Three studies reported at the Alzheimer's Association International Conference 2013 (AAIC) demonstrate the vitality and diversity of Alzheimer's disease research being conducted in Boston, the host city for this year's conference.
The three research reports cover (1) early-stage drug development for new compounds to reduce beta-amyloid, (2) identifying genes that impact the rate of decline in Alzheimer's and (3) early detection of Alzheimer's, even in the preclinical stage of the disease before symptoms are evident.
"These Boston-based research projects will enable us to learn about the course and progression of Alzheimer's, how to create effective drugs for the disease and how to catch it early enough that we can eventually prevent it,” said Maria Carrillo, Ph.D., Alzheimer's Association vice president of medical and scientific relations.
One therapeutic approach being tested for Alzheimer's is to reduce the production of the beta amyloid protein and its accumulation into amyloid plaques by changing the action of two brain enzymes—beta-secretase and gamma-secretase—that create beta-amyloid from the amyloid precursor protein. Production and accumulation of beta-amyloid in the brain is thought to initiate a cascade of events leading to Alzheimer's dementia.
However, changing the function of these enzymes with minimal side effects, resulting in improved cognition, has proven to be a challenge, as shown in the phase II failure of Avagacestat (Bristol-Myers Squibb), a drug that inhibited the action of gamma secretase.
"The main mission of our laboratory is to identify new drugs, called gamma-secretase inhibitors, that block the ability of the brain enzyme called gamma-secretase to produce beta-amyloid protein," said Corinne E. Augelli-Szafran, Ph.D., director of the Laboratory for Experimental Alzheimer Drugs (LEAD) at Harvard Medical School and Brigham and Women's Hospital, Boston. "However, gamma-secretase also has a normal function in the body. Therefore, it is essential that any potential drug only blocks beta-amyloid production while leaving the normal function of gamma-secretase intact."
Augelli-Szafran said her laboratory has successfully identified several new compounds with these attributes. Based on studies in animals, these gamma-secretase inhibitors also possess other important advantages, such as smaller size, better solubility, improved brain entry and a greater ability to reduce beta-amyloid production while leaving the normal function of gamma-secretase intact, over similar drugs that had been tested in clinical trials and failed, according to the researchers.
Alzheimer's is characterized by progressive decline in cognitive functioning, especially in memory but also executive functioning (including planning, attention and problem solving) and global cognition. Each person may experience Alzheimer's differently and there are differences in rates of decline between affected individuals.
"If we can understand more about the genetic basis of this variability in rate of decline, it could help illuminate the biological pathways involved in disease progression," said Richard Sherva, Ph.D., research assistant professor in the department of Biomedical Genetics at Boston University School of Medicine. "It also could inform the development of therapies to slow the progression of disease."
Sherva and colleagues are utilizing research funds awarded by the Alzheimer's Association to study the genetics of the rate of Alzheimer's-related cognitive decline in a large population from a completed clinical trial. By expanding their work into a multi-institutional consortium (known as Genetic Architecture of Rate of Alzheimer's Decline, or GENAROAD, led by Robert Green and Paul Crane), they have amassed a sample of Alzheimer's cases with longitudinal data.
"We found the genes that influence rate of decline are largely different than those that influence Alzheimer's risk in general but are genes involved in pathways related to Alzheimer's risk," Sherva said.
Multiple recent unsuccessful late-stage drug trials in people with mild to moderate Alzheimer's disease have lead some to believe that treating people when dementia symptoms are apparent is too late in the disease process and that detection and intervention must be moved earlier in order to be effective. Some experts believe the best time to treat individuals with Alzheimer's is when cognitive performance is still normal but there is evidence of Alzheimer's changes in the brain.
In the Anti-Amyloid treatment in Asymptomatic Alzheimer's Disease (A4) trial, researchers from the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital test an amyloid-clearing drug in older individuals thought to be in the pre-symptomatic stage of Alzheimer's. The trial will enroll 1,000 older individuals with PET scan evidence of amyloid in their brains—a hallmark of Alzheimer's—but who do not show clinical symptoms of the disease. A key challenge is how to measure and track their cognitive status throughout the trial.
Dorene M. Rentz, Psy.D., an associate professor of Neurology at Harvard Medical School and a neuropsychologist in the Departments of Neurology at Massachusetts General Hospital and Brigham and Women's Hospital, tested whether performance on tests of memory and thinking in cognitively normal individuals was related to preclinical Alzheimer's.
The study included 129 normal older adults, age 65 to 85, with cognitive tests and two PET brain scans: one that measures how the brain uses glucose (FDG metabolism) and another scan that measures the amount of brain amyloid plaques (PiB deposition).
The study found people with worse memory performance had higher PiB deposition and lower FDG metabolism in regions of the brain commonly affected in Alzheimer's. In contrast, individuals who performed worse on non-memory thinking tests had lower FDG metabolism but a normal PiB scan.
It also found more highly educated individuals in the study performed normally on tests of memory despite lower FDG metabolism and higher PiB retention. "This may mean education has a protective effect on cognitive performance in the early stages of preclinical Alzheimer's," Rentz said.