Public Release: 

Results from trials of DHA in Alzheimer's disease and age-related cognitive decline

Mixed results emphasize the need for earlier detection and intervention

Alzheimer's Association

Vienna, July 12, 2009 - Results from two large studies using DHA, an omega 3 fatty acid, were reported today at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD 2009) in Vienna.

One of the trials was conducted by the Alzheimer's Disease Cooperative Study (ADCS) supported by the National Institute on Aging (NIA), and the second by Martek Biosciences Corporation (Martek), the primary company that makes algal DHA for supplementation. The NIA trial lasted 18 months and was conducted in people with mild to moderate Alzheimer's. Martek's trial was six months, and the compound was tested in healthy people to see its effect on "age related cognitive decline" (ARCD). Both studies used Martek's algal DHA.

The results of the ADCS trial show no evidence for benefit in the studied population. The Martek trial showed a positive result on one test of memory and learning, but that study was in healthy older adults, not people with Alzheimer's or another dementia. The results need confirmation, as is standard scientific practice.

"These two studies - and other recent Alzheimer's therapy trials - raise the possibility that treatments for Alzheimer's must be given very early in the disease for them to be truly effective," said William Thies, PhD, Chief Medical & Scientific Officer at the Alzheimer's Association. "For that to happen, we need to get much better at early detection and diagnosis of Alzheimer's, in order to test therapies at earlier stages of the disease and enable earlier intervention."

Other research studies from ICAD 2009 show advances made in biomarkers and early detection from the Alzheimer's Disease Neuroimaging Initiative (ADNI), and also survey results from doctors about the enablers and barriers they face in diagnosing people with Alzheimer's.

DHA (docosahexaenoic acid) is naturally found in the body in small amounts, and is the most abundant omega 3 fatty acid in the brain. DHA oil is abundant in some marine microalgae, which provide the DHA that makes fatty fish a good source of DHA. Dietary DHA is also available in foods enriched with algal DHA or fish oils, and dietary supplements. Previous animal studies and epidemiology in humans suggested that DHA may be beneficial in people with Alzheimer's.

Alzheimer's Disease Cooperative Study 18-Month DHA Trial in Alzheimer's Disease

Researchers from the National Institute on Aging (NIA)-supported Alzheimer's Disease Cooperative Study (ADCS), led by Joseph Quinn, MD, Associate Professor of Neurology at Oregon Health and Sciences University, conducted a double blind, randomized, placebo-controlled clinical trial comparing DHA and placebo in 402 people (average age=76) diagnosed with mild to moderate Alzheimer's at 51 sites in the U.S.

At the beginning of the trial, all participants had a dietary DHA intake of less than 200 mg per day. Subjects were treated with DHA or placebo at a dose of two grams per day for 18 months. Those participants already taking approved Alzheimer's drugs could continue taking them during the trial. Co-primary outcomes were 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). These two measures are the current standard tests used by FDA when assessing new Alzheimer's drugs.

According to the researchers, treatment with DHA clearly increased blood levels of DHA, and also appeared to increase brain DHA levels, based on a measured increase of DHA in study participants' cerebrospinal fluid (CSF). However, DHA treatment did not slow the rate of change on tests of mental function (ADAS-cog), global dementia severity status (CDR-SOB), activities of daily living (ADL), or behavioral symptoms (NPI) in the study population as a whole. There was no different treatment effect between the mild and moderate Alzheimer's patients.

"These trial results do not support the routine use of DHA for patients with Alzheimer's," Quinn said.

In a pre-planned exploratory data analysis, study participants were divided according to whether or not they carried the "e4" version of the "ApoE" gene. ApoE-e4 increases the risk of developing Alzheimer's but does not appear to modify the rate of disease progression. In the people who had an ApoE-e4 gene, the researchers found no benefits of DHA treatment. In contrast, those without the ApoE-e4 gene who received DHA had a slower rate of decline on the primary test of mental function (the ADAS-cog). A trend in the same direction was seen on the Mini-mental state examination, another test of mental function.

"This is an intriguing exploratory result," said Quinn. "However it must be treated with appropriate caution. The finding requires further study for confirmation."

"One of the issues raised by this study - and other recent Alzheimer's and mild cognitive impairment therapy trials - concerns a possible interaction between certain therapies and genetic status. This issue needs to be explored more completely in future trials," Thies added.

Memory Improvement with DHA Study (MIDAS)

Researchers at Martek Biosciences Corporation examined the effects of algal DHA as a possible neuroprotective nutritional supplement for ARCD in their Memory Improvement with DHA Study (MIDAS).

Scientists led by Karin Yurko-Mauro, PhD, Associate Director of Clinical Research at Martek, conducted a randomized, double-blind, placebo-controlled, multi-center, six month study to determine the effects of 900 mg per day of algal DHA on improving cognitive functions in 485 healthy older people (average age=70) with mild memory complaint. The primary outcome measure was a change from baseline in CANTAB Paired Associate Learning (PAL), a visuospatial episodic memory test.

After six months, the researchers found that the study participants taking DHA supplements made significantly fewer errors on the PAL compared to when they started the study (-1.63 ± 0.76, p< 0.03). Plasma phospholipid DHA levels doubled over the course of the study in those people taking the supplements, and correlated with the PAL response (p< 0.04).

They also observed a significant decrease in heart rate in those taking DHA (change from baseline of -3.2 vs. -1 BPM, p< 0.03) that was highly correlated with week 24 plasma levels (p< 0.01). Blood pressure and body weight remained unchanged between groups. Plasma levels of Alzheimer's related proteins Abeta 1-40, 1-42 and hs-CRP were not significantly different.

The researchers observed no treatment-related serious adverse effects in the study, and the adverse effects profile for DHA was the same as for the placebo.

"In our study, healthy people with memory complaints who took algal DHA capsules for six months had almost double the reduction in errors on a test that measures learning and memory performance versus those who took a placebo," Yurko-Mauro said. "The benefit is roughly equivalent to having the learning and memory skills of someone three years younger."

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About ICAD 2009

The 2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009) brings together more than 3,000 researchers from 70 countries to share groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Association's research program, ICAD 2009 serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community. ICAD 2009 will be held in Vienna, Austria at Messe Wien Exhibition and Congress Center from July 11󈝼.

About the Alzheimer's Association

The Alzheimer's Association is the leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. For more information, visit www.alz.org.

Joseph Quinn, et al - A clinical trial of docosahexaenoic acid (DHA) for the treatment of Alzheimer's disease. (Funders: National Institute on Aging; Martek Biosciences Corporation)

Karin Yurko-Mauro, et al - Results of the MIDAS Trial: Effects of Docosahexaenoic Acid on Physiological and Safety Parameters in Age-Related Cognitive Decline (Funder: Martek Biosciences Corporation)

EMBARGOED FOR RELEASE UNTIL SUNDAY, JULY 12, 2009 8:00 a.m. (Vienna) / 2:00 a.m. ET (U.S.)

All materials to be presented at the 2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009) are embargoed for publication and broadcast until the date and time of presentation at the International Conference on Alzheimer's Disease, unless the Alzheimer's Association provides written notice of change of embargo date/time in advance.

EMBARGOED FOR RELEASE UNTIL SUNDAY, JULY 12, 2009, 8:00 a.m. (Vienna) / 2:00 a.m. ET (U.S.)

Control #: 09-A-875-ALZ O1-04 - Therapeutic and Therapeutic Strategies: Clinical Trial Results - Presentation #O1-04-02
Speaking Time: 7/12/2009, 3:15 - 3:30 PM

A clinical trial of docosahexanoic acid (DHA) for the treatment of Alzheimer's disease

Joseph F. Quinn1, Rema Raman2, Ronald G. Thomas2, Karin Ernstrom2, Karin Yurko-Mauro3, Edward B. Nelson3, Lynne Shinto1, Anil K. Nair4, Paul Aisen2
1Oregon Health and Science University, Portland, OR, USA; 2University of California, San Diego, San Diego, CA, USA; 3Martek Biosciences Corporation, Columbia, MD, USA; 4Boston University, Boston, MA, USA.

Disclosure Block: J.F. Quinn, None; R. Raman, None; R.G. Thomas, None; K. Ernstrom, None; K. Yurko-Mauro, Employee of Martek Biosciences, Employee; E.B. Nelson, Employee of Martek Biosciences, Employee; L. Shinto, None; A.K. Nair, None; P. Aisen, None.

Background: Epidemiologic studies and animal studies suggest that supplementation with the omega 3 fatty acid, docosahexanoic acid (DHA), will slow the rate of neurodegeneration in Alzheimer's disease (AD). The excellent safety profile of DHA was also a consideration in designing a clinical trial in AD.

Methods: A double blind, randomized, placebo-controlled clinical trial comparing DHA and placebo in AD patients was conducted by the National Institute on Aging Alzheimer's Disease Cooperative Study Unit. Fifty one sites in the United States enrolled 402 subjects between February and November 2007. Subjects had a diagnosis of probable AD with Mini-mental state exam score (MMSE) 14-26, and dietary DHA intake of ≤ 200 mg per day. Subjects were treated with DHA or placebo at a dose of 2 grams per day for 18 months, with the final subjects completing clinical activity in May 2009. Co-primary outcomes were rate of change on Alzheimer's disease assessment scale-cognitive (ADAS-cog) and rate of change on Clinical Dementia Scale-sum of the boxes (CDR-SOB).

Results: The study population was 52.2% female with a mean age of 76 ± 8.7 years, mean education of 14.3± 2.8 years, and mean MMSE=20.7 ± 3.6, with 59% ApoE4 positive and 41% ApoE4 negative. Mean plasma DHA at baseline was 3.15±1.12 weight percent.

Conclusions: A trial of DHA supplementation for mild to moderate AD will be completed in May 2009. Recruitment was completed ahead of schedule. The criteria for baseline dietary DHA consumption yielded a baseline plasma DHA level which will permit significant increases with supplementation. The primary analysis of the efficacy (ie, rate of change on ADAS-cog and CDR-SOB) and safety of DHA supplementation in patients with mild to moderate AD will be presented.

All materials to be presented at the 2009 Alzheimer's Association International Conference on Alzheimer's Disease (ICAD 2009) are embargoed for publication and broadcast until the date and time of presentation at the International Conference on Alzheimer's Disease, unless the Alzheimer's Association provides written notice of change of embargo date/time in advance.

EMBARGOED FOR RELEASE UNTIL SUNDAY, JULY 12, 2009, 8:00 a.m. (Vienna) / 2:00 a.m. ET (U.S.)

Control #: 09-A-2137-ALZ O1-04 - Therapeutic and Therapeutic Strategies: Clinical Trial Results - Presentation #O1-04-01
Speaking Time: 7/12/2009, 3:00 - 3:15 PM

Results of the MIDAS Trial: Effects of Docosahexaenoic Acid on Physiological and Safety Parameters in Age-Related Cognitive Decline

Karin Yurko-Mauro1, Deanna McCarthy1, Eileen Bailey-Hall1, Edward B. Nelson1, Andrew Blackwell2, MIDAS Investigators
1Martek Biosciences Corporation, Columbia, MD, USA; 2Cambridge Cognition, Cambridge, United Kingdom

Disclosure Block: K. Yurko-Mauro, Martek Biosciences, Employee; D. McCarthy, Martek Biosciences, Employee; E. Bailey-Hall, Martek Biosciences, Employee; E.B. Nelson, Martek Biosciences, Employee; A. Blackwell, Martek Biosciences, Consultant.

Background: Docosahexaenoic acid, (DHA), the principle omega-3 fatty acid in brain, plays an important role in neural function. Decreases in plasma DHA are associated with cognitive decline in healthy elderly and Alzheimer's patients. Higher DHA intake and plasma levels are inversely correlated with relative risk of Alzheimer's disease (AD). Diet supplementation with Martek algal DHA oil reduces Aβ and tau levels in transgenic AD mouse models. Based on this collective data, we examined the effects of DHA clinically as a nutritional neuroprotective supplement for age-related cognitive decline (ARCD).

Objectives: Memory Improvement with DHA Study (MIDAS) was a randomized, double-blind, placebo-controlled, multi-center, six month study to determine the effects of 900mg/d DHA on improving cognitive functions (assessed by CANTAB® cognitive battery) in healthy elderly with ARCD. Safety and tolerability were also assessed.

Methods: Four hundred eighty-five subjects with a Logical Memory (WMS III) baseline score >1 SD below the younger adult mean were enrolled across 19 US sites. Additional study details were presented at ICAD'07. Primary outcome was a change from baseline in CANTAB Paired Associate Learning (PAL), a visuospatial episodic memory test.

Results: Demographics: 59% female, mean age 70±9, mean education 14.6±2.6 years. Primary efficacy showed significantly fewer errors made on the PAL with DHA versus placebo at six months compared to baseline (diff. score -1.63±0.76, p< 0.03). A significant decrease in heart rate (DHA change from baseline of -3.2 vs. -1BPM, p< 0.03) occurred and highly correlated with week 24 plasma levels (p< 0.01). Blood pressure and body weight remained unchanged between groups. Abeta1-40,1-42 and hs-CRP plasma levels were not significantly different. Plasma phospholipid DHA levels doubled (3.2 to 6.4 weight%, p< 0.001) and correlated with the PAL response (p< 0.04). Compliance was >82%, no treatment-related SAEs were reported and the number of subjects with SAEs were equivalent across the 2 arms.

Conclusions: Six month supplementation with DHA (900mg/d) improves memory function and decreases heart rate in healthy older adults with ARCD. This improvement on the PAL is associated with a shift in the normative distribution to a younger age. DHA exhibits an excellent safety profile in this older population.

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