Vitality And Diversity Of Boston-Based Alzheimer's Disease Research Highlighted At Alzheimer's Association International Conference 2013

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Jul 12, 2013, 01:00 ET

BOSTON, July 12, 2013 /PRNewswire-USNewswire/ -- Three studies reported at the Alzheimer's Association International Conference® 2013 (AAIC® 2013) 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:

Early-stage drug development for new compounds to reduce beta-amyloid.
Identifying genes that impact the rate of decline in Alzheimer's disease.
Early detection of Alzheimer's, even in the preclinical stage of the disease before symptoms are evident.

"There is exciting work going on in Alzheimer's research throughout the world, and the Alzheimer's Association is proud to be a leader in research and support some of the most promising avenues of investigation globally and here in Boston," said Maria Carrillo, Ph.D., Alzheimer's Association vice president of medical and scientific Relations. "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.

"Yet our efforts alone and those of the scientists we fund cannot make the progress needed for the millions who have Alzheimer's now and the millions more who will get the disease unless we make bold steps now to wipe it out. Step one: the National Alzheimer's Plan must be fully implemented — $100 million more is needed in the federal commitment to Alzheimer's and dementia research this fiscal year," Carrillo concluded.

Boston Lab Seeks to Enhance the Drug Pipeline for Alzheimer's Disease

One therapeutic approach being tested for Alzheimer's disease 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 disease dementia.

However, changing the function of these enzymes, with minimal side effects, resulting in improved cognition has proven to be a mighty challenge, as shown in the recent Phase 2 failure of Avagacestat (Bristol-Myers Squibb), a drug that inhibited the action of gamma secretase.

Corinne E. Augelli-Szafran, Ph.D., is director of the Laboratory for Experimental Alzheimer Drugs (LEAD) at Harvard Medical School and Brigham and Women's Hospital, Boston, an academic-based medicinal chemistry and drug discovery laboratory. LEAD was founded in 2006 by Drs. Dennis Selkoe and Michael Wolfe and is unique to the medical school and hospital environment. LEAD's efforts are devoted to the discovery of new Alzheimer's disease therapeutics.

"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," Augelli-Szafran said. "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."

At AAIC 2013, Augelli-Szafran reported that 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.

Augelli-Szafran says some of the recent LEAD compounds demonstrate up to seven times the ability of Avagacestat at leaving the normal function of the enzyme intact. She says this attribute could translate to fewer side effects and less toxicity for these new compounds, but this still needs to be proven through further studies.

"Basic drug development work and animal studies are essential to fill the 'front end' of the drug development pipeline for Alzheimer's," Carrillo said. "With the Alzheimer's epidemic upon us, and the continued aging of the population, we need more treatment ideas developed and additional targets identified and the most promising therapies tested rigorously."

Boston-Based Group Identifies Genes Related to Rate of Decline in Alzheimer's

Alzheimer's disease 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 considerable 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 Drs. Robert Green and Paul Crane), they have amassed a relatively large sample of Alzheimer's cases with the longitudinal data necessary to study the topic in depth.

At AAIC 2013, Sherva reported genome wide association studies (GWAS) from participants in multiple research studies including the Alzheimer's Disease Neuroimaging Initiative (n=301), National Alzheimer's Coordinating Centers (n=865), Religious Orders Study/Rush Memory and Aging Project (n=323), and AddNeuroMed study (n=123). The combined GWAS identified at least four genetic variants strongly associated with rate of decline in Alzheimer's, including SPON1, MANB4A, KCNJ14, MAP3K1 and HIBADH.

"We found that the genes that influence rate of decline are largely different that those that influence Alzheimer's risk in general but are genes involved in pathways related to Alzheimer's risk," Sherva said. "The most interesting gene we identified is called SPON1, which has functions related to beta-amyloid generation and also regulates brain cell connectivity."

Combination of Cognitive Tests and Brain Scans Detect the Earliest Stages of Alzheimer's

Multiple recent unsuccessful late-stage drug trials in people with mild to moderate Alzheimer's disease have lead some in the field to believe that treating people when dementia symptoms are apparent is too late in the disease process and that we must move detection and intervention earlier in order to be effective. Some experts believe that 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. This is described as preclinical (or presymptomatic) Alzheimer's in new diagnostic criteria published by the U.S. National Institute on Aging and the Alzheimer's Association.

One example of testing this strategy this is the Anti-Amyloid treatment in Asymptomatic Alzheimer's Disease (A4) trial, where researchers from the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital, Boston, will test an amyloid-clearing drug in older individuals thought to be in the pre-symptomatic stage of Alzheimer's disease. 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., 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, Boston, and colleagues tested whether performance on tests of memory and thinking in cognitively normal individuals was related to preclinical Alzheimer's disease.

The group studied 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 researchers found that people in the study with worse memory performance had higher PiB deposition and lower FDG metabolism in regions of the brain that are 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.

They also found that more highly educated individuals in the study performed normally on tests of memory despite lower FDG metabolism and higher PiB retention. "This may mean that education has a protective effect on cognitive performance in the early stages of preclinical Alzheimer's," Rentz said.

"Overall, our findings suggest that poor memory performance with both FDG metabolism and higher PiB deposition may help identify people who are at high risk for progression to Alzheimer's disease dementia," Rentz said.

About AAIC
The Alzheimer's Association International Conference (AAIC) is the world's largest conference of its kind, bringing together researchers from around the world to report and discuss groundbreaking research and information on the cause, diagnosis, treatment and prevention of Alzheimer's disease and related disorders. As a part of the Alzheimer's Association's research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

About the Alzheimer's Association
The Alzheimer's Association is the world's leading voluntary health organization in Alzheimer care, support and research. Our mission is to eliminate Alzheimer's disease through the advancement of research; to provide and enhance care and support for all affected; and to reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer's. Visit www.alz.org or call 800.272.3900.

SOURCE Alzheimer's Association