No Effect of DHA Supplementation in Slowing Alzheimer's Progression

But an Otherwise Negative Trial May Have a Bright Spot

Caroline Cassels

November 02, 2010

November 2, 2010 — Supplementation with docosahexaenoic acid (DHA), an omega-3 fatty acid, does not slow the rate of cognitive or functional decline in individuals with mild to moderate Alzheimer's disease (AD), a large, randomized controlled trial suggests.

"Unfortunately, on all the clinical outcome measures [primary and secondary], we failed to see evidence of clinical benefit of DHA supplementation," principal investigator Joseph Quinn, MD, from the Oregon Health and Science University and the Portland VA Medical Center, told reporters attending a press briefing.

However, added, Dr. Quinn, data from a secondary analysis raise the possibility that DHA supplementation may have a "modest" therapeutic effect in non-APOe4 carriers.

The study is published in the November 3 issue of the Journal of the American Medical Association, a theme issue on aging.

Previous research has linked consumption of fish — the primary dietary source of omega-3 fatty acids — to a reduced risk for cognitive decline or dementia. Other studies suggest that only DHA, which is abundant in the brain, but not other omega-3 fatty acids, including eicosapentaenoic acid, may reduce AD risk.

Further, earlier research in a mouse model of AD showed that DHA reduced amyloid and tau pathology.

Multicenter Trial

On the basis of this evidence, the investigators conducted a clinical trial hypothesizing that DHA supplementation would slow the rate of cognitive and functional decline in individuals with AD.

The study was conducted at 51 centers in the United States between November 2007 and May 2009 and included 402 patients with mild to moderate AD.

Study participants were permitted to continue on stable doses of approved cognitive enhancers. However, said Dr. Quinn, participation was limited to individuals who consumed no more than 200 mg/day of DHA, assessed using a food frequency questionnaire, and who were not taking DHA or omega-3 fatty acid supplements.

Participants were randomly assigned to receive an algae-derived form of DHA. Algal contains approximately 45% to 55% DHA by weight and does not contain eicosapentaenoic acid.

The study's 2 primary outcome measures included the rate of change during 18 months on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) and on the Clinical Dementia Rating (CDR) sum of boxes — a global measure assessing memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.

Secondary outcome measures included change in scores on the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study's activities of daily living (ADCS-ADL) scale, as well as the Neuropsychiatric Inventory and the Quality of Life Alzheimer's Disease scale. All outcome measures were obtained at baseline, 6, 12, and 18 months.

In addition, a subgroup of participants underwent brain magnetic resonance imaging at baseline and 18 months to determine the rate of brain atrophy. Investigators also conducted cerebrospinal fluid testing in a subgroup of patients in both study groups to ensure DHA increased in the active treatment group compared with the placebo group.

No Effect of Disease Severity

A total of 295 patients completed the trial. Of these, 171 were in the active treatment group and 124 in the placebo group.

At study outset, patients' mean MMSE and ADAS-cog scores were 20.67 and 23.85, respectively. At the conclusion of the trial, there was no difference in the average rate of change on the ADAS-cog score, which was 8.27 points for the placebo group and 7.98 points for the DHA group.

There was also no statistically significant difference in the rate of points change on CDR sum of boxes over the course of 18 months between the 2 groups — 2.93 for placebo vs 2.87 for DHA.

Similarly, said Dr. Quinn, secondary outcome measures including activities of daily living and everyday function, as well as behavioral assessments, were concordant with primary outcome measures.

In addition, he noted that magnetic resonance imaging findings conducted in 102 patients (49 receiving placebo and 53 receiving DHA) showed similar rates of brain atrophy in both groups.

"We did not see an effect of treatment upon rate of brain volume loss, so again these were disappointing and essentially negative results," he said.

When investigators conducted a prespecified subgroup analysis of study patients according to dementia severity, they also found no difference between the placebo and active treatment groups.

"[We thought] that maybe the people who were the least impaired would benefit the most from intervention, and so the group was divided in half based on their MMSE scores. However, there was no difference conferred by treatment in either of these groups," he said.

A Bright Spot?

One possible bright spot in an otherwise negative trial, said Dr. Quinn, pertains to APOe4 status. When investigators examined the effect of treatment according to APOe4 carrier status, they found there was a beneficial effect of DHA treatment on ADAS-cog and MMSE among APOe4-negative participants.

One possible bright spot in an otherwise negative trial pertains to APOe4 status. When investigators examined the effect of treatment according to APOe4 carrier status they found there was a beneficial effect of DHA treatment on ADAS-cog and MMSE among APOe4-negative participants.

However, no treatment effect was seen on the CDR sum of boxes, ADCS-ADL, Neuropsychiatric Inventory, or brain atrophy in this group of patients.

"We present this [analysis] with considerable caution and a number of caveats," said Dr. Quinn. "First, it is a secondary analysis, and the significance is marginal. It is an analysis that occurs after several other analyses, and a rigorous approach to this would be to correct the statistical analysis for multiple comparisons. So it is a marginal effect, but something we can't help mentioning since it is the only positive result in the study," he added.

In contrast, he pointed out the sample size was "modest" (91 subjects in the DHA group and 67 in the placebo group), and at least 2 previous epidemiological studies suggest the protective effect of omega-3 fatty acids may be limited to APOe4-negative individuals.

Although this line of research might be worth pursuing, Dr. Quinn notes that the suggestion of a potential therapeutic effect is not solid enough to result in any recommendation or advice to the public to take DHA supplements to modify the course of AD.

The journal's editor-in-chief, Catherine DeAngelis, MD, MPH, told reporters that the study's findings, although negative, are findings that are "an important piece of the [Alzheimer's] puzzle."

I hear constantly that high-impact journals are not interested in publishing negative trials. This is just not true. A well-done negative trial like this can be just as important as a positive trial. This is an important study, and we are very proud to publish it.

"I hear constantly that...high-impact journals are not interested in publishing negative trials. This is just not true. A well-done negative trial like this can be just as important as a positive trial. No one study proves anything. Science is repetitive, and it is also incremental...and this is an important study, and we are very proud to publish it," she said.

In an accompanying editorial also appearing in the special issue on aging, Kristine Yaffe, MD, from the University of California–San Francisco and Veterans Affairs Medical Center, writes the finding "indicating possible benefit in patients without an APOE4 allele is of great interest because the benefit was observed for the cognitive outcomes but not for the functional or behavioral outcomes. However, as the authors point out, the clinical significance of this finding is uncertain."

The study was supported by the National Institute on Aging. The placebo and DHA study drugs were provided by Martek Biosciences. Dr. Quinn reports being named as a coinventor on a patent for DHA for the treatment of Alzheimer's disease in APOE4-negative individuals. Dr. Quinn has waived his personal right to royalties related to this patent. For full disclosure information on the other authors, see the original paper. Dr. Yaffe reports serving as a consultant to Novartis and serving on the data and safety monitoring boards for the National Heart Lung and Blood Institute, Pfizer, and Medivation, as well as the Beeson Scientific Advisory Committee.

JAMA. 2010;304:1903-1911, 1952-1953.


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