First Alzheimer's conference showcases research

The majority of the new treatment methods focused on the beta amyloid, a protein that builds up in the brains of persons with Alzheimer's disease, collecting in clumps called plaques or senile plaques.

While some researchers question whether beta amyloid is the cause of the dementia, most agree that it is involved in the disruption of thinking that is a hallmark of the disease.

Efforts at finding medications that would reduce the size or number of plaques are ongoing at research centres throughout the world. In the last several years, a number of approaches have shown promise for inhibiting beta amyloid plaques.

"Amyloid as a possible cause for Alzheimer's is the most mature theory of the disease, and must be thoroughly tested,"​ said William Thies, 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,"​ he added.

Researchers from the Weill Medical College of Cornell University reported on the use of intravenous immunoglobulin (IVIg) in eight individuals with mild to moderate Alzheimer's disease.

Marc Weksler, Wright Professor of Medicine, and Norman Relkin, Director of the Memory Disorders Program, at the university, treated subjects 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.

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.

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 per cent 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.

There are an estimated 18 million people in the world with dementia, accordng to the charity Alzheimer's Disease International, which estimates that by 2025 this figure could increase to 34 million. And finding a treatment that could delay onset by just five years could reduce the number of individuals with Alzheimer’s disease by nearly 50 per cent after 50 years.

In other research, scientists from the University of Bristol, UK, reported new results from the first multi- canter, 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.

(R)-flurbiprofen, 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.

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.

However, results from the 207 participants showed that (R)- flurbiprofen showed a weak positive trend in helping individuals with mild Alzheimer's disease, though results did not reach statistical significance.

More positive results were displayed for 128 participants with mild Alzheimer's were analysed separately. These again did not reach statistical significance.

(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.

With increasing patient numbers and the limitations of available therapies, the Alzheimer's disease (AD) market is an attractive investment with huge unmet need. Although it occupies a small share of the total CNS market it is currently experiencing massive growth. Alzheimer's disease market in the seven major markets is worth $4.7 billion (€3.8 billion) and will increase to $6.1 billion by the year 2005 and $ 7.8 billion by the year 2010.

An interesting discovery also featured at the conference included the benefits intranasal insulin had on 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.

Suzanne Craft, of the University of Washington School of Medicine and the Veterans Affairs Puget Sound Medical Centre, 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,"​ she added.

With anticipated increases in the future to the number of sufferers, considerable research is in progress to understand the pathomechanism of the disease and find a cure. While sufferers show improvements when taking acetylcholinesterase inhibitors, their mechanism of action does not correct the basic pathology of the disease, the beta amyloid deposits or neurofibrillary tangles that are characteristic of the disease.

The only current approved neuroprotective therapy in Europe is memantine ( Namenda, Axura), which is already approved in the US and has been for some time. Neuroprotection is seen as a better alternative to acetylcholinesterase inhibitors, which treat the symptoms of the disease and are the most viable form of treatment currently available.