Amyloid β protein makes comeback as therapeutic target for Alzheimer's disease

For many years amyloid β protein was considered to be a promising therapeutic target in Alzheimer's disease but, for a long time, research results were very disappointing. The protein, which, together with tau protein, is regarded as a significant biomarker for Alzheimer's disease, has now made a comeback. Also, a recent Phase III study conducted at MedUni Vienna under the direction of Elisabeth Stögmann from MedUni Vienna's Department of Neurology is testing a monoclonal anti-amyloid-β antibody. Preliminary studies have shown that monoclonal antibodies directed at amyloid deposits (plaques) in the brain, can dissolve them. It is now intended to investigate whether it is possible, by destroying the plaques, to at least slow down the deterioration of memory function in these patients.

"After many years of failures with anti-amyloid therapies, there is hope that these can now, at the very least, effectively attack their targets - amyloid β plaques - and clear them out of the brain. The improved results that we have now obtained with anti-amyloid antibodies are largely due to the fact that higher doses of these treatments are being used," explains Alzheimer's expert Elizabeth Stögmann. MedUni Vienna is conducting a Phase III study of the drug aducanumab, given intravenously once a month. It directly attacks the protein deposits that characterise Alzheimer's disease and helps to dissolve them in the brain. This significantly reduces the plaques that are so typical of the disease. "Now that this beneficial effect has been proven, we will investigate whether clearing of the plaques can also help to stop, or at least slow down, the deterioration of memory function in those affected. There is once again hope!" says Stögmann, speaking to mark World Alzheimer's Day this coming Friday. However, the neurologist believes that the first concrete results will only be obtained in around two to three years time.

Unfortunately, dose adjustment and greater efficacy goes hand-in-hand with a larger number of side effects: ARIA (amyloid related imaging abnormalities) refers to the occurrence of porous blood vessels, which cause cerebral oedema. However, this side-effect is easily managed. This oedema primarily occurs in the initial phase of antibody treatment - if the dosage is cut back again, the oedema resolves itself and treatment can then continue as planned, in most cases without any recurrence. Says Stögmann: "In many cases, the patient does not notice any clinical symptoms of this, but I can see the oedema on the regular MRI scans and respond accordingly." Around one third of patients develop these changes.

Early detection by blood test as a milestone?
It is presumed that antibodies against the amyloid β protein work better the earlier they are given to the Alzheimer's patient. Currently, early detection of the disease, which affects around 100,000 people in Austria (130,000 people in total have some form of dementia) relies on the first apparent cognitive symptoms noticed by the patients themselves or by those around them. And that is in spite the fact that amyloid β plaques have already been depositing themselves in the human brain for 20 years without being noticed. So, in a few years time, there might also be a significant improvement in early detection: Stögmann reports that, at the world's largest conference on the subject of Alzheimer's, the AAIC in Chicago (www.alz.org/aaic), there was a presentation about a blood test that is being developed. This test is able to indicate the presence of amyloid β deposits in the brain with hitherto unseen accuracy, even in 50 to 60-year-olds, and hence identify any elevated risk of subsequently developing Alzheimer's disease. Says Stögmann: "Within a few years, this test could radically alter the landscape of Alzheimer's research and treatment."