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