DHA Supplements Show Some Benefit in Cognitive Decline but Not Alzheimer's Disease

Susan Jeffrey

July 13, 2009

July 13, 2009 (Vienna, Austria) — Results of a clinical trial of docosahexaenoic acid (DHA) supplements, an omega-3 fatty acid, suggest some potential benefit in slowing the rate of progression of age-related cognitive decline in otherwise-healthy elderly.

However, a second trial showed no benefit from treatment with a higher dose of DHA after 18 months in patients with mild to moderate Alzheimer's disease. Post hoc analysis did suggest the possibility of benefit when patients were segregated by the presence or absence of the high-risk apolipoprotein E4 (APOE4) allele, with some signal of benefit among those negative for the allele.

Although supplementation appeared safe and well tolerated in both trials, it is too early to suggest use of DHA supplements to affect the rate of cognitive decline, said William Thies, PhD, chief medical and scientific officer for the Alzheimer's Association. "It is simply that we don't have enough data to make a firm recommendation," he told a press conference here.

For approval of any drug, the Food and Drug Administration (FDA) requires 2 clinical trials of adequate power that both point in the same direction, Dr. Thies added. "I would say that as an association, we would look for the same kind of data, and it's particularly an issue where we have 2 different populations showing different responses." While DHA is available and people can make their own decisions, he said, "you can't really say that everything is pointing in the same direction."

The findings were presented here at the 2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009).

Mild to Moderate AD

Epidemiological studies have suggested that DHA consumption, usually in the form of fish, is negatively associated with Alzheimer's disease risk, and animal studies have shown DHA supplementation reduces Alzheimer-type pathology in the brain, the researchers noted.

In a study conducted by the National Institute on Aging Alzheimer's Disease Cooperative Study Unit, researchers randomized 402 subjects with mild to moderate AD from 51 sites in the United States to treatment with 2 g per day of DHA or placebo for 18 months. Patients had a diagnosis of probable AD with a Mini-Mental State Examination score of 14 to 26 and dietary DHA intake of 200 mg/day or less. They could be taking other Alzheimer's medications as long as the dose was stable.

Mean plasma DHA at baseline was about 3 weight percentage, increased to 9 weight percentage with supplementation, showing that the dose was adequate.

Co-primary outcomes were the rate of change on the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) and rate of change on Clinical Dementia Scale-sum of the boxes (CDR-SOB).

Dr. Joseph F. Quinn

"Over the course of 18 months there is, I’m sorry to say, no difference in outcomes between the 2 groups," principal investigator Joseph F. Quinn, MD, from the Oregon Health and Science University, in Portland, reported.

There was no significant difference between the groups on the ADAS-cog (P = .407). A significant separation of the curves was seen at 12 months, he noted, but "the overall analysis unfortunately shows there is no durable treatment effect with DHA."

Similarly, there was no difference seen on the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale (P = 0.377), the CDR-SOB, or in behavioral symptoms as measured on the Neuropsychiatric Inventory (NPI) by treatment group (P = 0.108). Again there was a trend toward an effect in the latter part of the study on this end point, but it did not reach statistical significance.

In a post hoc but prespecified analysis, they looked at outcomes of treatment by the presence or absence of the apolipoprotein E genotype and found a benefit from treatment in the group that was negative for the APOE4 high-risk allele. "We're looking at this result as an important, provocative result, but not a conclusive result about the effect of this drug in this population," he told a press conference here.

Post Hoc Analysis of Outcomes by APOE4 Status

Group % of Overall Population DHA Placebo P
APOE4-positive 57.7 137 95 .659
APOE4-negative 42.3 91 67 .028

Although there is currently no mechanism known to link the apolipoprotein E genotype and DHA, 2 epidemiological studies have made a similar observation, showing a protective effect against AD development with higher consumption of DHA, Dr. Quinn told Medscape Neurology. "In coming across these epidemiological studies, I was more excited about the result, but it's still preliminary and we don't want to oversell it at this point."

They plan to look further into this data set for more information on the APOE4-negative group, he added. "I think the most valuable outcome is it's going to help us design the next trial along these lines; that is, maybe an interim population between cognitive aging and Alzheimer's disease, with careful attention to the issue of apolipoprotein E genotype," he said. "I think it's unlikely that we would just do an APOE4-negative group, but I think we would design the study carefully to make sure that we accounted for the fact that maybe that's where the money is in terms of treatment effects."

There will also be more data generated from this trial. The last patient was just seen in May of this year, so there are more analyses, including data from cerebrospinal fluid sampling and magnetic resonance imaging, to come, he added.

MIDAS Study

Dr. Karin Yurko-Mauro

Karin Yurko-Mauro, PhD, associate director of clinical research at Martek Biosciences, makers of the DHA supplement derived from algae used in this as well as the AD trial, presented more promising results with supplementation in healthy subjects 55 years of age and older with age-related cognitive decline. This kind of cognitive decline is described in Diagnostic and Statistical Manual of Mental Disorders, 4th ed (DSM-IV) as "decline in cognitive functioning consequent to the aging process that is within normal limits given a person's age."

The Memory Improvement with DHA Study (MIDAS) was also a double-blind, placebo-controlled trial including 485 subjects from 19 US centers stratified by age, randomized to receive 900 mg/day of DHA or placebo for 6 months. The primary end point was cognitive testing of memory and learning using the CANTAB Paired Associate Learning (PAL) test, a computerized cognitive battery measuring visuospatial and memory recall that has been shown to discriminate well between aging, mild cognitive impairment, and AD and to be sensitive to early changes in episodic memory.

"So in terms of our primary end point, the Paired Associate Learning test, what we found was that there significantly fewer errors made on this test with algal DHA for 6 months vs placebo," she said. Subjects taking DHA had almost double the reduction in errors on the PAL test, with a mean reduction of 4.5 errors from a baseline of 13.4, vs a reduction of 2.4 errors from a baseline of 12.1 in the placebo group (P = .032).

The net benefit is roughly equivalent to having the learning and memory skills of someone 3 years younger, Dr. Yurko-Mauro said. Plasma levels of DHA doubled with supplementation and a decrease in heart rate in treated patients correlated with the increased DHA levels, suggesting a potential cardiac benefit.

Finally, there was no difference in adverse events between groups, and the supplements were well tolerated, she noted.

"In conclusion, this MIDAS study is the first large randomized placebo-controlled study to demonstrate the benefits of algal DHA in maintaining and improving brain health in older adults," Dr. Yurko-Mauro concluded. The dose used improved learning and memory recall in these subjects with age-related cognitive decline and appeared to have a significant impact on early episodic memory changes.

Dr. Yurko-Mauro anticipates there will be further study in this population. "I think at this point it's premature to talk about the future plans, but we are closely looking at these results," she said. "There are actually some more data that are coming in from the [National Institutes of Health] NIH trial, and we definitely will be looking toward future development clinically."

During discussion of the trial results at the press conference, Dr. Thies suggested to Dr. Yurko-Mauro that DHA may "just cry for a mild-cognitive-impairment trial," which is the population between age-related cognitive decline and frank Alzheimer's disease. "I think that would be a logical next step," she agreed.

The Alzheimer's study was supported by the National Institute on Aging; the age-related cognitive-decline study was supported by Martek Biosciences. Dr. Yurko-Mauro is an employee of Martek Biosciences; Dr. Quinn reports no disclosures.

2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009): Abstracts 01-04-01, 01-04-02. Presented July 12, 2009.

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