Alzheimer Related News Items
News as of 11/01/04
For more info on these abstracts write/call Ed Cabic (edcabic@comcast.net or 410-992-7197)
For more AD information, see Alzheimer Information athttp://www.connext.net/~seniors/infoad.htm
Copies of these reports are posted there
This web page was started at the Florence Bain Senior Center in Columbia MD
Top Items
Anti-cholesterol Drug Treats AD in Mice - A drug that jams a key enzyme regulating cholesterol drastically reduces the levels of brain-clogging amyloid plaque in mice engineered to have a human form of the amyloid protein. According to Dora Kovacs and her colleagues at the Massachusetts General Hospital in Boston, the findings suggest that such inhibiting drugs could be used to treat and prevent AD. CP-113,818 mimics a cholesterol molecule that the enzyme, called “acyl-coenzyme A: cholesterol acyltransferase” (ACAT), converts into a form of cholesterol that the cell stores in droplets. When CP-113,818 is administered, it plugs into the “active site” of ACAT, jamming its operation and preventing the enzyme from processing cholesterol. Cholesterol is required in the production of the short protein called Aß peptide, the building block for the amyloid plaque that clogs the brain in AD, ultimately killing brain cells. In the mouse experiments, the researchers administered CP-113,818 by implanting slow-release biopolymer pellets under the skin of both normal mice and transgenic animals engineered to have the human form of the aberrant protein that leads to Aß peptide. The researchers found that treatment of the normal mice markedly reduced the levels of the storage form of cholesterol in their brains. And in the transgenic animals, the treatment reduced the accumulation of amyloid plaque by 88%–99% percent and reduced the storage form of cholesterol by 86%. When the researchers tested the treated versus untreated animals, they found a slight improvement in the animals’ ability to learn and remember the location of a submerged platform in a water tank--a standard test of learning and memory. “Our results suggest that slow-release biopolymer administration of ACAT inhibitors may be considered as a potential strategy for the treatment and prevention of AD, alone or in combination with statins,”they wrote. PR 10/13/04 Neuron, 44, No. 2, Oct. 14, 2004, pg 227–238
Drugs
FDA Approvals for New Formulations of ARICEPT AD Drug - Eisai has announced that its U.S. subsidiary, Eisai Medical Research Inc, has received approvals from the U.S. Food and Drug Administration (FDA) on 1018/04 for ARICEPT (donepezil hydrochloride) for an orally disintegrating tablet and a liquid formulation. ARICEPT, an acetylcholinesterase inhibitor developed by Eisai Co., Ltd. in Japan, increases the concentration of acetylcholine, a neuro-transmitter in the brain. The new forms of ARICEPT are designed to make administration easier for AD patients who have difficulty swallowing tablets. MedicalNewsToday.com 10/25/04
New Evidence to Help Explain Statins’ Effects in AD - Scientists at Jefferson Medical College and the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia have taken another step in understanding the potential effects of anti-cholesterol drugs on AD. They have identified a biochemical pathway that affects the activity of statins, particularly their ability to break down an early form of the protein amyloid that clusters and forms sticky plaques in the AD brain. The results may eventually help provide new targets for anti-amyloid drugs to help treat AD. Some epidemiological studies have found a link between people taking statin drugs to lower blood cholesterol and a lower incidence of AD. Statins work by inhibiting an enzyme involved in cholesterol production, and currently are being tested in clinical trials for their possible effects in slowing the progression of AD. In a series of experiments, Steve Pedrini, Ph.D., a postdoctoral fellow in Neurology in Jefferson Medical College of Thomas Jefferson University and in the Farber Institute for Neurosciences at Jefferson, and his co-workers found evidence suggesting that an enzymatic pathway called Rho/ROCK may play an important role in the metabolism of APP, which is an early form of amyloid, and in turn, the ability of statins to break down a form of APP. “It’s particularly important to understand the pathways involved in AD, especially to find more specific therapies,” Dr. Pedrini says. He presented his results October 25, 2004, at the annual meeting of the Society for Neuroscience in San Diego. PR 10/25/04
Janssen Pharmaceutica Products, L. P. Announces Campaign for Safe Medication
Dispensing - Janssen Pharmaceutica Products, L.P., announced 1022/04 it has learned of several
reports of errors in prescribing and dispensing of the medication REMINYL(R)
(galantamine hydrobromide), for mild to moderate AD. These errors were due to confusion
between REMINYL and the diabetes drug AMARYL®) (glimepiride), which is marketed by
Aventis Pharmaceuticals. The administration of AMARYL to patients with AD and without
diabetes mellitus has resulted in serious adverse events, including severe hypoglycemia and
death. In order to raise awareness and to educate prescribers and pharmacists about these
medication errors, Janssen is launching a campaign to help prevent medication prescribing
and dispensing errors. The program includes outreach to pharmacists, physicians and
consumers through a variety of targeted communications. PR 10/22/04
Genes & Genetic Issues
Research Uncovers Role of Apolipoprotein E in AD - A research team led by University of South Florida (USF) neuroscientist Huntington Potter, PhD, CEO of the Johnnie B. Byrd Sr. Alzheimer’s Center & Research Institute, for the first time has defined how the protein Apolipoprotein E (ApoE) contributes to both the formation of amyloid brain lesions and the memory loss associated with AD. The research was conducted jointly by USF and the Byrd Institute. Previous work has shown that the inflammatory protein ApoE can speed the buildup in the brain of amyloid plaques, the major pathological hallmark of AD. These deposits of plaques are composed primarily of the amyloid-beta protein (AB). However, the mechanism by which ApoE exerted its ill effects on AD was unclear. In the first paper the USF/Byrd Institute team found that ApoE is responsible for converting harmless AB into the toxic fibrous deposits, known as filamentous amyloid. The researchers showed that mice with ApoE possessed 3200 times more filamentous amyloid than those without the gene. Diffuse deposits of AB can occur in the elderly in the absence of AD, and are thought to be a normal aspect of aging, while filamentous amyloid is a toxic product of AD. In the second paper the researchers indicate that the process of altering AB from its diffuse form into filamentous amyloid is needed to damage nerve cells in parts of the brain controlling memory and cognition. Mice with AD showed memory deficits only when the ApoE gene was present. “The implication of these studies is that the amyloid promoting activity of ApoE is essential for the development of both AD pathology and cognitive decline,” said Dr. Potter, professor of biochemistry and molecular biology who holds the Pfeiffer Endowed Chair in Alzheimer’s Research at USF. “Thus, preventing ApoE from acting upon AB may prove to be an effective means of therapeutic intervention.” Medical News Today 1030/04 First Paper: Journal of Alzheimer’s Disease 6 (2004) 509-514 Second Paper: Neurobiology of Aging,25,(9):1153-1167 Oct 2004
Caregivers
Major Overhaul Needed in End-of Life Care for Patients with Dementia - Three University
of Chicago geriatricians are calling for creative and wide-reaching solutions to the problem of
sub-optimal end-of-life care for patients with dementia. An estimated 500,000 people die every
year in the United States suffering from AD or related diseases and many of them receive
inadequate pain control, are subjected to ineffective and invasive therapies such as tube feedings,
and do not receive the benefits of hospice care. “The nature of the illness is the root cause of the
problem,” said Greg Sachs, M.D., professor of medicine, section chief of geriatrics at the
University of Chicago and first author of the study. “Our health care system is oriented toward
treatment of acute illness but dementia produces a long, slow, unpredictable decline.”
The Chicago geriatricians list the barriers to optimal care for such patients and suggest ways to
get past them. The first hurdle is the unwillingness of physicians and families to think of
dementia as a terminal illness. A second barrier is the inability of physicians to predict the time
of death. A third barrier is the poor fit between dementia and health care financial incentives,
which reward providers for transferring rapidly declining patients into hospitals – where the
process of dying is prolonged. The solutions involve education, better prognostic tools, and
changes in the health care system. Geriatrics, dementia, and palliative and end-of-life care are all
under-represented in medical school curricula and deserve more attention as the numbers of
elderly continue to increase. PR 10/14/04 Journal of General Internal Medicine, Oct. 2004;
19:1057-1063
National Institute on Aging, Industry Launch Partnership, $60 Million AD Neuroimaging
Initiative - The National Institute on Aging (NIA) in conjunction with other Federal agencies,
private companies and organizations launched on 10/13/04 a $60 million, 5-year public-private
partnership — the AD Neuroimaging Initiative — to test whether serial magnetic resonance
imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and
neuropsychological assessment can be combined to measure the progression of mild cognitive
impairment (MCI) and early AD. The study could help researchers and clinicians develop new
treatments and monitor their effectiveness as well as lessen the time and cost of clinical trials.
The project is the most comprehensive effort to date to find neuroimaging and other
biomarkers for the cognitive changes associated with MCI and AD. “This is an extraordinary
pooling of talent and resources toward a common goal — delaying or preventing AD,” says
Richard J. Hodes, M.D., Director of the NIA. “The initiative should become a landmark study in
the development of neuroimaging and other biomarkers, helping us to find biological changes
early so that we can identify the people at highest risk of the disease and test the
effectiveness of new therapies more quickly and efficiently.” Information about the
participating research sites and co-investigators leading various aspects of research may be
obtained from the NIA. While recruitment for the study will not begin until spring 2005, people
interested in participating in the study can contact the NIA’s AD Education and Referral
(ADEAR) Center at 1-800-438-4380 for additional information. PR 10/13/04
New Oral Vaccine for AD - Researchers at the National Institute for Longevity Sciences, NCGG, Japan and Center for Neurological Diseases, Brigham & Women’s Hospital, Harvard Institute of Medicine shows that a new oral vaccine treatment is effective in reducing AD pathology. The researchers attached Aß DNA to an adeno-associated virus vector and administered this vaccine to mice orally. Not only were the Aß levels decreased, but un unwanted T-cell immune response was significantly reduced. A single dose of this vaccine enhanced the production of Aß-antibodies for more than 6 months. Immunohistochemistry of the mouse brain tissue showed that the extra-cellular amyloid deposits were clearly decreased compared to the non-treated mouse. Hideo Hara, M.D, writes “This new oral vaccine does not induce strong T cell immune reactions, and hence it could reduce the side effect of such meningoencephalitis…This new therapy seems to be effective for prevention and treatment of AD.” MedicalNewsToday.com 1026/04 Journal of Alzheimer’s Disease, Vol.6, No. 5:483-488
Drinking Tea Might Delay AD - Drinking tea appears to affect the brain in a similar way as drugs prescribed for AD, UK researchers report. The team, based at Newcastle University’s Medicinal Plant Research Center, investigated the properties of green and black tea, as well as coffee, in a series of laboratory experiments. The results showed that both types of tea inhibited the activity of enzymes associated with the development of AD. Coffee, however, had no significant effect, according to a report in the current edition of Phytotherapy Research. The teas inhibited the activity of acetylcholinesterase -- the same mechanism of action used by drugs such as Novartis’ Exelon and Pfizer’s Aricept. The teas also hindered the activity of the butyrylcholinesterase, which has been found in senile plaques in the brains of AD patients. Green tea obstructed the activity of beta-secretase, which also plays a role in the production of senile plaques. “Although there is no cure for AD, tea could potentially be another weapon in the armory which is used to treat this disease and slow down its development,” lead researcher, Dr. Ed Okello, said in a statement. However, he added in a telephone interview that there is no published evidence showing that rates of AD are any lower in tea-loving countries such as Britain, China and Japan. By Richard Woodman Reuters 1026/04 Phytotherapy Research, Aug. 2004 18,(8);624-627
High-fat Diet Could Harm the Brain - A high-fat diet could harm the brain. And trans-fats,
such as those found in margarine, and which are often used to increase the shelf-life of foods, are
the worst culprits, suggests a new study. Ann-Charlotte Granholm of the Medical University of
South Carolina in Charleston, US, says she became concerned about trans-fats after seeing how
they are made. Hydrogen is bubbled through an oil, and metals such as zinc and copper are added
to made it solid at room temperature. Zinc and copper are known to build up in the brain of
people with AD, she says, and there are signs that high fat diets could contribute to the risk
of this disease. Granholm presented the results of the study, which showed that trans-fats
adversely affected rat’s learning ability, at the Society for Neuroscience meeting in San Diego
102504 Granholm compared rats on a high-fat diet of about 12% soybean oil with those on a
high trans-fat diet, containing 10% hydrogenated fat and 2% cholesterol. Rats on the high
trans-fat diet showed learning difficulties, she reports. When the animals were required to
remember the position of hidden platforms in a water-filled maze, the animals on the trans-fat
diet learned more slowly and made more errors, particularly as the task was made harder. They
are about five times worse at the task, she says, than those animals on the soybean oil. The brains
of the animals also showed signs of damage in a region called the hippocampus, which is
important for learning and memory. “The high trans-fat diet may cause loss of a neural protein,”
she says. She also found that the brains of rats on this diet showed signs of inflammation. This is
a pilot study, stresses Granholm, and it is not clear yet whether these changes are temporary or
reversible. Barry Levin, an expert on obesity from the Veterans Affairs Medical Center in East
Orange, New Jersey, adds: “We must regard these as preliminary studies.” There may be many
factors involved - insulin levels, obesity, lack of exercise - rather than the fats themselves. “And
we all work on rats, so we can not necessarily extrapolate this to humans.” But he agrees that
there are many reasons to be cautious about a high fat diet. Granholm suggests preferentially
eating natural foods, rather than those with additives to increase shelf life. “A longer shelf-life
may make for a shorter life span for humans,” she cautions. NewScientist.com news service
1027/04
Other Items
2003 Progress Report on AD - Important AD research advances by scientists supported by the National Institute on Aging and other Institutes of the National Institutes of Health are presented in the new 2003 Progress Report on Alzheimer’s Disease. Included are descriptions of the impact of AD, current understanding of the possible causes of AD, research into new techniques for diagnosis, and studies of AD treatment. Other highlights include discussions of the transformation from healthy aging to AD, and the easliest cognitive and pathological changes in the development of AD. Summaries of recent studies are described, including: *biological markers; *oxidative stress; *beta-amyloid; *presenilins; *genetics; *inflammation; *lifestyle, diet, and other AD risk factors. NIA-sponsored initiatives in neuroimaging and genetics, and ongoing prevention and treatment clinical trials are also described. To obtain a copy of the 80 page report call 1-800- 438-4380. To view and download the report in pdf go to http://www.alzheimers.org/pr03/2003_Progress_Report_on_AD.pdf
Experiments Point to New Way to Combat AD - Researchers may have hit upon a strategy to prevent or treat AD-- although the technique has only been tested in the lab at this point. The signature of AD is the accumulation of plaques and tangles made up of abnormal amyloid protein, called amyloid beta, in the brain. The amyloid beta aggregations are toxic to nerve cells, and some way of stopping this clumping-together is needed. “To approach this problem, we envisioned a Trojan horse strategy,” Dr. Isabella A. Graef and colleagues write in the journal Science. The pathologists, from Stanford University Medical School in California, created “a small bifunctional molecule” that can bind to amyloid beta and at the same time latch on to a large “chaperone” protein. The intention was to create an entity bulky enough to stop amyloid beta proteins forming plaques. The team synthesized the key “linker” molecule by combining the dye Congo red, which is absorbed by amyloid, with an artificial structure that attaches to a large protein called FKBP. In a lab dish, low concentrations of the resulting three-part molecule virtually prevented beta amyloid from forming fibrils, although it was still able to form small aggregates. The researchers next showed that neurons growing in culture were damaged or killed by beta amyloid, but neurotoxicity was significantly reduced by the addition of the new compound. Graef’s group concludes that “the recruited-chaperone approach might provide a viable complement” to other research efforts to prevent amyloid beta accumulation in AD. However, it will be some time before this technology has clinical application, a chemist at Harvard Medical School in Boston comments in a Science news release. For one thing, Dr. Peter Lansbury points out, Congo red does not enter cells or cross the blood-brain barrier so another component of the linker molecule will have to be found. Reuters Health 10/28/04 Science, 306, 5697, 865-869 29 Oct. 2004
Sirenade Pharmaceuticals Announces Breakthrough in the Development of Tau-Directed
Therapeutics to Treat AD - Sirenade Pharmaceuticals AG announced 10/11/04 the expansion
of its Tau program, having demonstrated proof-of-concept in the first successful preclinical study
for a tau-directed protein to treat AD. Tau-related tangles and beta-amyloid peptide related
plaques are the two known pathologies associated with AD. Until now, attempts to develop
therapies directed at tau-related tangles have had only limited success. Sirenade’s lead product
has the potential to be the first tau-directed disease-modifying agent for AD and as such
represents a breakthrough in the industry. Sirenade’s lead tau-directed product is a kinase inhibitor that represses the formation of tau-protein related neurofibrillary tangles (NFTs) in AD. In the study, this kinase inhibitor demonstrated the ability to delay the onset of Tau-related pathology in an animal model of NFT formation, and as such is the only drug candidate with proven efficacy in this model. Along with the formation of beta-amyloid plaques, the formation of NFTs is one of the hallmarks of the neurodegeneration seen in AD. The results of this preclinical study were presented at the 9th International Conference on Alzheimer’s Disease and Related Disorders on 19th July. PR 10/11/04
adn1104.htm