the model we used lacks tangles: data from Paul Coleman and others suggest that progressive synaptophysin loss in AD is largely dependent on tangles—tangle-bearing neurons have big deficits in synaptophysin mRNA relative to adjacent tangle-free neurons. Putting these results together, our animal model data show that DHA protects against synaptic defects that occur early and but do not progress—consistent with an early intervention.

    Our first DHA study supported the hypothesis that DHA protects insulin/trophic factor-like signaling through PI3K >Akt pathway to protect drebrin. A second study implicated Aβ oligomer-induced alterations in PAK signaling as the cause of drebrin loss (Zhao et al., 2006 and ARF related news story). The reviewers of that paper asked us to remove data showing that insulin protected against Aβ oligomer-induced drebrin loss, but we have presented this data at meetings, the point being that enhanced insulin/neurotrophic factor signaling protects against at least some of Aβ oligomers’ effects on drebrin and spines and that enhancing this signaling seems a major factor in DHA’s synaptic effects. There have been several efforts to enhance cognitive function in AD by either treating with insulin (Craft and colleagues; see, e.g., Reger et al., 2005) or by treating with insulin-sensitizing agents (Craft et al., 2003) or TZDs (PPARγ ligands, Risner et al., 2006) .

    These insulin signaling studies have shown much reduced or no efficacy in patients with ApoE4. Similarly, and consistent with a DHA effect on insulin-like signaling, recent epidemiology suggests no protective effect of fish consumption for ApoE4 patients (Huang et al., 2005). This negative Swedish study by Levi et al. was heavily weighted with ApoE4 patients (68/89 or 76% of the omega-3/omega-3 patients were ApoE4 positive and 67% in the placebo/omega-3 group). Thus, it is possible that, like insulin and insulin-sensitizing drugs, DHA will have more impact in non-ApoE4 patients and possibly even at later stages. However, it is important to note that the authors report no ApoE genotype difference distinguishes the early stage, apparently omega-3 responsive group. New studies will be required to determine whether ApoE influences omega-3 efficacy or whether omega-3s are efficacious at all and can really be used for AD prevention. In the meantime, we remain cautiously optimistic and encouraged by these initial trial results and secure, along with the American Heart Association, in recommending fish oil to the public on the basis of known deficiency in typical Western diets and the solid clinical trial data supporting cardiovascular benefits. Cardiovascular disease risk factors are AD risk factors.

    References:

    Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N, Ashe KH, Frautschy SA, Cole GM. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 2004 Sep 2;43(5):633-45. PubMed.

    Counts SE, Nadeem M, Lad SP, Wuu J, Mufson EJ. Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment. J Neuropathol Exp Neurol. 2006 Jun;65(6):592-601. PubMed.

    Zhao L, Ma QL, Calon F, Harris-White ME, Yang F, Lim GP, Morihara T, Ubeda OJ, Ambegaokar S, Hansen JE, Weisbart RH, Teter B, Frautschy SA, Cole GM. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat Neurosci. 2006 Feb;9(2):234-42. PubMed.

    Reger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006 Mar;27(3):451-8. PubMed.

    Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, Purganan K, Wait C, Petrova A, Latendresse S, Watson GS, Newcomer JW, Schellenberg GD, Krohn AJ. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology. 2003 Aug;28(6):809-22. PubMed.

    Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD, . Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 2006 Jul-Aug;6(4):246-54. PubMed.

    Huang TL, Zandi PP, Tucker KL, Fitzpatrick AL, Kuller LH, Fried LP, Burke GL, Carlson MC. Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. Neurology. 2005 Nov 8;65(9):1409-14. PubMed.

    View all comments by Gregory Cole

  2. I think that it is very encouraging that just 6 months on dietary DHA/EPA results in a slower decline in MMSE in the mildest cases. I am relieved Freund-Levi et al. used a high ratio of DHA to EPA, because EPA may compete for reincorporation of DHA into membranes. I wonder whether much higher doses or longer treatments might have helped the moderate-stage patients. Anecdotal information from a neurologist in Florida (Dr. Diana Pollack) has demonstrated an impact of high fish oil (8 grams a day) on mild cases, and even improvements in PET and MRI scans. Alternatively, DHA-related improvements in function may require polytherapy and environmental enrichment designed to stimulate synaptogenesis. The data is strong that there is a dramatic loss of DHA in the brain of AD patients, and we know that is important for neuron function. Therefore, even if DHA/EPA alone is not sufficient, it would seem that it is necessary.

    View all comments by Sally A. Frautschy

  3. To determine the efficacy of any drug, randomized clinical trials (RCTs) remain the gold standard. The same is true to find out if omega-3 polyunsaturated fatty acids (n3PUFAs) are beneficial in Alzheimer disease (AD), and Freund-Levi et al. published the first placebo-controlled RCT studying the effect of long chain n3PUFAs on the performance of patients on cognitive tests [1]. This report is a very important and a long-awaited step toward a better knowledge of the role of n3PUFAs in AD. However, there are several factors that make it hard to detect the efficacy of n3PUFAs in such a small RCT. First, n3PUFAs are endogenous components of our body, especially in our brain in the case of docosahexaenoic acid (DHA). Therefore, every patient is expected to have a different basal brain level of n3PUFAs at the start of the study [2,3]. Patients with a low level of DHA in their brains might be more likely to benefit from n3PUFA treatments than a patient with a sufficient n3PUFA reserve. Second, in animal studies, the effects of DHA were detected in n3PUFA-depleted Tg2576 mice [4-6]. If this can be extrapolated to humans, it indicates that the consequence of n3PUFA supplementation would be dependent upon the dietary consumption of n3PUFAs before and during the study. For most people, the daily intake of n3PUFAs usually ranges between 40 and 300 mg., which is a significant disparity [7]. Third, it is also quite possible that the incorporation of exogenous n3PUFAs into the brain differs among patients. Variation in the metabolism of the EPAX1050TG triglyceride formulation, in the ability to concentrate DHA into synapses, or in the blood-brain barrier penetration may account for this. Overall, these factors suggest that 1) the variability of patient response (or the experimental error) is probably more important with n3PUFAs than with regular synthetic drugs usually tested with RCTs, and 2) this variability is harder to assess and is unlikely to be determined by blood assays.

    The study from Freund-Levi et al. is well done, and the product and the dose chosen sound reasonable. The duration of the assay should have been sufficient to detect changes in cognitive performances. However, for the above reasons, the results are not so surprising because a study including roughly 200 patients may not have the statistical power to detect any effect of n3PUFAs in the chosen population of AD patients. The results of the same study in a population under-consuming DHA would perhaps have been different. To substantiate the cognitive testing data, assessment of brain function using PET scan or other non-invasive methodologies might have been helpful. On the other hand, on a more positive note, slight beneficial effects of n3PUFAs were detected in patients with very mild cognitive dysfunction. This would suggest that n3PUFA administration might become useless as the disease progresses into significant neuron loss. This observation also argues in favor of a possible preventive effect. As the authors rightly conclude, the bottom line is that we still need RCTs with larger numbers of carefully selected patients to draw a conclusion on the efficacy of n3PUFAs in AD. The next challenge is to gather sufficient funding for such large studies, given the fact n3PUFAs are non-patentable [8].

    See also:

    Salem, N., Jr., Omega-3 fatty acids: molecular and biochemical aspect. In G.A. Spiller and J. Scala (Eds.), Current topics in nutrition ans disease: New protective roles for selected nutrients, Vol. 22, Alan R. Liss, New York, 1989, pp. 109-228.

    References:

    Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8. PubMed.

    Julien C, Berthiaume L, Hadj-Tahar A, Rajput AH, Bédard PJ, Di Paolo T, Julien P, Calon F. Postmortem brain fatty acid profile of levodopa-treated Parkinson disease patients and parkinsonian monkeys. Neurochem Int. 2006 Apr;48(5):404-14. PubMed.

    Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8. PubMed.

    Calon F, Lim GP, Morihara T, Yang F, Ubeda O, Salem N, Frautschy SA, Cole GM. Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease. Eur J Neurosci. 2005 Aug;22(3):617-26. PubMed.

    Calon F, Lim GP, Yang F, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem N, Ashe KH, Frautschy SA, Cole GM. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron. 2004 Sep 2;43(5):633-45. 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.

    Maclean CH, Issa AM, Newberry SJ, Mojica WA, Morton SC, Garland RH, Hilton LG, Traina SB, Shekelle PG. Effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases. Evid Rep Technol Assess (Summ). 2005 Feb;(114):1-3. PubMed.

    Calon F. Nonpatentable drugs and the cost of our ignorance. CMAJ. 2006 Feb 14;174(4):483-4. PubMed.

    View all comments by Frederic Calon

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References

News Citations

  1. Talking Fish Fat And Cholesterol
  2. Fish Oil Swims Ahead in Dietary Brain Protection Race
  3. Presenilins Work Overtime to Control Akt, Tau, and Aβ—n-3 Fatty Acids Aid and Abet

Paper Citations

  1. Calon F, Lim GP, Morihara T, Yang F, Ubeda O, Salem N, Frautschy SA, Cole GM. Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease. Eur J Neurosci. 2005 Aug;22(3):617-26. PubMed.
  2. 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.
  3. Kyle DJ, Schaefer E, Patton G, Beiser A. Low serum docosahexaenoic acid is a significant risk factor for Alzheimer's dementia. Lipids. 1999;34 Suppl:S245. PubMed.

Further Reading

Papers

  1. Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol. 1997 Nov;42(5):776-82. PubMed.
  2. Barberger-Gateau P, Letenneur L, Deschamps V, Pérès K, Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study. BMJ. 2002 Oct 26;325(7370):932-3. PubMed.

Primary Papers

  1. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, Basun H, Faxén-Irving G, Garlind A, Vedin I, Vessby B, Wahlund LO, Palmblad J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8. PubMed.

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