Developing drugs that effectively slow the course of Alzheimer’s disease has been notoriously difficult. Scientists and drug developers believe that a large part of the problem is that they are testing these drugs too late in the progression of the disease, when significant damage to the brain makes intervention much more difficult.
“Drugs like Lilly’s gamma secretase inhibitor failed because they were tested in the wrong group of patients,” says Sangram Sisodia, director of the Center for Molecular Neurobiology at the University of Chicago. People in the mid or late stages of the disease “are too far gone, there is nothing you can do.”
New brain imaging research may help solve that problem. Two studies presented at the Society for Neuroscience conference in San Diego this week identified changes in the brains of people who would go on to develop the disease. Researchers ultimately hope to use these changes to select patients for clinical tests of new drugs before they have developed signs of dementia.
“Brain changes that predict progression will hopefully allow us to detect the disease early, before it has caused irreversible damage,” said Sarah Madsen, a graduate student at the University of California, Los Angeles, at a press briefing at the conference.
Recent research has focused on people with a condition known as mild cognitive impairment, which involves memory loss and other cognitive problems and can be a precursor to Alzheimer’s. However, not everyone with this disorder will go on to develop the disease. A reliable method of predicting who will develop Alzheimer’s would enable drug developers to focus their clinical testing. By testing drugs only in this carefully selected group, drug makers could more easily see the potential benefit of an experimental drug. It would also help them to avoid unnecessarily subjecting people to health risks.
Sarah George, a graduate student at Rush University Medical Center, in Chicago, analyzed brain scans of 47 people with mild cognitive impairment, 22 of whom went on to develop Alzheimer’s over the next six years. She focused on a part of the brain called the substantia innominata, which is known to be severely affected in Alzheimer’s. Existing drugs for treating the disorder target a chemical messenger, acetylcholine, made by neurons in this part of the brain.
While George didn’t find differences in the volume of the substantia innominata between the two groups, she did find differences in the parts of the brain that those neurons connect to. People who went on to develop the disease had significant thinning in three connected areas of the cortex involved in memory, attention, and integration of sensor and motor information.
The results are promising, says Sisodia. He says the findings may also shed light on the earliest progression of the disease. Research from animal studies suggests that synapses—the connections between neurons—are the first part of the brain to suffer. While still just a theory, it’s possible that the brain regions that receive input from the substantia innominata shrink before that region itself does because they are losing their incoming synapses. However, he says, larger studies are needed to determine how accurate a predictor of Alzheimer’s this measure can be.
In a second study, UCLA’s Madsen analyzed MRI scans from 400 elderly individuals, some healthy, some mildly impaired, and some severely impaired, who had previously undergone brain scans, cognitive testing, and other types of medical testing. She focused on a c-shaped region in the center of the brain known as the caudate nucleus, which plays a key role in motor control and attention. Using mathematical tools to compare the size and shape of the caudate nucleus across different groups, she found that the caudate had shrunk most significantly in people with Alzheimer’s disease—it was 7 percent smaller than in healthy people. People with mild cognitive impairment also showed some decline, about 4 percent compared to controls. Within the latter group, those who went on to develop Alzheimer’s within the next year had a smaller caudate than those who did not.
Before drug developers can begin to use markers such as these to select patients for clinical testing, researchers need to better document early changes associated with the disease, says Sisodia. He points to one ongoing trial in Colombia that involves studying families who carry a genetic mutation that guarantees development of Alzheimer’s. Because scientists know approximately when people with the mutation will develop the disease, they can carefully analyze their brains for early changes.
“Before drug trials, we need to better solidify the data,” says Sisodia. “That’s why doing the study in Colombian people to study the natural history of disease is so important. They can study the progression from a normal individual with perfect cognition to abnormal cognition and look for the cellular correlates of behavior.”