Hitting the Target: Researchers Take Aim to Find a Drug Therapy for Alzheimer’s Disease.
The latest clinical studies investigate different paths to a cure.
By Kevin Gault
There is no drug that can cure Alzheimer’s disease, but there are reasons for hope. A group of medications can ease the symptoms of Alzheimer’s and researchers are tirelessly exploring many paths in their quest for a cure.
It’s important to understand how existing drugs work as well as their limitations. “These drugs work for some people in slowing the progression of symptoms,” says Laurie Ryan, Ph.D., Program Director for Alzheimer’s Disease Clinical Trials at the National Institute on Aging. “They can help for a period of time, but as the disease progresses, it overpowers the drugs and they lose their effectiveness.”
During mild to moderate stages of Alzheimer’s, FDA- approved medications called cholinesterase inhibitors (sold as Aricept, Exelon and Razadyne) slow progression of the disease and sharpen learning and attention span. Scientists don’t have a complete understanding of how they work, but research shows that these drugs prevent the loss of a chemical in the brain that is essential for memory and reasoning.
Namenda, a drug classified as an NMDA antagonist, helps in the moderate to severe phases of Alzheimer’s. This medication keeps the amount of the brain chemical glutamate at a steady level, which helps maintain normal brain function longer.
Temporary improvement from these drugs is beneficial for people with Alzheimer’s, but researchers are constantly searching for a treatment that will permanently restore normal brain function and quality of life.
A Long, Complex Process
Research for a drug that cures Alzheimer’s is a complex, challenging process that relies on scientific discoveries of new ways to attack the disease. The process is expensive. According to the National Institutes of Health (NIH), it takes 10 to 15 years from the discovery of a way to create a new drug until it reaches the marketplace, with an average total cost of $1.8 billion for research and development.
Scientists are making large-scale efforts to find a drug that cures Alzheimer’s. One example is the Alzheimer’s Disease Translational Research Program. Orchestrated by the NIH, this program has conducted more than 60 research projects and produced several compounds that pharmaceutical companies have chosen for further development.
A Variety of Approaches
Researchers at the University of Minnesota Center for Drug Design have created a promising synthetic compound that, in laboratory trials with mice, prevents the mental decline from Alzheimer’s.
“The goal of our research was to find a way to stop the body from producing beta-amyloid protein, which can accumulate in the brain and form hard plaque that causes changes in the brain associated with Alzheimer’s,” says Swati More, Ph.D., Research Associate at the Center for Drug Design. “We developed a drug candidate called psi-GSH that prevents the accumulation of this protein. Psi-GSH acts in a way that has never been tried before for the treatment of Alzheimer’s disease.”
Another new path that researchers are taking is using brain imaging to assess the effects of early treatment for Alzheimer’s. Many current drug trials include brain imaging and testing of blood or spinal fluid.
One reason for this is that scans of the brain—such as magnetic resonance imaging (MRI) and positron emission tomography (PET)—can now detect plaque in the brain thanks to a substance called Amyvid. This liquid, which is injected into the bloodstream, attaches to beta-amyloid plaque in the brain, making the plaque visible in the scan.
“Until now, we haven’t been able to detect beta-amyloid plaque in the brain,” says Richard Mohs, Ph.D., Executive Director, Neuroscience Clinical Development, Eli Lilly and Company, “but with the diagnostic agent Amyvid, we can use a PET scan to estimate the amount of plaque in adult patients who are being evaluated for Alzheimer’s disease and other causes of cognitive decline.”
Many researchers believe that a drug therapy that cures or manages Alzheimer’s will involve a “cocktail” of medications aimed at several targets, an approach that is similar to current treatments for many cancers, hypertension and diabetes.
One of these possible targets is a protein called tau. With Alzheimer’s, this protein in the brain becomes tangled and reduces the ability of brain cells to function properly. Finding drugs that prevent tau from twisting into tangles is a goal of current research.
Inflammation is another research target. Studies have revealed a lot about the body’s overall inflammatory response and these insights might lead to anti-inflammatory treatments that manage Alzheimer’s.
Recent studies have shown that the way brain cells process insulin may be linked to Alzheimer’s disease. Scientists are assessing the role of insulin in the brain and these studies may produce medications that support cell function and prevent Alzheimer’s.
“Drug therapies hold great promise for the future, but it’s important to keep in mind that lifestyle factors can also have an impact,” says Dr. Ryan. “Exercise, good nutrition and staying mentally active lead to healthier brain aging, which won’t prevent someone from getting Alzheimer’s but will keep their quality of life at a higher level longer. We can’t change our genetic makeup, which is a factor in developing Alzheimer’s, but we can take control of our lifestyle.”
Three Drugs to be Tested
Researchers are preparing to test three drugs to determine their effectiveness in treating early-onset Alzheimer’s disease, which is genetically determined and can affect people who are as young as in their 40s. The goal is to find a treatment that can help prevent memory loss and thinking problems associated with Alzheimer’s from occurring in the first place. The drugs to be studied all combat the toxic effects of beta-amyloid. They are:
• Gantenerumab, an antibody that attaches to beta-amyloid and helps to remove it from the brain.
• Solanezumab, an antibody which binds to beta-amyloid before it clumps together, inhibits the plaque formation process.
• LY2886721, a drug that blocks an enzyme, beta-secretase, which is critical for beta- amyloid formation, thereby reducing the amount of beta-amyloid produced in the first place.
The study will involve 160 volunteers who have one of several genes that cause early-onset Alzheimer’s. “In most trials in Alzheimer’s disease, people are treating the disease after the damage is being done to the brain,” says study leader Dr. Randall Bateman of Washington University. “And in this trial we’re trying to treat the disease before that damage gets done.”