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Dementia Prevention Conference

Alzheimer's Treatment Innovations Show Promise

Drug treatments and lifestyle-based interventions share spotlight on disease most feared by senior citizens

June 20, 2005 - A number of innovative treatment possibilities — including a new version of an established pain drug, a combination of traditional Chinese herbs, and what may be the next chapter in the Alzheimer vaccine story — all show some promise for Alzheimer’s disease as demonstrated by five new research studies reported today in the second day  of the first Alzheimer’s Association International Conference on Prevention of Dementia.

“We are very encouraged to see a diversity of approaches to treating Alzheimer’s showing some level of success,” said Steven DeKosky, M.D., director of the Alzheimer’s Disease Research Center at the University of Pittsburgh and a member of the Alzheimer’s Association Board of Directors. “The urgency of developing better treatments for Alzheimer’s demands that we pursue every available avenue.”

Several of the new treatment methods target beta amyloid, an abnormal brain protein thought to have an important role in Alzheimer’s disease. The abnormal protein collects into sticky bundles in the brain called plaques. Investigators continue to study whether it is the beta amyloid itself, some further modified form of the abnormal protein, or the plaques that cause the death of brain cells in Alzheimer’s.

“Amyloid as a possible cause for Alzheimer’s is the most mature theory of the disease, and must be thoroughly tested,” said William Thies, Ph.D., Alzheimer’s Association vice president for Medical & Scientific Affairs. “We need an answer to the amyloid question so that we can sharpen our focus on amyloid and create better treatments and perhaps a cure, or change our focus to other areas if the theory is wrong.”

Intravenous Immunoglobulin (IVIg) improves mental function in small study

In 2002, the first trial attempting to focus the body’s own immune response on beta amyloid through active immunization was halted due to brain inflammation in about six percent of participants. To try to avoid these side effects, some scientists are focusing on passive administration of antibodies to beta amyloid in Alzheimer’s disease.

At the Alzheimer’s Association Prevention Conference, Marc Weksler, M.D., Wright Professor of Medicine, and Norman Relkin, M.D., Ph.D., Director of the Memory Disorders Program, at the Weill Medical College of Cornell University, and colleagues reported on the use of intravenous immunoglobulin (IVIg) in eight individuals with mild to moderate Alzheimer’s disease.

IVIg is a product derived from human donor blood that contains high concentrations of antibodies, including antibodies to beta amyloid. It is administered through an intravenous drip, much like a blood transfusion. Participants in the study were treated for six months with various doses of IVIg followed by a three-month period without IVIg therapy. Patients received IVIg doses every week, every two weeks or once per month.

After each infusion of IVIg, the researchers found that levels of anti-beta amyloid antibody in the plasma of all eight patients increased in a dose-dependent fashion. Test of cerebrospinal fluid in each of the six participants studied to date showed a lowering of beta amyloid to a greater degree than previously observed – an average 45 percent decrease.

Cognitive function in the study participants was measured before and after six months of IVIg therapy using the MMSE. None had lower scores after the intervention than before, and in six of eight patients there was a significant improvement after receiving IVIg.

“These results clearly justify further study in a larger, placebo-controlled, double blind trial. However, our evidence does not recommend IVIg as a current treatment for Alzheimer’s disease,” Weksler said.

(R)-flurbiprofen encouraging in mild Alzheimer’s

(R)-flurbiprofen (Flurizan, Myriad Genetics), a single enantiomer of flurbiprofen, has been shown to selectively lower brain levels of a toxic form of beta amyloid (Aß42) in a model of Alzheimer’s. At the Alzheimer’s Association Prevention Conference, researchers led by Gordon Wilcock, Professor of Care of The Elderly and Head of the Bristol Dementia Research Group, University of Bristol, UK, reported new results from the first multi-center, placebo-controlled, double-blind study of (R)-flurbiprofen in people. Participants in the 12-month trial received twice daily doses of either 400 mg or 800 mg of drug, or placebo.

When results for all 207 participants were considered as a whole, (R)-flurbiprofen showed a weak positive trend in helping individuals with mild Alzheimer’s disease, though results did not reach statistical significance. The researchers saw stronger positive trends when results for 128 participants with mild Alzheimer’s were analyzed separately; though, again, these did not reach statistical significance. Participants with mild Alzheimer’s who were taking the highest dose of (R)-flurbiprofen did better than those receiving the placebo on tests of memory and thinking skills, ability to carry out daily activities, and overall function.

Study results were further subdivided to focus on participants with mild Alzheimer’s taking the highest dose who also developed high levels of the drug in their bloodstream. That group experienced a statistically significant benefit in their ability to carry out daily activities and their overall function, but not on measures of memory and thinking skills.

(R)-flurbiprofen is one of the three possible forms of flurbiprofen that seems to have the greatest impact on beta-amyloid but has little or no anti-inflammatory effect. (R)-flurbiprofen, unlike the other forms, is not an NSAID (nonsteriodal anti-inflammatory drug); it does not inhibit the cyclooxygenase (COX) enzyme as NSAIDS do. It is the COX inhibition aspect of NSAIDs, such as with the combined form of flurbiprofen, that is associated with side effects, including bleeding in the stomach and intestines and increased risk of heart attack and stroke.

"There is little risk of stomach problems with (R)-flurbiprofen because of the lack of COX inhibition in this form of the drug. The compound has been shown to be well tolerated in healthy older volunteers at doses of up to 1,600 milligrams per day in a phase I study and in this study," Wilcock said.

Intranasal insulin benefits Alzheimer patients with abnormal insulin regulation

An increased risk of developing Alzheimer’s has been associated with high blood insulin levels and reduced insulin effectiveness. These conditions reduce the amount of insulin that reaches the brain, which may be cause for concern given that insulin plays an important role in the regulation of many chemicals and processes that support cognitive activity. Insulin and other small proteins can be transported directly to the brain through a nose-to-brain pathway, and intranasal insulin administration has been shown to improve memory in younger adults.

In research also reported at the conference, Suzanne Craft, Ph.D., of the University of Washington School of Medicine and the Veterans Affairs Puget Sound Medical Center, and colleagues tested the hypothesis that intranasal administration of insulin would enhance memory for adults with early Alzheimer’s disease and amnestic mild cognitive impairment (MCI). They also examined whether patients with Alzheimer’s who have a specific genetic risk factor (known as ApoE4) would differ from patients without the risk factor. Alzheimer patients without the risk factor are more likely to have insulin abnormalities.

Twenty-six memory-impaired subjects (13 with early Alzheimer’s, 13 with MCI) and 35 healthy older adults underwent three treatments consisting of placebo or insulin (20 or 40 IU). The scientists found that insulin improved recall of a story at both doses for patients without ApoE4, and also improved their ability to remember a list of words at the higher insulin dose. Normal adults and memory-impaired patients with ApoE4 showed no improvement with insulin. Both AD and MCI patients responded similarly to insulin.

“Our findings suggest that intranasal insulin administration may have therapeutic benefit for adults with Alzheimer’s who have abnormal insulin regulation,” Craft said. “Our findings also provide further evidence for APOE-related differences in insulin metabolism in Alzheimer’s. Finally, intranasal administration of other peptides should be explored as possible therapeutic strategies for the treatment of Alzheimer’s.”

Herbal extract improves memory in people with MCI

In another study reported at the conference, Jinzhou Tian, M.D., Ph.D., of Dongzhimen Hospital at Beijing University of Chinese Medicine, and colleagues found that an herbal extract known as GETO (from ginseng, epimedium herb, thinleaf milkwort root and two other herbs), taken daily, improved the memory of people with MCI.

In a randomized, double-blind study, 75 patients with MCI aged 65 years and older were randomly assigned to a GETO group (given four GETO capsules with two placebos), or a piracetam group (given two tablets of piracetam with four placebos), or a placebo group (given six placebos), three times a day for three months. Piracetam is a psychoactive drug that some believe may improve cognitive function, but this theory has not been clinically tested.

All subjects received clinical assessments composed of a battery of memory and learning tests at baseline, endpoint (three months), and follow-up point (one year after treatment was stopped).

Researchers found that, overall, patients who took the GETO capsules increased their cognitive function (measured by average MMSE score) from 27.5?1.7 at the start of the study to 28.3?1.7 after three months. Although their average MMSE score showed a slight decrease to 26.9?1.9 at the one year follow-up, this was still significantly higher than that those patients who took placebo tablets (average 26.33?1.03). In addition, verbal learning and recognizing abilities, and the total score for five-item memory measures, increased significantly at a one-year follow-up point in patients who took GETO capsules compared with those who took piracetam and placebo.

“This small preliminary clinical study shows that GETO extract capsule may effectively improve memory function in patients with MCI,” Tian said. “At this point, it is necessary to conduct a multiple-center clinical trial of the efficacy and safety of GETO extract in patients with MCI.”

“The ingredients in GETO have been used to treat forgetfulness in traditional Chinese medicine for centuries, and merit further study,” Tian added. “Chinese herbal medicine is not only less expensive than standard chemical medications, but also more readily accepted by Chinese elderly people.”

Mild exercise program improves memory in elderly with MCI

A team led by Hideaki Soya, Ph.D., of the University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Japan, sought to assess the effect on cognitive functioning of an exercise intervention including mild intensity calisthenics. Previous studies by this team had shown increased blood flow to the prefrontal section of the brain during even mild intensity exercise, which was enhanced when participants sang a favorite song.

The trial consisted of two types of exercise — a community-based program offered up to six times per month with one hour of exercise, and a home-based program of 10 to 60 minutes per day. The calisthenics, called "Furfuri-Guppa," were combined with the singing of a favorite song. The program was intentionally created to be simple, enjoyable, and of mild intensity to encourage compliance. Memory function, peak torque of leg extension, aerobic capacity, reaction time, and daily energy expenditure were measured. Complete data was obtained on a group of 265 subjects with normal cognitive function and MCI.

After one year of the exercise intervention, 70 percent of participants showed significant improvement in memory function as measured on the 5-Cog Test. Further, a significant correlation was found between the memory function score and energy expenditure through Furfuri-Guppa®.

“It is of particular interest that the rate of memory improvement was greater in participants with MCI than cognitively normal subjects,” Soya said. “Though the exact reason is still uncertain, our program may have the potential to delay cognitive decline and improve the physical fitness of elderly people, including people with MCI.”

About the Alzheimer’s Association

The Alzheimer’s Association, the world leader in Alzheimer research and support, is the first and largest voluntary health organization dedicated to finding prevention methods, treatments and an eventual cure for Alzheimer’s. For 25 years, the donor-supported, not-for-profit Alzheimer’s Association has provided reliable information and care consultation; created supportive services for families; increased funding for dementia research; and influenced public policy changes.

The Alzheimer’s Association’s vision is a world without Alzheimer’s and its dual mission is to eliminate Alzheimer’s disease through the advancement of research and to enhance care and support for individuals, their families and caregivers. For more information, visit www.alz.org or call 1.800.272.3900.

Today's presentations:

Marc Weksler – Drug-ranging Study of Intravenous Immunoglobulin in Patients with Alzheimer's (funders: Alzheimer's Association, Dana Foundation, Institute for the Study of Aging, Baxter BioScience)

Gordon K. Wilcock – A Placebo-controlled, Double-blind Trial of the Selective Aß-42 Lowering Agent, Flurizan (MPC-7869, (R)-flurbiprofen) in Patients with Mild to Moderate Alzheimer’s Disease (funder: Myriad Pharmaceuticals Inc.)

Suzanne Craft – Therapeutic Effects of Intranasal Insulin in Patients with AD and Amnestic MCI (funders: Department of Veterans Affairs, Institute for the Study of Aging)

Jinzhou Tian – The Effectiveness of GETO Extract in the Treatment of Mild Cognitive Impairment in Community Elderly (funders: Ministry of Education of China, National Foundation Commission on Natural Sciences of China, and Ministry of Science and Technology of China)

Hideaki Soya – Enhanced Memory Function of Elderly People by Exercise Intervention With Enjoyable And Mild Intensity: Tone Project (funder: Ministry of Health, Labour and Welfare of Japan)

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