05 Nov 2010

It is touted as brain food, but the polyunsaturated fatty acid DHA (docosahexaenoic acid) failed to slow mental decline in Alzheimer’s patients who took it in pill form for one and a half years, according to a study in the this week’s Journal of the American Medical Association. The JAMA paper describes an Alzheimer’s Disease Cooperative Study (ADCS) trial initially reported by Joseph Quinn, Oregon Health and Science University, Portland, at the 2009 International Conference on Alzheimer’s Disease in Vienna (see ARF related news story). The disconcerting results add to a string of AD trial failures despite what some see as the field’s tremendous scientific progress over the last few decades. Several European trials are testing DHA-rich formulations in frail elderly (see Toulouse Study) and people with prodromal AD (see LipiDiDiet Project), but plans for similar studies in early-stage populations have not yet moved forward in the U.S.

The ADCS study randomized 402 patients with mild to moderate AD at 51 U.S. sites to two grams of DHA, or placebo capsules, daily for 18 months. Primary outcome measures were rate of change on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) and on the Clinical Dementia Rating (CDR) sum of boxes. Secondary outcome measures included change in scores on the Mini-Mental State Exam, the Neuropsychiatric Inventory (NPI), and several functional batteries (ADCS’s Activities of Daily Living and Quality of Life Alzheimer’s Disease scales).

At 18 months, the control and DHA groups did not differ on any of these measures. About a quarter of the participants also received magnetic resonance imaging (MRI), which revealed no treatment effects on the rate of brain atrophy. The findings hit hard because the trial was large and well-conducted, noted Kristine Yaffe of the University of California, San Francisco, in an accompanying JAMA editorial. “The ADCS trial attempted to overcome some prior methodological issues by enrolling patients who consumed 200 mg/d or less of DHA and documenting [plasma] elevation of phospholipids and DHA with treatment,” confirming supplementation in the treatment group.

If the trial had any ray of hope, it came from an exploratory analysis suggesting that DHA helped ApoE4-negative participants. Compared with ApoE4 carriers, this subgroup declined more slowly on the ADAS-Cog and MMSE when given the fatty acid. Some epidemiological studies of omega-3 fatty acids have also found selective benefits in ApoE4 non-carriers (Huang et al., 2005; Barberger-Gateau et al., 2007; Whalley et al., 2008). Some scientists suspect that this difference could reflect the ApoE4-negative AD patients being, in effect, a little less advanced than ApoE4-carrying patients of the same age, because this risk gene on average brings on disease earlier in life.

The negative outcome of the trial intensifies ongoing soul-searching by the field at large. “Why, despite a remarkably productive two decades of neuroscientific advances in the underpinnings of AD and other forms of dementia, are there still only minimally effective treatments and only rough estimates for prognostication?” wrote Yaffe. “The field seems to be at a crossroads.”

The trial echoes what has become a mantra in the AD clinical trial arena—would the treatment work better at earlier stages of disease, or as a preventive therapy? In light of growing evidence that pathological changes build up within the brain for years before onset of memory loss, there is a prevailing sense that “treatment of mild to moderate AD may be ‘too late,’” Yaffe noted. “Viewing dementia more in a life course model with earlier interventions for those at risk might yield greater results.” A recent review of the role of diet in Alzheimer’s makes a similar point (Kamphuis and Scheltens, 2010).

A hint that earlier intervention might work can be found in the analysis of an earlier six-month trial led by Jan Palmblad and colleagues at the Karolinska Institute in Stockholm, Sweden. In that trial, omega-3 fatty acids also failed to slow cognitive decline in mild to moderate AD patients. However, post-hoc analysis revealed benefits in a subgroup of less demented patients who had baseline MMSE scores above 27 (Freund-Levi et al., 2006 and ARF related news story).

Quinn said that a DHA trial in people with mild cognitive impairment (MCI) would be “a logical next step.” However, “we do not have [financial] support for going forward with it at this point,” he told ARF. Early intervention trials are costly because they are lengthy and require larger cohorts. The ADCS’s trial of donepezil and vitamin E followed about 750 MCI subjects for three years (Petersen et al., 2005 and ARF related news story). For the proposed MCI trial of DHA, “we could try to reduce the number of subjects by requiring CSF biomarker evidence of high risk, and might reduce the duration by using rates of cognitive decline rather than ‘conversion’ to AD,” Quinn noted. “But we would want to be powered to detect an effect in E4 non-carriers, who appear to have a lower risk of progression than carriers. The main message is that an MCI trial would almost certainly have to be larger and longer than the AD trial in order to draw a reliable conclusion.”

Meanwhile, a study published online October 22 in the Journal of Biological Chemistry suggests that DHA may help stave off Aβ production in AD transgenic mice, but only if given with a low-fat diet (Amtul et al., 2010). It is not clear if other dietary fats could have interfered with the ADCS DHA trial.—Esther Landhuis

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References

News Citations

1. Medical Foods—Fallback Option for Elusive AD Drug Status? 14 Oct 2009
2. First Trial of Fish Fats Shows Promise for Early AD 13 Oct 2006
3. Early Intervention Trial Bears Little Fruit, but Sows Hope 15 Apr 2005

Paper Citations

1. 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.
2. 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.
3. Whalley LJ, Deary IJ, Starr JM, Wahle KW, Rance KA, Bourne VJ, Fox HC. n-3 Fatty acid erythrocyte membrane content, APOE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood. Am J Clin Nutr. 2008 Feb;87(2):449-54. PubMed.
4. Kamphuis PJ, Scheltens P. Can nutrients prevent or delay onset of Alzheimer's disease?. J Alzheimers Dis. 2010;20(3):765-75. PubMed.
5. 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.
6. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, Galasko D, Jin S, Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, Alzheimer's Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005 Jun 9;352(23):2379-88. Epub 2005 Apr 13 PubMed.
7. Amtul Z, Uhrig M, Rozmahel RF, Beyreuther K. Structural insight into the differential effects of omega-3 and omega-6 fatty acids on the production of Abeta peptides and amyloid plaques. J Biol Chem. 2011 Feb 25;286(8):6100-7. PubMed.

External Citations

1. Toulouse Study
2. LipiDiDiet Project

Further Reading

Papers

1. Kamphuis PJ, Scheltens P. Can nutrients prevent or delay onset of Alzheimer's disease?. J Alzheimers Dis. 2010;20(3):765-75. PubMed.
2. 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.

News

1. DHA Study—Could Alzheimer’s Be a Liver Disease? 17 Sep 2010
2. First Trial of Fish Fats Shows Promise for Early AD 13 Oct 2006
3. Medical Foods—Fallback Option for Elusive AD Drug Status? 14 Oct 2009
4. Early Intervention Trial Bears Little Fruit, but Sows Hope 15 Apr 2005