Alzheimer's Club

"WEDNESDAY, Dec. 28 (HealthDay News) -- Americans are living longer than ever, and by modifying their lifestyles they can also live healthier, happier lives well into their 80s, researchers report.

In a new study, researchers found that in a predominantly Mormon county in Utah, the majority of people reported enjoying good or excellent health, even past age 85. In addition, their later life is not necessarily a steady decline in health, but rather more healthy years followed by a short period of ill health right before death.

The report appears in the February 2006 issue of the Journal of the American Geriatrics Society.

"We tend to hear about physical illness and conditions that are more common with aging," said lead researcher Kathleen Welsh-Bohmer, director of the Bryan Alzheimer's Disease Research Center at Duke University. "So we tend to get a negative perspective of aging. But many older Americans are aging into their 80s, perhaps having some physical illnesses, but having a greater quality of life."

"Overall many of the [study] participants were enjoying what could be considered a healthy life," Welsh-Bohmer added. "They had excellent to very good self-reported health, and in many areas."

For its study, Welsh-Bohmer's team collected data on 3,413 men and women, all 65 and older, who participated in the Cache County Memory Study, an ongoing population-based study of dementia and other health problems. Cache County, located in northern Utah, has the highest conditional life expectancy for men at age 65 in the country, and 91 percent of the population belongs to The Church of Jesus Christ of Latter-day Saints.

The researchers found that 80 percent to 90 percent of participants aged 65 to 75 reported excellent or good health, as did about 60 percent of those over age 85. In addition, 90 percent of participants were healthy enough to live at home, including people 85 and older.

Up to 50 percent of those surveyed had no major disease. The rest were living with at least one physical ailment. As people got older, the percentage of those with a chronic illness increased slightly. However, 40 percent of men and 42 percent of women 85 and older did not suffer from any major disease, Welsh-Bohmer's group found.

"A substantial part of our population is aging beyond age 65," Welsh-Bohmer said. "Despite having some illnesses, they perceive their life and their health to be very good."

Welsh-Bohmer noted that the majority of the people in Cache County don't smoke or drink, and have strong family and community support.

But she believes these findings can be generalized to the U.S. population as a whole.

"There may be some things that are unique to this population," she said. "But it gives us a starting point to identify the factors that are important in giving overall quality to life at 70, 80 and beyond."

One expert thinks the religion of the people in the study accounts for their longer, healthier lives.

"Odds are the findings are significantly related to the underlying religious beliefs of this population," said Richard Suzman, the director of the Behavioral and Social Research program at the National Institute on Aging.

Suzman noted that other studies in special populations, such as Seventh Day Adventists, showed similar results. Dietary restrictions such as no smoking, no drinking, plus social cohesion are important factors in maintaining health and extending life expectancy, he said.

"A good part of how long you live and your health while you're alive is related to your health habits and being socially engaged," Suzman said. "A good part of life expectancy and health are under individual control."

Source: Forbes Magazine (last viewed 30 Dec (2005) [FullText]

"Signing a deal worth up to $300 million for one product - and possibly more if others come into play - Targacept Inc. partnered worldwide rights to its Phase II cognitive disorder drug, TC-1734, with AstraZeneca plc.

The agreement will result in a $10 million up-front payment from AstraZeneca to Winston-Salem, N.C.-based Targacept, as well as $26 million in research funding, a $20 million milestone payment for the start of Phase II development of TC-1734, and further milestone payments related to development, regulatory and commercial achievements of the product, all totaling up to about $300 million.

That figure does not include stepped double-digit royalties for rising sales of TC-1734, nor does it take into account additional milestone payments and royalties for other products that come out of their four-year research collaboration, which will begin once the agreement becomes effective following government clearances.

"It's not our first [partnership], but it's certainly our most significant to date," said J. Donald deBethizy, Targacept's president and CEO. "This is a key business milestone for us because it increases our probability of success" for TC-1734 and other cognitive disorder drugs.

With worldwide development and commercialization rights to TC-1734 (ispronicline) for Alzheimer's disease, cognitive deficits in schizophrenia and other cognitive disorders, AstraZeneca will fund all costs going forward, with one exception. Targacept will complete independently its ongoing Phase II trial of the product as a treatment for age-associated memory impairment (AAMI). The indication falls under AstraZeneca's global license because it covers the field of cognition.

"They support the AAMI indication, but it's not been a labeled indication up to this point," deBethizy told BioWorld Today, "and there's still quite a bit of work to be done with the FDA."

London-based AstraZeneca intends to start additional safety and product characterization studies of TC-1734. Following that, it could decide to move into Phase II development for Alzheimer's disease, cognitive deficits in schizophrenia or a related indication, triggering the milestone payment to Targacept.

AstraZeneca also would be responsible for development and commercialization of compounds that come out of the research collaboration. Targacept intends to use its Pentad drug discovery technology as part of that research. Each discovered drug that enters development would trigger additional milestone payments to Targacept, which also would receive royalties on those that reach the market.

If any of the compounds, including TC-1734, reach commercialization, Targacept has a co-promotion option for the U.S. market, but the company has not yet disclosed whether it plans to build its own sales force.

"We are not elaborating on that component of the deal at this point," deBethizy said. "It's sufficient to say that we are fortunate to have a co-promote option as part of this deal."

The agreement also contains a mechanism by which Targacept can offer to AstraZeneca compounds that act on different neuronal nicotinic receptor (NNR) subtypes than TC-1734.

TC-1734 has shown neuroprotective properties in preclinical studies, deBethizy said. "Its primary focus is symptomatic treatment, but it also offers the potential for disease modification if the preclinical data we have translates into clinical results."

NNRs are found on nerve cells. Targacept's products selectively target specific NNR subtypes to promote therapeutic effects and to limit side effects. Alzheimer's disease is one example of a cognitive disorder that has few treatment options and could benefit from Targacept's research.

"The current therapies are marginally effective," deBethizy said, adding that Alzheimer's disease represents a $3 billion worldwide market.

TC-1734 selectively targets the NNR subtype alpha4 beta2. With superior selectivity, the company has been able to "virtually eliminate activity," deBethizy said, at ganglionic and muscle NNR subtypes known to be involved in side effects of potential competitor drugs. The compound also could address a wide-open market of people with cognitive deficits in schizophrenia.

"Scientists estimate that 75 percent of the 9 million schizophrenics worldwide have cognitive deficits, and there is no approved therapy," deBethizy said.

Targacept has one marketed product, Inversine (mecamylamine hydrochloride), which was acquired from Sunnyvale, Calif.-based Layton Bioscience Inc. and is sold for hypertension. The drug was first developed by Merck & Co. Inc., of Whitehouse Station, N.J.

It also is developing mecamylamine HCl in a Phase IIb trial for depression, and TC-2696 in a Phase I dose-escalating trial for pain. A preclinical compound to treat depression and anxiety, TC-2216, should be ready for an investigational new drug application by the third quarter, while an IND for another preclinical compound for schizophrenia could be filed in the first half of 2007.

Originally formed as a wholly owned subsidiary of R.J. Reynolds Tobacco Co., Targacept became an independent company in August 2000. It filed for an $86.25 million initial public offering in May 2004, but withdrew it in March, citing unfavorable market conditions. (See BioWorld Today, May 18, 2004.)

The company plans to raise money sometime in 2006, possibly trying for an IPO again.

"We are certainly looking at that possibility," deBethizy said, adding that the company would be "looking at both public and private markets.""

Source: Karen Pihl-Carey. Targacept, AstraZeneca Enter TC-1734 Deal For Up To $300M. BioWorld (online 29 Dec 2005) [FullText]

"Neuroscientists say they've made substantial progress toward developing a new way to diagnose early-stage Alzheimer's disease: through brain scans.

Anne Fagan, Ph.D., associate professor of neurology at Washington University, led a study on these new detection tests. She presented the results at the Nov. 15 meeting of the Society for Neuroscience in Washington, D.C.

Fagan says that early detection of Alzheimer's could eventually prove useful in the clinical prevention and treatment of the disease.

"When clinical symptoms start," Fagan said, "the disease process has already been at work in the patient for many years and possibly even decades. Up to 30 percent of neurons in vulnerable areas are already dead, and you can't get them back. So finding markers that can help us identify patients prior to symptoms is really our big push now."

Fagan and her colleagues studied a group of 24 people, some of whom had cognitive impairments believed to be signs of mild Alzheimer's disease and some who were cognitively normal.

In those subjects with suspected Alzheimer's, the researchers found low levels of amyloid-beta 42 in their cerebrospinal fluid (CSF), which bathes the spinal cord and brain. This finding was not a surprise, as A-beta 42 is known to be the primary ingredient in the plaque buildups that are consistently found in Alzheimer's patients' brains. Decreasing levels of A-beta 42 in CSF would be expected as excess protein accumulates in the brain instead of being swept away in the fluid like it normally is.

For the second component of their research, the scientists looked at positron emission tomography (PET) scan results from these same patients' brains. The scans used a new imaging agent called PIB (Pittsburg compound B) that sticks to amyloid plaque long enough to be detected through a PET scan. The researchers found that the scans showed plaque in all those patients with low CSF levels of A-beta 42.

Interestingly, low CSF levels of A-beta 42 and corresponding brain scans positive for plaque were also found in three of the cognitively normal patients.

This raised a question: Will these three people develop the cognitive impairments characteristic of Alzheimer's disease sometime in the future?

"For now, definitive diagnosis of Alzheimer's disease still cannot be made until autopsy," Fagan said. "It's going to take a number of years for us to fully assess these results, because all we can do now is follow the participants closely, waiting to see if they eventually develop Alzheimer's dementia."

Fagan added that the study results provide new hope in the ongoing fight to find effective ways to detect and treat Alzheimer's disease.

"The hope is that 10 to 20 years from now, we'll give people a PIB scan, draw and analyze their CSF, and combine that with other factors to get a global score for their personal risk of Alzheimer's disease," she said. "We have disease-modifying treatments on the way to clinical trials right now, and tests that can help us detect Alzheimer's earlier will both help us put those treatments to better use and assess the results they produce in patients."

Alzheimer's disease affects up to 4.5 million Americans, most of them age 60 and older. The most common form of dementia among elderly people, Alzheimer's interferes with the parts of the brain controlling thought, memory and language. The cause of Alzheimer's disease is unknown, and for now there is no cure.

Neurologist Steve Poceta, a member of myDNA's Medical Advisory Board, says definitive diagnosis of Alzheimer's remains virtually impossible, especially early in the disease.

"This is frustrating for many patients and their families, which adds to the burden of this disease. Definitive diagnosis is presently desirable for prognosis and for social planning, but eventually is desirable so that treatments can be started as early in the process as possible."

He adds that the findings suggest that it might be possible to distinguish those people who have "mild cognitive impairment" suggestive of Alzheimer's from other patients.

"Unfortunately, this study suffers from the same problem that other studies have - the results are not 100 percent or even 99 percent. Some of the patients who appeared to be normal also had abnormal PET scans, so we do not yet know if this research tool will be useful in the clinic trying to diagnose patients."

"As the authors point out, early detection will be very important once we have medications that can treat the underlying disease process, as opposed to current medications that only treat the symptoms," Poceta says.

Currently, neither definitive early diagnosis nor disease-modifying therapy is possible at this time, but Poceta is excited about the study.

"Studies exactly like these are exciting and are beginning to show more promise in the battle against Alzheimer's. In the meantime, patients with Alzheimer's or related illnesses benefit the most from close contact with physicians, family members and other caregivers, as well as from available medications."

Source: Test predicts Alzheimer's? myDNA News (28 Dec 2005) [FullText]

"Increased communication between brain cells increases levels of amyloid beta, the key ingredient in Alzheimer's brain plaques, scientists at Washington University School of Medicine in St. Louis have found.
The findings showed that turning up brain cell firing rates drove up levels of amyloid beta in the spaces between brain cells. Corresponding drops in amyloid beta levels occurred when brain cells' ability to send messages was dampened or blocked completely.

The results, produced in mouse models of Alzheimer's, will appear in the journal Neuron on Dec. 22. They complement a Washington University study published earlier this year that used functional brain imaging to show that the brain areas that develop Alzheimer's plaques are also the regions that are the most active in healthy young people who are daydreaming or not carrying out a specific cognitive task (http://news-info.wustl.edu/news/page/normal/5621.html).

The two papers have researchers considering the possibility of someday slowing or preventing the development of Alzheimer's disease by using pharmaceuticals to selectively reduce some communication between brain cells. However, researchers still have to determine if increased levels of amyloid beta can be partially linked to particular classes of the nerve cell messengers and receptors that cells use to communicate with each other.

"Ideally, we will be hoping to find a drug or mechanism that could very specifically target the processes that lead to increased amyloid beta levels," says lead author John Cirrito, Ph.D., a postdoctoral research associate in neurology and psychology. "If we can identify these and find ways to modulate them, we'd have new ways of intervening in Alzheimer's disease."

Senior author David Holtzman, M.D., the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology, says that the results do not contradict earlier studies that suggested crossword puzzles, exercise and other mental stimulation can reduce the chances of developing Alzheimer's disease.

According to Holtzman, their new results and the WUSTL study published earlier this year instead offer further evidence that "cognitive idleness is not good from the perspective of Alzheimer's risk." The lead author of the earlier study, published in The Journal of Neuroscience, was Randy Buckner, Ph.D., associate professor of psychology at the School of Arts and Sciences and associate professor of neurobiology and radiology at the School of Medicine.

Together, these two studies may provide an explanation why specific regions are vulnerable to this disease. Holtzman and Cirrito speculate that activities such as crosswords and exercise may increase activity in brain areas less likely to be damaged by Alzheimer's and cause a corresponding reduction in activity levels in the regions consistently damaged by Alzheimer's disease.

"Almost all neurological diseases involve selective vulnerability--only certain classes of nerve cells or nerve cells found in particular regions are affected," Holtzman says. "Why that vulnerability is so selective often can be very difficult to determine, and Alzheimer's disease is no exception."

Washington University researchers became interested in connections between nerve cell activity levels and amyloid beta production when they read a paper two years ago from researchers at Cold Spring Harbor Laboratory and the University of Chicago that linked increased activity in nerve cell cultures to increased levels of amyloid beta.

Cirrito had previously modified a technique known as microdialysis to enable repeated sampling and measurement of amyloid beta levels in the brains of mice genetically modified to model human Alzheimer's disease. With Holtzman, Steven Mennerick, Ph.D., associate professor of psychiatry, and others, Cirrito used direct electrical stimulation and a variety of injected compounds to turn nerve cell communication up and down in the brains of living mice. They assessed the resulting effect on amyloid beta levels once every 30 minutes.

Through a series of these experiments, researchers linked increased amyloid beta levels to the release of synaptic vesicles, small packets containing chemical messengers known as neurotransmitters. The primary way nerve cells send messages to each other is to release the vesicles waiting at the synapse, a structure where the arms of two nerve cells almost touch. The neurotransmitters cross the synapse and bind to receptors on the surface of the receiving nerve cell. Normal brain physiology produces amyloid beta and naturally clears it from the brain, so Cirrito conducted a series of follow-up experiments to try to get a sense for whether increased synaptic vesicle release was affecting amyloid beta production or clearance.

"It's probably not clearance, and the effect on production is probably pretty small," he says. "Instead, it appears that synaptic activity is regulating the amount of amyloid beta that gets released from inside brain cells, where amyloid beta is produced. We're going to follow up with studies of whether particular neurotransmitters can be linked to changes in amyloid beta levels."

Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates brain ISF Aß in vivo. Neuron, Dec. 22, 2005.

Funding from the National Institutes of Health, the Alzheimer's Association, Eli Lilly and the MetLife Foundation supported this research.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

View online: http://mednews.wustl.edu/news/page/normal/6324.html?emailID=7540"

Source: Brain cell activity increases levels of key ingredient in Alzheimer's plaques. [FullText at Eurekalert (21 Dec 2005]

Eisai Co., Ltd. (Headquarters: Tokyo, President and CEO Haruo Naito) and Eisai Inc. (Headquarters: Teaneck, NJ, Chairman and CEO Hajime Shimizu) announced today that a reformatted version of the supplemental New Drug Application (sNDA) for ARICEPT® (donepezil HCl tablets) for treatment of severe Alzheimer's Disease has been resubmitted to the U.S. Food and Drug Administration (FDA). Eisai Medical Research Inc. (Headquarters: Ridgefield Park, President Mindell Seidlin, MD) submitted the revised application on December 16, 2005. The sNDA was originally submitted on August 31, 2005, but the FDA did not accept the application for filing due to deficiencies in its format.

An acceptance decision regarding the sNDA resubmission will be made by FDA within 60 days after receipt and review of its contents, according to FDA's usual procedure. Eisai will issue a press release to announce the status.

ARICEPT, which is co-promoted in the United States by Eisai Inc. and Pfizer Inc, is currently approved for treatment of mild to moderate Alzheimer's disease.

Information About ARICEPT Treatment in Alzheimer's disease

While there is no cure for Alzheimer's disease, medical treatments are available to manage symptoms of the disease. Once-a-day prescription ARICEPT® (donepezil HCl tablets) is indicated for mild to moderate Alzheimer's disease.

ARICEPT® is an acetylcholinesterase inhibitor and is believed to work by inhibiting the breakdown of acetylcholine, thereby increasing available levels of this chemical in the brain. There is an established association between the loss of acetylcholine, a brain chemical involved in memory and thinking, and Alzheimer's disease.

In a progressively degenerative disease such as Alzheimer's, improvement, stabilization, or a less-than-expected decline over time is considered a positive response to treatment. These types of responses have been observed in patients treated with ARICEPT in clinical trials for Alzheimer's disease. Individual responses to treatment vary, and some patients may not respond.

ARICEPT is well tolerated but may not be for everyone. Some people may have nausea, diarrhea, not sleep well or vomit. Some people may have muscle cramps, feel very tired, or may not want to eat. In studies, these side effects were usually mild and went away over time. People at risk for stomach ulcers or who take certain other medicines should tell their doctors because serious stomach problems, such as bleeding, may get worse. Some people who take ARICEPT may experience fainting.

For more information about managing Alzheimer's disease and about ARICEPT, and for prescribing information on ARICEPT, please see accompanying full prescribing information or visit http://www.aricept.com.

About Eisai Co., Ltd.
Eisai Co., Ltd. is a research-based human health care company that discovers, develops and markets products in more than 30 countries. Through a global network of research facilities, manufacturing sites and marketing subsidiaries, Eisai actively participates in all aspects of the worldwide health care system. Eisai employs more than 8,000 people worldwide.

About Eisai Medical Research Inc.
Eisai Medical Research Inc. is a U.S. pharmaceutical subsidiary of Eisai Co., Ltd. Eisai Medical Research Inc. was established to focus on clinical research and to expedite clinical drug development of new chemical entities and of new indications for marketed products.

About Eisai Inc.
Eisai Inc. is a U.S. pharmaceutical subsidiary of Eisai Co., Ltd. Established in 1995, Eisai Inc. began marketing its first product in the United States in 1997 and has rapidly grown to become an integrated pharmaceutical business with sales of approximately $2 billion in fiscal year 2004 (year ended March 31, 2005).

Source: Medical News Today (27 Dec 2005) [FullText].

"The search for new biomarkers to detect Alzheimer's disease before signs of memory loss appear has advanced an important step in a study by researchers at Washington University in St. Louis, and the University of Pittsburgh.

The researchers combined high-tech brain imaging with measurement of beta-amyloid protein fragments in cerebrospinal fluid ( CSF ). They found that greater amounts of beta-amyloid containing plaques in the brain were associated with lower levels of a specific protein fragment, amyloid-beta 1-42, in CSF...

The study, published in the Annals of Neurology, is the first to examine the relationship between levels of amyloid plaque deposits in the brain and different forms of beta-amyloid in CSF in living humans.
The method studied might one day help to more accurately diagnose Alzheimer's disease , even before the appearance of cognitive symptoms, and to monitor disease progression. In the near term, the findings could be useful in a research context, allowing scientists to track the effects of potential beta-amyloid lowering treatments in clinical trials.

" We presently don't have fully validated imaging or biomarker measures that can help us monitor the development or progression of Alzheimer's in living people," explains Neil Buckholtz, chief of the Dementias of Aging Branch at the NIA. "T his study represents one step in the progress being made toward identifying clinically useful biological measures for Alzheimer's disease."

The study included 24 people ages 48 to 83 years who were cognitively normal or had very mild, mild, or moderate dementia.
The researchers used positron emission tomography ( PET ), a brain imaging technique, with a tracing substance called Pittsburgh Compound B ( PIB ), to determine the amount of plaques in the participants' brains. PIB travels through the bloodstream into the brain and then binds to beta-amyloid containing plaques in the brain. PIB makes it possible to see on PET images any areas of the brain with high concentrations of plaques.

The researchers also analyzed samples of study participants' CSF and blood plasma for levels of specific protein fragments, including two forms of beta-amyloid and the protein tau.

The seven participants whose PET scans showed PIB binding -- and therefore deposits of beta-amyloid containing plaques in the brain -- had the lowest levels of amyloid-beta 1-42 in their CSF.
Those without PIB binding had the highest levels of CSF amyloid-beta 1-42.
No relationship was seen between PIB binding and the other CSF or blood-plasma biomarkers studied, including plasma amyloid-beta 1-42. As shown in previous studies of mice, decreases in CSF beta-amyloid may result from plaques acting as a "sink," hindering movement of soluble beta-amyloid between the brain and CSF, the researchers hypothesize.

Importantly, three of the participants had normal cognitive evaluations but had high PIB binding and low CSF amyloid-beta 1-42, suggesting the possibility that this combination of methods may be useful as "antecedent" biomarkers of Alzheimer's disease, identifying the presence of Alzheimer's disease amyloid pathology before the development of cognitive impairments. Alternatively, if these subjects never develop cognitive decline, it is possible that plaque number is not always a predictor of the disease.

" Although this study involved a very small sample, the findings suggest that amyloid imaging and CSF beta-amyloid measures together may have utility as biomarkers of Alzheimer's disease before symptoms develop and as the disease progresses," says Fagan. " These measures hold potential for identifying individuals with Alzheimer's disease pathology before cognitive symptoms, improving the accuracy of clinical diagnosis of Alzheimer's disease and facilitating the testing of future therapies."

However, she cautions, " It is important to recognize that this is still a research study and the findings must be carefully validated before this approach can be considered for clinical use."

Source: National Institutes of Health, 2005. As seen at XagenaMedicine2005 (last viewed 26 Dec 2005) [FullText]

"NEW YORK (Reuters Health) - Post-mortem studies of the brains of women with Alzheimer's disease (AD) show a much lower estrogen content than similar women without the disorder, researchers report.

The findings may help explain the higher prevalence of AD in women than men, since animal experiments show brain estrogen deficiency accelerates the brain "plaque" build-up that characterizes the disease.

Blood estrogen analysis did not support the brain tissue findings, since serum estrogen was low in both the AD patients and normal subjects, Dr. Rena Li and colleagues at the University of Chicago note in the Proceedings of the National Academy of Sciences.

Li told Reuters Health that "brain estrogen deficiency is more specific than blood estrogen deficiency" in the development of AD. "That is the key finding -- the brain can't manufacture estrogen."

To examine the correlation between brain tissue findings and the onset and severity of AD, Li's team conducted animal studies in which they crossed mice lacking an estrogen-synthesizing enzyme with mice carrying a protein related to AD plaque build-up.

The resulting animals had greatly reduced brain estrogen levels and early onset plaque formation. By contrast, mice that underwent ovary removal did not develop estrogen-deficient brain disease.

Li said the findings in these "ovariectomized" mice support the fact that not all post-menopausal women develop AD. "It is brain-specific...and may have a genetic basis," she explained.

She said potential treatment of AD with estrogen therapy would require drug formulations that cross the tissue barrier that separates blood from the brain. Her team is currently screening a number of natural estrogen products to assess their ability to cross this barrier."

Source: Proceedings of the National Academy of Sciences, December 19, 2005, and Martha Kerr. Low brain estrogen linked to Alzheimer's in women. (22 Dec 2005) [FullText]

"TORONTO (22 Dec. 2005)- Amorfix (AMF) Life Sciences announced today that it has successfully completed its first research and development milestone to develop a test for the detection of prions in blood from laboratory animals. The company is now ready to verify that its EP-vCJD(TM) assay can be an ante-mortem blood test for the human form of "mad cow disease" known as variant Creutzfeldt-Jakob Disease or vCJD. A test is urgently needed to screen human blood for transfusion as it is now known that vCJD is transmitted by blood transfusions.

Dr. George Adams, Amorfix's CEO said, "I am very pleased to report that we have reached this milestone. It marks a turning point for the company as we move from experiments in model systems to the detection of vCJD prions in human blood".

As a next step, the assay will be optimized for human samples. The National vCJD Surveillance Unit (NCJDSU) and the British National Institute for Biological Standards and Controls (NIBSC) have recently issued a series of rigorous assessments that vCJD blood diagnostic tests must pass through in order to be accepted. Amorfix has been approved to start this validation process and will be given access to human CJD samples. Dr. Neil Cashman, Amorfix's CSO said, "We have learned all we can from animal blood and it is time to begin testing human blood for infectious prions to secure the blood transfusion systems worldwide."

The company has upgraded its laboratory and has received regulatory approval from the Public Health Agency of Canada to work with vCJD material. This is the first commercial laboratory in Canada approved to work with tissue and blood samples containing vCJD prions.

The NCJDSU has blood and tissue samples from approximately 150 people who have been diagnosed with vCJD and subsequently died. The process to access these samples and validate a blood test for vCJD has recently been revised and now has 3 steps which culminate in a test panel containing peripheral blood or plasma samples from patients with variant CJD, patients with sporadic CJD, patients with other neurological conditions and "normal controls" from blood donors. At the completion of each step the British Department of Health, Tissue Management Group will review the data and approve the continuation of the process and the release of the next series of samples. This tissue bank is the only way to verify vCJD can be detected in blood. Since no company, academic or research group has completed this validation process before, it is uncertain exactly how long it will take. The company expects to complete the process in 3 to 6 months.

About Amorfix: Amorfix is an emerging theranostics company focused on the diagnosis and treatment of neurodegenerative diseases, where aggregated misfolded proteins (AMPs) are prevalent. These include aggregated misfolded prion protein which makes up "prions," the infectious agents of the Transmissible Spongiform Encephalopathies (TSE), such as Bovine Spongiform Encephalopathy (BSE or "mad cow disease") and the human form, variant Creutzfeldt-Jakob Disease (vCJD), as well as degenerative diseases such as Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD). Amorfix was formed to commercialize epitope protection (EP) technologies and related discoveries to become the world leader on AMP diseases. The company will use this new knowledge to develop diagnostic kits, therapeutics and prophylactics for AMP diseases.

The TSX Venture Exchange has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This information release may contain certain forward-looking information. Actual future results may differ materially from those contemplated. The risks, uncertainties and other factors that could influence the actual results are described in documents filed with regulatory authorities.

For further information: visit the website at www.amorfix.com or contact: Dr. George Adams, President and CEO, Amorfix Life Sciences Ltd., (416) 557-4647, george.adams@amorfix.com; James Parsons, CFO, Amorfix Life Sciences Ltd., (416) 705-5686, james.parsons@amorfix.com

Source FullText

While adherent to the phrasing of the amyloid dogma (AK: otherwise how this report would be favorable reviewed and published in Neuron?) the study by Cirrito et al. says amyloid beta is a functional activity-dependent synaptic protein. What a Holiday gift for Alzheimer's field members combating amyloid cascade hypothesis dogma. The abstract of the study and recent related essential reading citations follow:

"Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development."

Source: Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic Activity Regulates Interstitial Fluid Amyloid-beta Levels In Vivo. Neuron. 2005 Dec 22;48(6):913-922 [PubMed Abstract and FullText link] [Associated Neuron Commentary]

Essential related reading:

Koudinov A and Koudinova N. Amyloid b protein restores hippocampal long term potentiation: a central role for cholesterol? Neurobiology of Lipids 1, 8 (2003). Published online September 15, 2003. [Free FullText] [AlzForum hypothesis]

Koudinov AR, Berezov TT. Alzheimer's amyloid-beta (A beta) is an essential synaptic protein, not neurotoxic junk. Acta Neurobiol Exp (Wars). 2004;64(1):71-9 2 [Free .PDF FullText]

Grimm MOW, Grimm HS, Patzold AJ, Zinser EG, Halonen R, Duering M, Tschape JA, De Strooper B, Muller U, Shen J, Hartmann T. Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nature Cell Biology (9 October 2005) ePub ahead of print. [Abstract Link and SFN presentation][AlzForum Discussion]

Hasbrouck Heights, N.J. (19 December 2005) - Nymox (NASDAQ: NYMX) Has Global Patent Rights for Statin Drugs for the Treatment and Prevention of Alzheimer's Disease

There are a number of ways by which statin therapy may reduce patients' risk of Alzheimer's disease (AD) according to Dr. Steven DeKosky, an AD expert at the Alzheimer Disease Research Center, University of Pittsburgh Medical Center Health System, in a new review article published in a special supplement of The American Journal of Medicine (Statin Therapy: Clinical Trials, Guidelines, and New Directions, December, 2005; 118: 48S-53S). According to Dr. DeKosky, in addition to lowering cholesterol levels, statins may also help suppress production of an amyloid protein believed to play a role in the AD disease process, improve bloodflow function and reduce inflammation, each of which may positively impact on AD risk. The American Journal of Medicine is the official journal of The Association of Professors of Medicine and has the eighth highest scientific impact rating in the world among all general medical journals.

Nymox Pharmaceutical Corporation (NASDAQ: NYMX) holds U.S. and global patent rights for the use of statin drugs for the prevention and treatment of Alzheimer's disease (AD), including for patients at risk for AD because of vascular-related risk factors or disease. Statins are a class of cholesterol-lowering drugs that are the biggest-selling prescription pills in pharmaceutical history with estimated 2004 global sales of up to $26 billion. Alzheimer's disease is the leading cause of dementia in the elderly, afflicting an estimated 4.5 million people in the U.S. alone.

The potential use of statins to treat Alzheimer's disease (AD) has been widely reported in the peer-reviewed medical literature, both in terms of clinical data, (such as J Neurol Neurosurg Psychiatry (2005; 76:1624-1629); The Lancet Neurology (2005; 4:521-2); Arch Neurol (2005; 62:1047-51); Neurology (2005; 64:1531-8); Arch Neurol (2005; 62:753-7); J Neurol Sci (2005; 229-230:147-50); Curr Opin Lipid (2005; 16:619-623); Arch Gen Psychiatry (2005; 62:217-24)) and possible mechanisms through which statins may prevent or slow the progression of Alzheimer's disease (such as J Neurosci Res (2005; 82:10-19); J Biol Chem (2005; M505268200); PLoS Med (2005; 2:e18); J Neurosci (2005; 25:299-307)).

More information about Nymox is available at www.nymox.com, email: info@nymox.com, or 800-936-9669.

This press release contains certain "forward-looking statements" as defined in the United States Private Securities Litigation Reform Act of 1995 that involve a number of risks and uncertainties. There can be no assurance that such statements will prove to be accurate and the actual results and future events could differ materially from management's current expectations. Such factors are detailed from time to time in Nymox's filings with the United States Securities and Exchange Commission and other regulatory authorities.

For more info on Statins and Alzheimer's see major subject journal Neurobiology of Lipids, ISSN 1683-5506)

Source: Statin Drugs May Help Reduce Alzheimer's Disease Risk in Many Ways, According to Expert. CCNMatthews (19 Dec 2005) [FullText]

"The first study of the effects of testosterone on mood, behavior and psychological health in men with mild Alzheimer's disease finds significant improvements in quality of life, as assessed by caregivers.

Led by neuroscientists at the University of California, Los Angeles, Alzheimer's Disease Research Center and detailed in an early online release of the peer-reviewed journal Archives of Neurology, the double-blind, placebo-controlled study used caregiver assessments to evaluate quality of life and used a battery of tests administered by clinicians to evaluate cognitive skills.

Alzheimer's patients treated with testosterone showed significant improvement on a quality-of-life instrument that encompasses memory, interpersonal relationships, physical health, energy, living situation and overall well-being, compared with patients who received a placebo. However, researchers found no significant differences in memory or other cognitive skills as assessed by tests administered by clinicians.

"The results suggest that testosterone replacement therapy holds potential for improving the quality of life of Alzheimer's patients and merits further testing with a larger group of patients and with a longer treatment period," says Po-Haong Lu, Psy.D., the study's lead author and assistant clinical professor of neurology at the research center and the David Geffen School of Medicine at UCLA.

Alzheimer's disease, which causes memory loss, behavior changes and difficulties with thinking, affects an estimated 4 million Americans.

The 24-week study included 16 male patients diagnosed with mild Alzheimer's disease and 22 healthy male control subjects. Each group was randomly subdivided into two treatment arms. One group received daily testosterone treatment in the form of hydroalcoholic gel (75 mg) and the other received a gel with no active medication.

The research team assessed subjects' cognitive function, neuropsychiatric symptoms, global functioning and quality of life. Among patients with the disease, the testosterone-treated group had significantly greater improvements in the scores on the caregiver version of the quality-of-life scale than those who received the placebo. No statistically significant differences were seen in cognitive or other scores at the end of the study, though numerically greater improvement or less decline in measures of visual-spatial abilities were found in the group treated with testosterone.

In the healthy control group, a nonsignificant trend toward greater improvement in self-rated quality of life was observed in the testosterone-treated group compared with placebo treatment."

Source: Testosterone improves life with Alzheimer's. myDNA News. (14 December 2005) [FullText]

"Applied NeuroSolutions, Inc. (OTCBB:APNS), a Company focused on the development of an integrated product portfolio for the diagnosis and treatment of Alzheimer's disease, today announced it has renewed its consulting agreement with Peter Davies, Ph.D.

Dr. Davies, the Judith and Burton P. Resnick Professor of Alzheimer's Disease Research at Albert Einstein College of Medicine (AECOM), is the Company's founding scientist and a world-renowned pioneer in the area of tau pathology and Alzheimer's disease. In partnership with Dr. Davies and a team of distinguished scientists at AECOM, Applied NeuroSolutions is primarily engaged in the research and development of a diagnostic test to detect, and novel therapeutics to treat, Alzheimer's disease. The three-year renewal of Dr. Davies agreement allows Applied NeuroSolutions and Dr. Davies to continue building on the scientific successes the close working relationship has achieved.

Applied NeuroSolutions has a long-term agreement with AECOM that grants Applied NeuroSolutions the exclusive licensing rights to commercialize Dr. Davies' neurodegenerative disease related discoveries.

"I am pleased to continue my relationship with the team at Applied NeuroSolutions," said Dr. Davies. "We have worked very closely over the past twelve years, and they have done a fantastic job creating viable commercial products from the research tools my lab has provided."

"Peter has played an integral role in the development of our lead product, a diagnostic test for Alzheimer's disease," said John DeBernardis, Ph.D., President and Chief Executive Officer of Applied NeuroSolutions. "As a result of Dr. Davies' research, we are also involved in the discovery and development of a unique therapeutic that may represent the first therapy able to stop the progression of AD. We are pleased to continue our collaboration and look forward to building our product pipeline in conjunction with Peter and the scientists at Albert Einstein."

About Applied NeuroSolutions

Applied NeuroSolutions, Inc. (OTCBB:APNS) is developing products to diagnose and treat Alzheimer's disease based on a novel hypothesis of AD pathology. In partnership with Dr. Peter Davies and a scientific team at Albert Einstein College of Medicine, Applied NeuroSolutions has developed a cerebrospinal fluid (CSF) test to detect Alzheimer's disease at a very early stage with 85%-95% accuracy in more than 3,000 patient samples. There are approximately 2 million new patients annually worldwide who are candidates for an AD CSF diagnostic test, according to Datamonitor. The company is also developing a blood serum-based screening test, as well as a new class of therapeutics to treat AD. Alzheimer's disease currently afflicts over 4 million Americans, and the market for AD therapy is expected to grow to 21 million patients by 2010 in the seven major pharmaceutical markets (USA, France, Germany, Italy, Spain, U.K. and Japan) according to BioPortfolio, Ltd. For more information, visit www.appliedneurosolutions.com.

There are currently no FDA-approved diagnostic tests to detect Alzheimer's disease.

This press release contains forward-looking statements. Applied NeuroSolutions wishes to caution the readers of this press release that actual results may differ from those discussed in the forward-looking statements and may be adversely affected by, among other things, the risks associated with new product development and commercialization, clinical trials, intellectual property, regulatory approvals, potential competitive offerings, and access to capital. For further information, please visit the company's website at www.appliedneurosolutions.com, and review the company's filings with the Securities and Exchange Commission."

CONTACT: Applied NeuroSolutions, Inc. John F. DeBernardis, Ph.D., 847-573-8000 or Financial Dynamics Julie Huang or Courtney Wen (Investors), 212-850-5600 or Monarch Communications Jeff Siegel (Media), 516-569-4271

Source: GenEngNews (12/12/2005) [FullText]

"TOKYO (8 Dec 2005) - Eisai Co. Ltd. (4523.T: Quote, Profile, Research), Japan's fourth-largest drug maker, said on Thursday it was suing Teva Pharmaceutical Industries Ltd. (TEVA.O: Quote, Profile, Research) over the Israeli firm's plans to launch a copycat version of its top-selling Alzheimer's disease drug Aricept.

Eisai filed the patent infringement lawsuit against the generic drug maker in the U.S. District Court for the District of New Jersey. The Japanese drug maker received a notice from Teva in late October that it had applied to U.S. regulators to market a generic version of Aricept, an Eisai spokeswoman said. Teva was not available for comment.

Sales of Aricept, which is marketed in 76 countries worldwide, totalled 162.9 billion yen ($1.35 billion) for the year ended March 2005 and is projected to rise to 188 billion yen this year. "Eisai believes that its ... patent is valid until its expiration date of Nov. 25, 2010. Eisai intends to vigorously enforce and defend that patent," the company said in a news release.

Shares in Eisai were up 0.2 percent at 4,980 yen at the midday break, in line with the pharmaceutical sector index (.IPHAM.T: Quote, Profile, Research). ($1=121.08 Yen)

Source: Eisai sues Teva over Alzheimer's disease drug. Reuters. (8 December 2005) [FullText]

"Research and Markets ( researchandmarkets.com/reports/c1616 ) has announced the addition of Alzheimer Disease - New Drugs, Markets and Companies to their offering.

Alzheimer's disease remains a challenge in management. With nearly 8 million sufferers from this condition in the seven major markets of the world and anticipated increases in the future. Considerable research is in progress to understand the pathomechanism of the disease and find a cure. The only drugs approved currently are acetylcholinesterase inhibitors but they do not correct the basic pathology of the disease, beta amyloid deposits and neurofibrillary tangles. Several new approaches emphasize neuroprotection as well.

Early diagnosis of Alzheimer's disease is an important first step in management. Several biomarkers in cerebrospinal fluid, blood and urine can detect the disease. They provide a valuable aid to the clinical examination and neuropsychological testing which are the main diagnostic methods supplemented by brain imaging. Genotyping, particularly of ApoE gene alleles is also useful in the evaluation of cases and planning management.

The current management of Alzheimer's disease is reviewed and it involves a multidisciplinary approach. Acetylcholinesterase inhibitors are mostly a symptomatic treatment but some claims are made about a neuroprotective effect. Currently the only approved neuroprotective therapy in Europe is memantine which is awaiting approval in the US. Management of these patients also require neuroleptics for aggressive behavior and antidepressants. There is an emphasis on early detection at the stage of mild cognitive impairment and early institution of neuroprotective measures. The value of mental exercise in delaying the onset of Alzheimer's disease is being recognized.

Research in Alzheimer's disease still aims at elucidating the basic pathomechanisms. Animal models are important for research, particularly in testing some of the potential therapeutic approaches. There is considerable research in progress at the various centers, some of which is funded by the National Institute of Aging of the National Institutes of Health.

Over 130 different compounds are at various stages of development for the treatment of Alzheimer's disease. These are classified and described. There are non-pharmacological approaches such as vagal nerve stimulation and cerebrospinal fluid shunting, which are in clinical trials. Various clinical trials are listed including those that failed in the past.

Alzheimer's disease market in the seven major markets is worth $6.1 billion in the year 2005 and will increase to $ 7.8 billion by the year 2010. The share of currently approved drugs specifically for AD is expected to be $3.1 billion in the year 2005 and $4.1 billion by the year 2010 provided all of them stay in the market. Several new therapies are expected to be in the market and the shares of various types of approaches are estimated for the future up to the year 2015. As a background to the markets, pharmacoeconomic aspects of care of Alzheimer disease patients and patterns of practice are reviewed in the seven major markets.

Profiles of 127 companies involved in developing diagnostics and therapeutics for Alzheimer's disease are presented along with their collaborations. The bibliography contains over 500 publications that are cited in the report. The report is supplemented with 38 tables and 10 figures."

Source: Alzheimer's Disease Market in the Seven Major Markets is Worth $6.1 Billion in the Year 2005 and is Forecast to Increase to $7.8 Billion by the Year 2010 . Genetic Engineering News (12 December 2005) [FullText]

"For 14 years, neurologist Allen Roses has argued that a gene discovery he made about Alzheimer's disease would lead to new treatments for the mind-robbing illness. His prediction may finally be coming true.

Roses, a research executive at drugmaker GlaxoSmithKline Plc, provided evidence yesterday that the company's best-selling diabetes pill Avandia may slow the effects of Alzheimer's. At a science meeting in San Diego, he presented a 500-patient study showing Avandia enhanced memory when compared with a placebo.

The study supports a hypothesis that the disease, which affects 4.5 million Americans, is caused by some of the same biological malfunctions that are involved in diabetes. The Glaxo researchers found that only people with a particular gene linked to a protein that transports cholesterol through the blood responded to the treatment.

"It is one of the first studies to indicate that a drug works for some people and not others based on a test of their genetics,'' Roses, 62, said before his presentation at the University of San Diego School of Medicine. The results, he said, suggest ``a totally new approach to treating the disease.''

If the Glaxo results are reproduced in future studies, doctors would have to conduct a gene test on patients before prescribing Avandia, Roses said. Glaxo and other drugmakers are researching ways to determine who will benefit most from drugs by analyzing patients' genetic profiles.

Preliminary Findings

Avandia generated $2 billion in worldwide sales last year and was London-based Glaxo's second-biggest drug, behind the asthma medicine Advair. In a statement released by spokesman Rick Koenig, Glaxo said the study was "exploratory'' and Avandia isn't approved for Alzheimer's.

The research involved a longer-lasting version of the drug called Avandia XR that isn't yet approved in U.S. for treating diabetes. Koenig said Glaxo is planning further tests of Avandia XR and no Alzheimer's disease trials of the drug are yet scheduled.

"The findings are too preliminary to apply to clinical practice without confirmation in subsequent clinical trials,'' Koenig said in the statement.

The new study will be published in The Pharmacogenomics Journal in a few weeks. The findings may help explain a mystery Roses set in motion with his gene discovery in 1992.

Brain Glucose

The drug works by improving the body's use of the hormone insulin, which moves glucose from the bloodstream into the body cells. Glaxo's research indicates Avandia's impact on Alzheimer's disease isn't related to the drug's effect on insulin. Instead, the drug appears to increase the availability of blood sugar in the brain, which may extend the life of neurons involved in memory, Roses said in the interview.

Alzheimer's disease is the most common form of dementia among the aged in the U.S., according to the U.S. National Institute of Aging. The best-selling drug in the U.S. for Alzheimer's is Aricept, sold by Pfizer Inc., with sales of $308 million in 2004. The product doesn't affect the underlying cause of the disease, which even when treated by the drug typically causes severe degeneration of mental functions after five to 10 years.

The U.S. institute says the precise cause of Alzheimer's is unknown. One idea is that brain cells are killed by clumps of so-called amyloid plaques that are often seen in X-ray images of the brains of deceased victims.

A Clue

Another notion was first greeted with skepticism by scientists when uncovered in the early 1990s by a genetics lab run by Roses at Duke University in Durham, North Carolina. Roses and his research colleagues found that people who are born with a version of a gene that makes a natural substance called apolipoprotein E, or APOE, are at a high risk of developing Alzheimer's disease. APOE carries cholesterol through the blood.

Research by other scientists over the years confirmed that people who inherit one type of the gene, called APOE4, are at higher risk than others of developing Alzheimer's, according to the U.S. institute of aging.

In 1997, Roses joined Glaxo to direct its genetics program and continue his APOE work. In 2002, Glaxo hired his wife, Ann Saunders, who helped lead the initial APOE research at Duke. In 2003, researchers at the Gladstone Institute in San Francisco provided Saunders a critical clue.

The Gladstone lab published an experiment showing that the No. 4 version of the APOE blood protein interfered with the ability of neurons to make use of glucose in the brain. This inability to access glucose might be killing off crucial brain cells, the Gladstone and Glaxo researchers guessed.

"We decided to try drugs like Avandia because they appear to promote glucose production by neurons,'' Roses said.

New Analysis

To test the hypothesis in people, Glaxo undertook a study of 500 patients with mild forms of Alzheimer's who were being treated in Europe and New Zealand. After six months, Avandia showed no benefit when compared with a placebo. When Glaxo separated patients on the basis of their genetics, it found that those who didn't have the type 4 variant of the gene showed a ``statistically significant'' improvement in memory, Roses said.

"The first analysis of the drug showed it failed,'' Roses said. ``Only after we re-analyzed the results based on patients' genetics did we uncover a strong response.''

Roses said Glaxo is seeking U.S. Food and Drug Administration approval for future studies that would include DNA analysis of test subjects. Glaxo said it may undertake larger trials after it gets an agreement from the FDA.

Source: Michael Waldholz. Glaxo Diabetes Drug Avandia May Help Treat Alzheimer's Disease. Bloomberg.com (7 Dec 2005) [FullText]

"Researchers have found evidence that may partially exonerate a protein known to be a culprit in the progression of Alzheimer's disease. Their new studies show that the protein p25, which wreaks havoc in the brains of patients with Alzheimer's disease, also has a good side in promoting the plasticity of the brain.

In studies in mice, the scientists have shown that the enzyme promotes structural changes in the brain associated with learning and memory. The studies indicate that when the concentration of the protein reaches excessive levels, it contributes to the brain cell death associated with Alzheimer's disease (AD). Their discovery of the dual nature of p25 suggests that drugs that partially inhibit p25's target enzyme could protect the neurons of patients with AD.

The research team, which was led by Howard Hughes Medical Institute investigator Li-Huei Tsai, reported its findings in the December 8, 2005, issue of the journal Neuron. Tsai and her colleagues at Harvard Medical School collaborated on the studies with researchers from the National Institute of Mental Health.

In earlier studies, Tsai and her colleagues discovered that an enzyme called cyclin-dependent kinase 5 (Cdk5) plays a central role in AD pathology. Like other kinases, Cdk5 switches on enzymes by attaching a phosphate group to them. Under tight regulation by a protein called p35, Cdk5 controls the construction and maintenance of neuronal connections in the brain.

Tsai and her colleagues showed that in the neurons of people with AD, however, p35 is snipped apart abnormally, which leaves behind a different regulatory protein called p25. The resulting increase in the level of p25 in the brain hyperactivates Cdk5. Mice with prolonged expression of p25 exhibit pathological hallmarks of AD such as brain atrophy, neuronal loss and neurofibrillary tangles.

In their latest studies, the researchers explored what happened when the brains of mice are exposed to a transient pulse of p25. They used mice that were genetically engineered so that adding the antibiotic doxycycline to their food would suppress production of p25. If doxycycline were removed from the food, p25 would be overproduced in the neurons of the mice.

“In our earlier studies with these mice, we had found that inducing p25 expression for eight to twelve weeks produced severe neurodegeneration,” said Tsai. “So in this new study, we wanted to trace the early time-course of the pathology. When we looked at the effects of six weeks of exposure, we saw the first sign of neurodegeneration. But when we induced p25 for only two weeks, we saw absolutely no sign of neurodegeneration.”

In fact, said Tsai, when they tested the learning and memory of mice that produced high levels of p25 for only two weeks, they saw enhanced neural function. “We saw significantly higher learning ability in these animals, and that was very surprising,” she said. “It took us a while to get used to those observations.”

The researchers tested the mice using two widely applied measures of learning and memory. In one of those tests, they measured how well the mice remembered the association between a tone or a particular cage chamber with a harmless but unpleasant electrical shock to their paws. In the other test, the researchers measured how well the mice remembered the location of a submerged platform in a tank of murky water. These tests revealed that p25 enhanced learning and memory during the two-week pulse, and for many weeks beyond — even when p25 is no longer produced in the transgenic mice.

The researchers also studied the effects of p25 on the circuitry and physiology of the hippocampus — the brain's learning and memory center. Their electrophysiological measurements revealed that the two-week pulse of p25 enhanced long-term potentiation, which underlies learning and memory. The hippocampi of these mice also had a higher density of dendritic spines and more synapses. “These findings showed us why the effects of the p25 pulse lasted so long,” said Tsai. “They showed actual structural changes in the mouse brains.”

Overall, said Tsai, the findings exonerate p25 as a complete villain in AD. “We always associated p25 with pathological conditions, especially since previous studies had found it to be quite toxic,” she said. “Now, we think there is a very intriguing possibility that p25 is normally produced at a low level in the brain, perhaps to maintain synaptic plasticity. But if there is a systemic or chronic neurotoxicity, then p25 might be produced in large quantity, perhaps as the brain attempts to compensate for impaired synaptic function.” What's more, said Tsai, p25 production might also naturally increase with normal aging, to compensate for normal neuronal loss.

Tsai said that the new findings suggest that a drug that offsets p25 hyperactivation of Cdk5 by partially inhibiting Cdk5 might also protect AD patients against neuronal loss. “Obviously, however, you cannot completely inhibit Cdk5, because that would impair synaptic plasticity," she said. "So, as is the case with many drugs, there would have to be a fine balance in such drug treatment to achieve benefits without being harmful.”

In further studies, Tsai and her colleagues plan to trace the machinery Cdk5 uses to regulate synaptic plasticity, for example by increasing the density of dendritic spines. Also, she said, her laboratory is pursuing the critical question of how p25-hyperactivated Cdk5 kills neurons."

Source: Research News. Howard Hughes Medical Institute (8 Dec 2005) [FullText]

"Acetyl-L-carnitine may offer unprecedented hope for people suffering from Alzheimer's disease or the aftereffects of a stroke. The human brain is uniquely powerful and complex, but it is sometimes difficult for it to fully recover from damage. People who have been affected by stroke, traumatic brain damage or age-associated dementia know this all too well. Fortunately, research studies suggest that the vitamin-like nutrient L-carnitine may be able to slow down, or even reverse, brain deterioration. Plus, it may give people the ability to think clearer and remember things like, "Where did I put my keys?"

If you're worried about developing Alzheimer's disease, Parkinson's disease or age-associated dementia, studies suggest that acetyl-L-carnitine (ALC) may delay the onset of the disease, according to Prescription for Dietary Wellness by Phyllis A. Balch. Furthermore, if you've already been diagnosed with Alzheimer's, ALC can help slow down its progression and improve your mental functioning. In fact, experimental and clinical studies demonstrate that ALC may have a "significant capacity to slow, and even reverse, the effects of aging on the brain," writes Dr. Russell L. Blaylock in Health and Nutrition Secrets.

So, how exactly does ALC work? Mind Boosters author Dr. Ray Sahelia believes that Alzheimer's patients may benefit from ALC in three ways: It is able to travel through the blood-brain barrier, where it then helps form the brain chemical acetylcholine; it keeps mitochondria working efficiently by clearing them of toxic fatty-acid metabolites; and it helps regenerate neurons damaged by free radicals.

The results of numerous research studies support Dr. Sahelia's theory, including electron microscope analysis of the hippocampus region of the brain, which demonstrated ALC's ability to reverse the age-related deterioration of mitochondria. Furthermore, according to Professor Gary Null, autopsies show that people who had Alzheimer's experienced 25 to 40 percent less ALC transferase activity than people without Alzheimer's. In other words, perhaps the reason why ALC supplementation is so beneficial to Alzheimer's patients is because they are deficient in L-carnitine in the first place.

Of course, the benefits of ALC's ability to regenerate lost brain function extends far beyond Alzheimer's disease, making it a promising treatment for victims of stroke as well. If it is administered to stroke victims soon after the stroke occurs, ALC may actually reduce the level of brain damage caused by the interrupted blood flow, according to an Italian animal study reported in Dr. Russell L. Blaylock's Health and Nutrition Secrets. But even if it was not possible to give a patient ALC soon after the stroke first occurred, ALC supplementation may help the patient improve memory, task performance and cognition during his or her road to recovery.

Popular Alzheimer's Drug Found to Be All But Worthless in Independent Study

Furthermore, ALC may even be able to help people with Down's Syndrome, even though it is a congenital disease, rather than an age- or trauma-related one. In one 90-day study, ALC supplementation improved both the visual memory and attention of test subjects with Down's Syndrome. Further research into this scope of ALC's benefits should be promising...."

Source: Dani Veracity. How Acetyl-L-Carnitine prevents Alzheimer's disease and dementia while boosting brain function. News Target (7 December 2005) [FullText]

"Researchers at the Gladstone Institute of Neurological Disease have identified a potential new way to stop brain cell death related to Alzheimer's disease.

Working with cell cultures, the scientists investigated how amyloid beta proteins, which build up in the brain tissue of people with Alzheimer's disease, kill neurons. The cell cultures were established from brain tissue of laboratory rats. Study findings showed that amyloid beta could be prevented from causing neuronal cell death with a compound called resveratrol, which is also found as a natural ingredient in red wine.

"Our study suggests that resveratrol and related compounds may protect against neuronal loss associated with Alzheimer's disease," explains senior author Li Gan, PhD, a staff research investigator at the Gladstone Institute of Neurological Disease and an assistant professor of neurology at UC San Francisco. "This could certainly open up new avenues for drug development."

The research results are reported in the December 2 issue of the Journal of Biological Chemistry.

According to the research team, it was particularly interesting that the beneficial effect of resveratrol was not due to a direct impact on amyloid beta or on neurons but rather on other types of brain cells, called microglia.

Microglia are the immune cells of the brain. They can protect or hurt neurons, depending on which of their powerful defense or attack pathways are activated. The investigators found that amyloid beta triggers a pathway in microglia that makes them attack neurons with poisonous chemicals. A key mediator in this pathway is a protein called NF-kB, which resveratrol happens to block. Without resveratrol, amyloid beta activates NF-kB in microglia, turning them into powerful neuron killing machines. Researchers found that, in the presence of resveratrol or of other molecules that blocked NF-kB, microglia were well behaved, and amyloid beta was unable to harm the neurons.

The study thus pinpoints NF-êB as an important contributor to the destructive power of amyloid beta, making it a key drug target, and it singles out resveratrol as holding the most promise for therapeutic intervention.

Research co-authors are Jennifer Chen, Sarah Mueller-Steiner, and Lennart Mucke of the Gladstone Institute of Neurological Disease and the UCSF Department of Neurology; Yungui Zhou and Saili Yi of the Gladstone Institute of Neurological Disease; and Lin-Feng Chen and Hakju Kwon of the Gladstone Institute of Virology and Immunology.

The research was supported by the Alzheimer's Disease Research Center at UCSF, the McBean Family Foundation, the National Institutes of Health, and the Swiss Science Foundation.

The Gladstone Institute of Neurological Disease is one of three research institutes of The J. David Gladstone Institutes, a private, nonprofit biomedical research institution. It is affiliated with UCSF, a leading university that consistently defines health care worldwide by conducting advanced biomedical research, educating graduate students in the life sciences, and providing complex patient care."

Contact: John Watson, jwatson@gladstone.ucsf.edu , Gladstone Institutes, Gladstone.ucsf.edu

Source: Medicalnewstoday.com (5 December 2005) [FullText]

Helping shined Harvard University Medical School, premier Science Magazine and its' Chief Editor, Nature, Elsevier Neuron, Society for Neuroscience, American Academy of Neurology & major AlzForum to disclose Selkoe conflict:

"CONSULTING AGREEMENT

This CONSULTING AGREEMENT (the "Agreement") is made by and between Dennis J. Selkoe, MD an individual with an address of Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, 221 Longwood Avenue--LMRC, Boston, MA 02115 ("Consultant"), and Elan Pharmaceuticals, Inc., a Delaware corporation with an address of 800 Gateway Boulevard, South San Francisco, California 94080 ("Elan"), and is effective as of April 1, 2002 ("Effective Date").


RECITALS

A. Consultant possesses special expertise and knowledge in the field of Alzheimer's disease, including but not limited to issues related to immunological response to AB ("Consultant Field"); and

B. An Affiliate of Elan and American Home Products Corporation, a Delaware corporation, together with its Affiliates, acting through its Wyeth-Ayerst Laboratories Division (collectively, "AHP") have entered into a collaboration with respect to the treatment and/or prevention of Alzheimer's disease and/or Mild Cognitive Impairment using immunological approaches directed at one or more epitopes of AB (the "Project").

C. Elan has need for Consultant's services with respect to Alzheimer's disease in connection with the Project ("Elan Field"); and

D. Elan and Consultant now desire to enter into this Agreement whereby Consultant shall perform consulting services for Elan on the terms and conditions set forth below.

AGREEMENT

NOW, THEREFORE, Consultant and Elan agree as follows:

1. Description of Services. Subject to the terms and conditions of this Agreement, Consultant shall perform services for Elan, at times and locations determined by Elan. Such services shall include, without limitation, serving on the Project's Scientific Advisory Panel to the Joint Leadership Team, attending committee meetings, and providing review of and advice on the merit or value of the Project's research and development, as well as information on new
developments and opportunities in the Elan Field.

2. Term and Renewal. This Agreement shall be effective as of the Effective Date and shall remain in effect for a period of one (1) year, renewable each year thereafter, unless terminated pursuant to this Agreement. This Agreement may only be renewed for additional periods on terms mutually agreed upon in writing by the parties. Neither party shall have any obligation to renew this Agreement.


3. Fees and Expenses.

a) In return for services actually rendered, Elan will pay Consultant at a rate of Four Thousand Dollars ($4,000) for the term of this Agreement and an additional One Thousand Two Hundred Dollars ($1,200) per day for each meeting.

(b) Elan shall also reimburse Consultant for all out-of-pocket expenses actually incurred by Consultant in rendering services under this Agreement so long as such expenses, in Elan's opinion, are reasonable and necessary. Such expenses will include reasonable and necessary travel (air travel to be coach class only), lodging and meals. Consultant shall provide Elan with a written expense report, complete with receipts or other reasonable documentation, for all such expenses requested for reimbursement.

(c) The aggregate fees and expenses payable to Consultant hereunder shall not exceed Twelve Thousand Dollars ($12,000) for the term of this Agreement without Elan's prior written consent.

4. Invoices. Amounts due hereunder shall be payable no later than thirty(30) days from Elan's receipt of a written invoice with an expense report and accompanying supporting documentation therefor.

5. Confidentiality; Proprietary Information; Intellectual Property.

(a) Any and all information which Elan may disclose to Consultant under this Agreement will be considered confidential, including, but not limited to, information related to the Elan Field.

(b) Consultant further agrees that all discussions and negotiations with respect to this Agreement are confidential.

(c) Consultant understands that Elan and/or AHP possesses and will continue to possess information that has been created, discovered or developed, or has otherwise become known to Elan and/or AHP or their respective Affiliates and/or in which property rights have been assigned or otherwise conveyed to it, which information has commercial value in the business in which such entity is engaged. Affiliate(s) shall mean, with respect to any person or entity, any other person or entity which controls, is controlled by or is under common control with such person or entity. A person or entity shall be regarded as in control of another entity if it owns or controls at least fifty percent (50%) of the equity securities of the subject entity entitled to vote in the election of directors (or, in the case of an entity that is not a corporation, for the election of the corresponding managing authority), provided, however, that the term "Affiliate" shall not include subsidiaries or other entities in which a Party or its Affiliates owns a majority of the ordinary voting power necessary to elect a majority of the board of directors or other governing board, but is restricted from electing such majority by contract or otherwise, until such time as such restrictions are no longer in effect.
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All such information, including the information described in Sections 5 (a) and (b) above, and including any other information developed by or on behalf of Consultant pursuant to this Agreement, is hereinafter referred to as "Proprietary Information." By way of illustration, but not limitation, Proprietary Information includes trade secrets, processes, formulae, data and know-how, improvements, inventions, techniques, marketing plans, strategies, forecasts and customer and contact lists. Accordingly, Consultant further agrees as follows:

(i) All Proprietary Information shall be the sole property of Elan and/or AHP and their respective Affiliates and assigns, and such parties shall be the sole owners of all patents and other rights in connection therewith. At all times during this Agreement and at all times after expiration or termination of this Agreement, Consultant will keep in confidence and trust all Proprietary Information, and will not use or disclose any Proprietary Information without the prior written consent of Elan, except as may be necessary in the ordinary course of performing the duties of Consultant hereunder. No announcement, oral presentation or publication of any kind relating to any Proprietary Information shall be made by Consultant without the prior written consent of Elan; and (ii) All documents, data, records, apparatus, equipment and other physical property, whether or not pertaining to Proprietary Information, furnished to Consultant by or on behalf of Elan or developed by or on behalf of Consultant pursuant to this Agreement, shall be and remain the sole property of Elan and/or AHP and their respective Affiliates and assigns and shall be returned promptly as and when requested by Elan except that Consultant shall be permitted to retain one (1) copy of such Information in its legal files solely for the purposes of verifying compliance with the terms thereof. Should Elan not so request, Consultant agrees to return and deliver all such property upon expiration or termination of this Agreement for any reason and Consultant shall not retain or reproduce any such property upon expiration or termination.

Nothwithstanding the foregoing, Proprietary Information shall not be deemed to include information that Consultant can demonstrate (a) was lawfully in Consultant's possession prior to the date of disclosure, (b) becomes public or available to the public through no fault or omission of Consultant amounting to breach of this Agreement, (c) has been lawfully obtained by Consultant from a third party which is in lawful possession of such information, or (d) is required to be disclosed by law, in which case Consultant will give Elan as much advance notice of the proposed disclosure as is practical (including a copy of any written request or order), and will cooperate with Elan in any effort to limit or restrict such disclosure, via a protective order or otherwise.

(d) Consultant further agrees as folows:

(i) Consultant shall promptly disclose to Elan or its designee all intellectual property (including, but not limited to any inventions, improvements, formulae, processes, techniques, know-how, data, patents or applications for patents, trade secrets, trademarks, copyrights and confidential information as described in this Section 5), made or conceived or reduced to practice or learned by Consultant (collectively, "Intellectual Property") which: (A) result from the tasks assigned to Consultant hereunder; (B) are funded by or on behalf

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of Elan or AHP; or (C) result from the use or property or premises owned, leased or contracted for by or on behalf of Elan or AHP.

(ii) Consultant agrees to and does hereby sell, assign, transfer and set over to Elan, and/or AHP or their respective successors or assigns, as the case may be, all right, title and interest in and to all Intellectual Property developed or conceived individually or in conjunction with others in performance of this Agreement, to be held and enjoyed by Elan, and/or AHP or the respective successors or assigns, as the case may be, to the full extent of the term for which any Letters Patent may be granted and as fully as the intellectual property would have been held by Consultant had this Agreement, sale or assignment not been made.

(iii) Consultant shall execute and deliver any and all instruments and documents and perform any and all acts, necessary to obtain, maintain or enforce patents, trademarks, trade secrets and copyrights for such Intellectual Property, and shall make, execute and deliver any and all instruments and documents and perform any and all acts necessary to obtain, maintain or enforce patents, trademarks, trade secrets and copyrights for such Intellectual Property as Elan may designate in any and all countries. All costs and expenses of application and prosecution of such patents, trademarks, trade secrets and copyrights shall be paid by Elan.

(iv) Any copyrightable material prepared by Consultant as a result of Consultant's activities with Elan, in performance of this Agreement, are prepared as works for hire for the benefit of Elan and/or AHP. Consultant hereby assigns to Elan and/or AHP, as Elan shall designate, any copyright to which Consultant is entitled for any copyrightable material prepared in the course of the performance of this Agreement for Elan. Elan and or AHP shall have the right to reproduce, modify and use such material and all results generated as the result of services rendered under this Agreement for any purpose related to its lawful business.

(v) Upon the written request of Elan, Consultant shall make any assignment provided for in this Section 5 directly to, or for the benefit of, an Elan Affiliate or Elan's designee, including Consultant's performance of any related obligations hereunder.

6. Remedies. (a) Consultant acknowledges that Elan will have no adequate remedy at law if Consultant breaches the terms of Section 5 hereof. Accordingly, in such event, Elan shall have the right, in addition to any other rights it may have at law or equity, to obtain in any tribunal of competent jurisdiction injunctive relief to restrain any breach or threatened breach. (b) If, due to reasons within Consultant's reasonable control, Consultant's products or
services fail to meet standards generally accepted in the applicable industry, or if Consultant fails to provide agreed-upon products or services in a timely manner Elan shall have the right, in addition to any other remedy it may have at law or equity, to: (i) terminate this Agreement immediately upon written notice to Consultant; (ii) require that defective products or services be replaced or remedied, as the case may be, without charge to Elan; and (iii) correct, or have
corrected by a third party, the defective product or service and withhold from amounts owing to Consultant hereunder all amounts incurred by Elan in taking such corrective measures.

7. Termination. This Agreement may be terminated (a) by Elan with or without cause upon thirty (30) days' prior written notice to Consultant, or (b) by Consultant in

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the event of a material breach by Elan, provided that Consultant provides Elan with written notice of such breach and Elan fails reasonably to cure such breach within thirty (30) days of receipt of such notice.

In the event this Agreement is terminated by Elan pursuant to this Section prior to completion of the work to be performed, Consultant shall be entitled to receive an equitable proration of the fee for work performed through the effective date of termination.

The provisions of Sections 5-6 and 9-14, inclusive, shall survive any termination of this Agreement.

8. Independent Contractor. Nothing in this Agreement shall be construed to create an employment relationship between Consultant and Elan or AHP. Consultant shall be an independent contractor and shall have no authority to enter into contracts on behalf of Elan or AHP, bind Elan or AHP to any third parties or act as an agent on behalf of Elan or AHP in any way. Consultant shall not be entitled to receive any compensation, or medical or other benefits as an Elan or AHP employee. Accordingly, Consultant shall account for and report, and be liable for the payment of all applicable federal and state income taxes, social security taxes, and all other taxes due on payments received by Consultant hereunder. Consultant hereby acknowledges that Elan will report as compensation all payments to Consultant hereunder.

9. Consultant's Representations and Warranties. Consultant hereby represents and warrants to Elan that (a) Consultant has the authority to enter into and perform this Agreement and (b) performance of Consultant's services as contemplated by this Agreement will not result in the breach or violation of any contract, arrangement or understanding (including without limitation any intellectual property rights or any agreement of confidentiality or non-disclosure, whether written or oral) which Consultant may have with any third party (including without limitation current and former employers of Consultant and any other companies or persons for which Consultant has performed or is performing consulting services).

10. Compliance Standards. During the term of this Agreement and any renewal term, Consultant shall comply with all applicable laws, rules and regulations in the conduct of the services being performed.

11. Severability. If any provision of this Agreement is declared void or unenforceable, such provision shall be deemed modified to the extent necessary to allow enforcement, and all other portions of this Agreement shall remain in full force and effect.

12. Entire Agreement Amendments. This Agreement contains the entire and complete agreement between the parties with respect to the subject matter hereof, and supersedes all prior oral and/or written agreements with respect to the subject matter hereof, other than any currently effective confidentiality agreement. Any changes to this Agreement must be in writing and signed by both parties.

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13. Successors. No portion of this Agreement may be assigned by Consultant without Elan's prior written consent. This Agreement shall be binding upon and inure to the benefit of the successors, permitted assigns and legal representatives of the parties.

14. Governing Law. This Agreement shall be governed by and construed in accordance with the laws of the State of California, and the parties agree to personal jurisdiction and venue in the state and federal courts of San Francisco, California, in any suit or proceeding arising out of the subject matter of this Agreement.

15. AHP shall be a third party beneficiary hereof.

DATED as of the Effective Date, and executed by:


ELAN PHARMACEUTICALS, INC.

By: /s/ Dale B. Schenk
--------------------------
Name: Dale B. Schenk, Ph.D.
--------------------------
Title: Senior Vice President
--------------------------
Discovery Research"



DENNIS J. SELKOE, MD

By: /s/ Dennis J. Selkoe
------------------------

Source: Sample Business Contracts [FullText]

" CONSULTING AGREEMENT
--------------------

This Consulting Agreement, made as of this the first day of July, 1986, is between ATHENA NEUROSCIENCES, INC., a Delaware corporation, (hereinafter "COMPANY"), having principal offices in care of Fairfield Venture Partners,
650 Town Center Drive, Suite 810, Costa Mesa, California 92626, and DENNIS J. SELKOE, M.D., (hereinafter "CONSULTANT"), having an address at 166 Moss Hill Road, Jamaica Plain, Massachusetts 02130.

The following terms and conditions will govern the parties to this Agreement:

1. Prior and Other Work of Consultant.

(a) CONSULTANT is a member of the Professional Staff of Brigham and Women's Hospital ("Brigham"), is a member of the Faculty of Medicine of Harvard University ("Harvard"), is responsible for a variety of clinical and research duties, and is subject to all requirements imposed by the following instruments, warranted by CONSULTANT to be in force on the Effective Date (as hereinafter defined), a copy of each of which is attached hereto and made a part hereof: (a) Brigham and Women's Hospital Patent Policy, (b) Brigham's Statement of Policy on Consulting Agreements, and (c) a certain Brigham and Women's Hospital Participation Agreement, dated March 16, 1986 between Brigham and the CONSULTANT (all of which individually or collectively are referred to hereinafter as "instruments").

(b) Subject to his obligations under the instruments, the CONSULTANT hereby warrants that he is free to enter into this Agreement with the COMPANY and to provide the consulting services required hereunder and the CONSULTANT represents that he is not a party to any existing agreement which would prevent his entering into this Agreement or which would affect the COMPANY'S rights or the CONSULTANT'S duties under this Agreement.

(c) The CONSULTANT advises the COMPANY that the CONSULTANT is a member of the professional staff of Brigham and the faculty of Harvard, as described above, and that to his best knowledge and belief, this Agreement is not in conflict with the patent and copyright policy of Brigham or Harvard, if any, or in conflict with the instruments or any of the CONSULTANT'S commitments thereunder. The CONSULTANT agrees to use his best efforts to (i) segregate work done under this Agreement from his work done for Brigham or Harvard, as the case may be, so as to minimize any questions of disclosure of, or rights under, any inventions to Brigham or Harvard, as the case may be, and (ii) assist the COMPANY and Brigham or Harvard, as the case may

2

be, in fairly resolving any such questions which may arise.

(d) The CONSULTANT agrees that for the term of this Agreement, and for a period of six (6) months thereafter, the CONSULTANT will not, without the prior written consent of the COMPANY, enter into any agreement with anyone other than the OMPANY to consult or otherwise render services in the Field (as hereinafter defined), provided that this Agreement shall not abrogate the CONSULTANT'S obligations to Brigham or Harvard. During the term of this Agreement, and for a period of six (6) months thereafter, CONSULTANT will not (i) own, manage, operate or control, or participate in the ownership, management, operation or control of (except that, for purposes of this subparagraph, an ownership interest of one percent (1%) or less of a corporation with a class of securities registered under the Securities Act of 1934, as amended, shall not be prohibited), or (ii) be associated with as a director, officer, employee, partner or consultant (whether or not for compensation), or (iii) permit the use of his name in connection with any corporation, partnership, joint venture, sole proprietorship or any other form of business which is or will be, directly or indirectly,

3

selling products or services in the Field (as hereinafter defined). Before performing any services for others, as a consultant or otherwise, in the Field other than the services required by his principal employment, CONSULTANT shall, during the term of this Agreement, and for a period of six (6) months thereafter, notify the COMPANY of the general nature of the services to be performed and the party for whom they will be performed, in order that the COMPANY may determine whether a conflict of interest may arise.

(e) The CONSULTANT agrees not to disclose to the COMPANY any trade secrets or other information which he does not have the right to disclose, and which the COMPANY is not free to use without liability of any kind. The CONSULTANT further agrees to inform the COMPANY of any patents, known to him, which the COMPANY may be in a position to violate as a result of information provided by the CONSULTANT. Consistent with and during the term of this Agreement, the CONSULTANT agrees to inform the COMPANY of any other research he is involved in which is or becomes directly within the scope of the work described on Appendix A attached hereto and related to the

4

subject matter of this Agreement. It is understood and agreed that as a member of the professional staff of Brigham, CONSULTANT is responsible to disclose to Brigham any discovery or inventions made by him as defined in the Brigham Participation Agreement and to file this present Consulting Agreement with Brigham, before execution hereof, in order that Brigham can fully comply with its contractual obligations and commitments.

2. Term. Effective as of the date this Consulting Agreement is executed by CONSULTANT ("Effective Date"), and continuing for the next following year (365 days), CONSULTANT shall serve as a consultant and scientific advisor to COMPANY within the field of research and clinical practice pertaining to diagnostic strategies relating to Alzheimer's Disease, as and to the extent described on the attached Appendix A (hereinafter "Field"), and also including such other work as hereinafter from time to time may be designated by the parties in writing to be part of the Field, to the extent his commitments to Brigham and Harvard do not preclude such engagement. This Agreement shall renew automatically for consecutive one-year (365 day) terms, unless either party notifies the other at least 60 days prior to any anniversary of the Effective Date hereof of an intent not to renew under the terms hereof.

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3. Role. CONSULTANT shall make himself personally available to COMPANY to the extent set forth in Appendix A during the term of this Agreement for the purpose of providing services hereunder at the request of COMPANY. Such consultations shall be held at such times and locations as may be designated by the COMPANY.

4. Compensation.

(a) As compensation for the services to be performed hereunder, COMPANY shall pay CONSULTANT a fee in an amount to be fixed annually by agreement between COMPANY and CONSULTANT. Such Compensation shall be in accordance with a budget prepared by CONSULTANT and approved by the COMPANY, such budget to be approved at least sixty (60) days prior to the commencement of any renewal term thereof.

(b) COMPANY shall also reimburse CONSULTANT for all reasonable travel and other expenses incurred upon its behalf and when authorized in advance by COMPANY. Such expenses shall be confirmed by appropriate receipts and shall be submitted in accordance with COMPANY'S standard expense account procedure.

5. Duties of CONSULTANT. The responsibilities of CONSULTANT shall consist of:

(a) providing the services in the Field described in

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Appendix A toward the objective of developing inventions of commercial value to COMPANY, and reporting thereon as requested by COMPANY; and

(b) refraining, during the term of this Agreement and for a period of one (1) year thereafter, from recruiting or otherwise soliciting or inducing any employees of COMPANY or any of its affiliates to terminate their relationship with the COMPANY or any of its affiliates.

Nothing under this paragraph 5 shall:

(i) be construed to permit or require the CONSULTANT to disclose, and the CONSULTANT shall not disclose, to COMPANY any information, including without limitation any advice or suggestions regarding any product, product development, formula, or technological or manufacturing process, whether or not relating to the Field, which the CONSULTANT shall be under any duty, express or implied, to Brigham, Harvard or any other person or persons to keep secret, develop or otherwise to deal with; or

(ii) grant to COMPANY any license under any patent or patent application not expressly assigned or assignable to COMPANY in accordance herewith.

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6. Inventions, Trade Secrets, Confidential Information. Except as may be determined otherwise in accordance with sections (a) and (c) of paragraph 1 above:

(a) The CONSULTANT agrees to keep confidential, and not to use, other than for the purposes of the Agreement, all information furnished by the COMPANY and all information developed by the CONSULTANT pursuant to this Agreement, except to the extent that such information was already known to the CONSULTANT or is, or later becomes, publicly known under circumstances involving no breach of this Agreement, or other fault of the CONSULTANT, or is lawfully furnished to CONSULTANT without restriction or disclosure by a third party.

(b) The CONSULTANT agrees to keep, separate and segregated from other work, all documents, records, notebooks, correspondence, deposits of micro-organisms, cells or parts thereof, cell lines, parts and progeny thereof, and all products produced thereby, including modified or unmodified compounds such as DNA or parts thereof whether or not included in a vector or host system which directly relate to his consulting work under this Agreement. Subject to paragraphs 1 and 5 hereof, all rights, title and interest therein shall be in the COMPANY, and upon

8

expiration or other termination of this Agreement, all documents, records, notebooks, and similar repositories of or containing confidential information (the CONSULTANT may retain all copies thereof but he will not, except to the extent permitted in paragraph 6(a) or with the prior written consent of the COMPANY, provide such information to anyone other than the COMPANY for a period of three years after the termination of this Agreement, unless the COMPANY shall terminate this Agreement) then in CONSULTANT'S possession or subject to his control, whether prepared by him or others, will be turned over to the COMPANY.

(c) CONSULTANT shall promptly disclose any and all concepts, ideas, inventions, discoveries or developments, whether or not patentable, relating to the Field which become known during the term of, or by virtue of, this Consulting Agreement. CONSULTANT shall assign to COMPANY or any person or organization designated in writing by the COMPANY, at no additional consideration other than the consideration for this Consulting Agreement, all of CONSULTANT'S right, title and interest in any invention, whether or not patentable, in the Field that is conceived or

9

first reduced to practice during the provision of the services of CONSULTANT to COMPANY during the term of this Consulting Agreement, or for a period of 90 days thereafter, whether conceived and/or reduced to practice either solely or jointly with others. In addition, CONSULTANT shall render all assistance reasonably requested by COMPANY, and not of such a nature as to impair his obligations to Brigham and Harvard, in order to enable COMPANY to file, obtain and enforce any Letters Patent, whether foreign or domestic, on said invention, including the execution of such papers and documents as may be necessary to obtain patents in the United States and abroad, and shall otherwise provide full cooperation to COMPANY in obtaining those patents in which CONSULTANT is named as an inventor or co-inventor, even though such cooperation may be required to take place at a time following the expiration and/or termination of this Agreement. COMPANY shall promptly reimburse CONSULTANT in providing the assistance required by this paragraph upon the submission to COMPANY of an itemized statement of such expenses.

(d) Nothing contained in this Agreement shall prevent CONSULTANT from publishing the results of his

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work in the Field, provided that such publication is made in accordance with the procedures set forth in this paragraph 6. CONSULTANT shall submit to COMPANY a copy of any early draft of any manuscript to be published by CONSULTANT, solely or in co-authorship with others, or with scientists in COMPANY'S employ, containing information developed during any project undertaken pursuant to this Agreement, at least sixty (60) days prior to the submission thereof for publication, and to delay submission thereof upon written notice from COMPANY for a reasonable period not to exceed sixty (60) days to allow COMPANY to perfect its interest in any patentable subject matter disclosed therein, or otherwise protect the property rights of the subject information, in a manner to be determined by the COMPANY. At the end of said period the CONSULTANT at his sole discretion, shall have the right to submit the manuscript for publication.

(e) It is understood and agreed that CONSULTANT shall receive the principal scientific credit for any inventions, ideas, developments or research results conceived or reduced to practice by CONSULTANT, or by COMPANY in consultation with the CONSULTANT, relating to an immuno-diagnostic

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test or a DNA probe for Alzheimer's Disease, and the primary authorship of any articles, abstracts or other publications by the COMPANY or any of its employees relating thereto. The scientific responsibility and credit will, however, be shared by CONSULTANT and, if appropriate, Dr. Kosik.

(f) CONSULTANT, shall use all reasonable efforts to ensure that any invention by CONSULTANT which is conceived or reduced to practice during the term of this Agreement, which invention relates both to CONSULTANT'S work under this Agreement and to CONSULTANT'S research is defined under the aforesaid Participation Agreement, shall be vested in the COMPANY.

7. Miscellaneous.

(a) The CONSULTANT shall be deemed to be an independent contractor of the COMPANY and not an employee or agent of the COMPANY; the CONSULTANT shall have no power to bind or subject the COMPANY to liability in any way.

(b) Any previous agreements, oral or written, between the COMPANY and the CONSULTANT are superseded to the extent that this Agreement is inconsistent therewith.

(c) This Agreement is to be governed by and construed in accordance with the laws of the Commonwealth of Massachusetts.

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(d) If any one or more of the provisions of this Agreement are held to be invalid, illegal or unenforceable in any respect, the validity, legality, and enforceability of the remaining provisions shall not in any way be affected or impaired thereby; but such provisions and/or this Agreement shall be reformed and construed so as to be valid, operative, and enforceable to the maximum effect allowed in law or in equity.

(e) All notices given pursuant to this Agreement shall be in writing and shall be deemed to have been sufficiently given if delivered by hand or sent by certified or registered mail, postage prepaid, addressed to either party hereto at the respective addresses set forth at the beginning of this Agreement.

(f) COMPANY may assign all rights under this Agreement to any successors or assigns of all or substantially all of the business of the COMPANY.

(g) The COMPANY shall have the right to obtain injunctive relief, including, without limitation, specific performance, for breach or threatened breach of the terms of paragraphs 1 or 6, and the obligations of the CONSULTANT under those paragraphs will survive the termination for any reason of this Agreement. It is expressly understood and agreed that nothing herein

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contained shall be construed as prohibiting the COMPANY from pursuing any other remedies available for such breach or threatened breach, including, without limitation, the recovery of damages by the COMPANY.

Agreed to and Accepted:

CONSULTANT ATHENA NEUROSCIENCES, INC.

/s/ Dennis J. Selkoe By: /s/ Authorized Signatory
-------------------- ----------------------------------
Dennis J. Selkoe

Effective Date: July 1, 1986"

[FullText at Source]

Beware simplicity of lay reports, see major subject journal now: Neurobiology of Lipids
"A new study suggests that cholesterol-lowering drugs like statins and fibrates may slow the course of Alzheimer's disease.

The study followed the progression of 342 patients for three years. Of them, 234 had high cholesterol, and 129 of those were given medicine to lower their cholesterol. The patients were scored on a test of mental function at the beginning and end of the study. Those treated with anti-cholesterol drugs were significantly less likely to show declines in cognitive abilities than those left untreated. The study was published in the December issue of the Journal of Neurology, Neurosurgery and Psychiatry.

An editorial accompanying the paper points out that previous evidence that lowering cholesterol may help prevent Alzheimer's disease says nothing about whether it slows its progress once it has begun, and that this paper presents a well-designed study showing that treatment can also delay dementia once the disease takes hold.

Still, the study has weaknesses: it does not sort out the cholesterol-lowering effects of these drugs from any other effects they may have, and it provides no suggestion about possible mechanisms of the effect.

Source: Cholesterol drug for Alzheimer's? By Nicholas Bakalar The New York Times (30 November 2005) [FullText]

Axonyx Inc. (NASDAQ: AXYX) reports today the results of an additional analysis of a subgroup of patients from its two curtailed Phase III clinical trials (AX-CL-09/010) with Phenserine, in development for mild to moderate Alzheimer's disease (AD). The subgroup of patients, who received Phenserine 15mg twice daily, demonstrated a statistically significant benefit over placebo as measured by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), when treated for more than 12 weeks. Additionally, this subgroup showed a positive trend towards improvement in the Clinical Interview Based Impression of Change (CIBIC+) test, which approached statistical significance. There were no unexpected safety or tolerability concerns associated with Phenserine treatment. This analysis was undertaken in addition to the previously announced results of the primary pre-defined statistical analysis.
While additional clinical trials would be required to further confirm the results of this additional analysis, the Company believes that they support its stated position that higher doses of Phenserine could potentially be efficacious in treating the signs and symptoms of mild to moderate AD in future potential Phase III trials of 26 weeks duration.

On September 20, 2005, the Company announced the top line results from its primary efficacy analysis of all patients that participated in the curtailed Phase III clinical trials; this analysis did not demonstrate a statistically significant benefit associated with Phenserine over placebo after 12 weeks of treatment in either the ADAS-cog or CIBIC+, the primary efficacy endpoints for the study. At that time, the Company indicated that it would continue to evaluate the Phenserine program. On November 7, 2005, the Company indicated it would not commit further resources to the development of Phenserine and would seek a partner for the compound.

This additional analysis was recently completed as part of the program to identify a partner for the further development of Phenserine. The analysis included 182 patients who received Phenserine treatment or placebo for more than 12 weeks and up to 26 weeks of treatment. The statistically significant benefit was based on the ADAS-cog test; one of the FDA approved measurements of efficacy in Alzheimer's disease clinical trials. The improvement in the CIBIC+ test, another approved efficacy endpoint, for the 15mg twice daily group approached statistical significance compared to the placebo group. The patients who received Phenserine 10mg twice daily did not show a statistically significant benefit compared to placebo..." [Read Full Article at Genetic & Engeneering News, 29 Nov 2005]

Beware simplicity of lay reports: read major subject science journal now: Neurobiology of Lipids

"Ann Todd was shocked when she first realized something was wrong with her husband, Ronald.

"He called the sheriff's office to report that some of his tools had been stolen," she said. "And when I came home from work he told me about it. I realized he had forgotten that he had given them to our son."

That day marked the beginning of the Monterey couple's nine-year struggle with Alzheimer's disease. Ronald died last year.

Like many Alzheimer's patients, Ronald Todd had high cholesterol. But the side effects of the cholesterol-lowering drug he was taking forced him to quit the medication.

Since then, Ann Todd, a registered nurse, said she has read about studies that found similar drugs might actually slow the progression of the disease.

"That's hopeful," she said.

Now, several California universities are participating in a nationwide study of 400 patients to determine whether a drug commonly prescribed to reduce cholesterol can, in fact, slow the progression of Alzheimer's disease.

The large-scale study, which began in December 2002, is specifically focused on the drug simvastatin, commonly known as Zocor. Universities including Stanford and University of California campuses at Davis, Irvine, Los Angeles and San Diego recruited Alzheimer's patients to participate. Each of the 40 universities involved in the study chose 10 to 15 patients who had normal cholesterol levels and no signs of stroke or head injuries.

"We review patients' medical records and history," said Alena Penchonkina, who works at Stanford's Aging Clinical Research Center and is involved in the study. "They have complete physical and neurological evaluations, plus MRI scans of their brains to rule out other causes of memory loss like stroke or tumors."

Unless a physician dissects a patient's brain, however, there is no way to confirm whether he or she has Alzheimer's disease. By ruling out all the other known causes of dementia and memory loss, physicians are about 90 percent accurate when diagnosing Alzheimer's disease.

Every patient in the study must also have a study partner to observe their progress, report any problems and make sure they are taking the medication.

Physicians monitor the patients' progress periodically and keep in regular contact with the study partner. They evaluate the patients by talking to them and by giving them tests. For example, patients can be tested to see if they can remember names, keep track of where they are or draw something specific.

When designing this study, scientists at the National Institute of Aging said they wanted to test a cholesterol-lowering drug that was commonly prescribed, relatively inexpensive and could cross the blood-brain barrier to gain access to the brains of Alzheimer's patients. They chose Zocor, which, according to manufacturer Merck & Co., was prescribed more than 200 million times over the past 12 years in the United States.

Study federally funded

Merck holds patents on the drug but did not sponsor the study, which is one of many being funded by the federal government. This year, Alzheimer's disease research received about $647 million from the federal government.

Some scientists believe that lowering cholesterol levels in the body changes chemical reactions in the brain and slows the progression of Alzheimer's disease. Already, studies have shown that controlling blood pressure, cholesterol and weight can help reduce the risk of the disease.

Previously, small-scale studies with 20 to 50 patients have shown that cholesterol-lowering drugs, such as Lipitor and Zocor, may slow the progression of Alzheimer's disease.

The disease, sometimes referred to as "the long goodbye," attacks the minds of the elderly over the course of decades. Alzheimer's patients typically begin by losing their memory. Eventually dementia takes over. As their minds degenerate, Alzheimer's patients can regress to the point of babbling like a baby and being unable to stand or swallow.

With the aging baby-boom generation, the number of Alzheimer's patients is likely to increase. Currently, an estimated 220,000 people in Northern California struggle with the disease, according to the Alzheimer's Association, a national research and advocacy group based in Chicago.

By 2050, the association estimates that more than 600,000 Northern Californians will be diagnosed with the disease..."

Source: Juhi Yajnik. Ray of hope in Alzheimer's struggle: Cholesterol drug may slow progress of brain disease. The Herald (29 November 2005) [FullText]

"Jim Lambright, former football coach at the University of Washington, and his wife Lynne have donated $100,000 to the UW School of Medicine, through the Jim Lambright Medical Research Foundation. The funds were raised during a celebrity golf tournament and banquet organized by the Lambrights in early June.

The donation will be used in a pilot project for research into an inherited neurological disorder, Niemann-Pick C disease (NP-C), that afflicts Lynne Lambright's two adult sons, Brad Mackie, 39, and Bart Mackie, 37. (A third son died a year and a half ago of a heart attack; ironically, he was unaffected by the disease.)

"We are very grateful to the Lambrights for their personal efforts in raising funds for research into this disease," said Dr. Paul Ramsey, vice president for medical affairs and dean of medicine. "We hope that research at the University of Washington School of Medicine will help turn their very difficult personal ordeal with this illness into the first steps toward a cure."

Niemann-Pick C Disease is caused by a recessive gene and is ultimately fatal; individuals with the disease are unable to metabolize cholesterol. Large amounts of cholesterol accumulate in the liver, spleen and brain, causing progressive deterioration of the nervous system. People with NP-C usually do not live past the age of 15, but occasionally live into adulthood.

Symptoms include difficulty with eye movements, slurred speech, difficulty swallowing, loss of motor skills, and ultimately dementia, seizures and death.

While there is no treatment for NP-C, researchers have recently isolated the primary gene that causes the disease. While studies are under way to determine the benefits of cholesterol reduction through diet and drugs, the most promising lines of investigation involve genetic therapy and cholesterol metabolism research.

Leading the research effort will be neurogeneticist Dr. Thomas Bird, UW professor of neurology and medical genetics who is also a research neurologist at the VA Puget Sound Health Care System. Bird sits on the foundation's board.

"Understanding of NP-C may also have important implications for more common disorders such as atherosclerosis, mental retardation, Alzheimer's disease and Parkinson's disease," said Bird. "The Jim Lambright Foundation is committed to stimulating novel research on NP-C within the University of Washington community."

"Lynne and I are pleased to be able to work with the University of Washington again on such an important matter," said Jim Lambright. "We look forward to the day when Niemann-Pick C Disease will be curable."

"When our sons became affected by this disease, we knew we had to do something," said Lynne Lambright. "We are grateful for the help of so many people in raising funds and increasing awareness."

Coincidentally, three grandchildren of another famed former college football coach, Ara Parseghian of Notre Dame University, inherited the same disease. One has died. The Lambrights and the Parseghians have joined forces through their two foundations to search for a cure. (Information on the Parseghian Foundation can be found on the web at http://www.parseghian.org/.)"

Source: Health and Medicine : Former Husky football coach and wife give UW $100,000 for research into rare genetic disease (11 August 1999) www.uwnews.org [FullText]