Treatment for Alzheimer's Disease: Brief summaries of research reports

Pilot drug studies

March 2008

Potential new drug target identified

A mouse study has successfully reduced the production of beta-amyloid peptides, and improved memory. These peptides are produced when enzymes cut APP at two places, called the beta-secretase and gamma-secretase sites. Previous research has focused on a mutant beta-secretase sequence only seen in one extended family of patients, the so-called Swedish mutation. The new study identifies a different enzyme, called Cathepsin B (CatB), which works to cut the normal beta-secretase site in more than 99% of patients with Alzheimer’s. Two compounds that inhibit CatB were successfully tested, producing great improvement in memory, as well as reduced brain levels of beta amyloid.
The study was published in the March 21 edition of the Journal of Biological Chemistry. Full reference
http://www.eurekalert.org/pub_releases/2008-03/uoc--pad031108.php

February 2008

PLMI factor in sleep disturbance for dementia patients

A study of 102 people diagnosed with both cognitive impairment and sleep disturbance (average nightly sleep of seven or less hours and daytime sleep of 30 minutes or longer) found that periodic leg movement disorder (a condition that causes people to jerk and kick their legs every 20 to 40 seconds during sleep) was predictive of reduced total sleep time in older adults with Alzheimer disease and related dementias. Given that sleep disturbance in persons with dementia is a highly prevalent and disabling symptom, and sedative-hypnotics are not recommended, this finding is important because it suggests treatment of periodic leg movements may be beneficial.
The study was published in the February 1 issue of SLEEP. Full reference
http://www.eurekalert.org/pub_releases/2008-02/aaos-ppt012808.php

May 2007

Reduction of tau protein protects against Alzheimer’s

A study using genetically engineered mice has found that when tau protein was reduced their memory function was retained and they lived a normal lifespan, even though amyloid-beta levels weren’t affected. They were also made mice more resistant to epileptic seizures.
The findings were reported in the May 4 issue of Science. Full reference
http://www.eurekalert.org/pub_releases/2007-05/gi-sin042707.htm

October 2006

Marijuana may slow progression of Alzheimer's disease

New evidence suggests that marijuana — which has strong anti-inflammatory effects — may contain compounds that slow the memory loss associated with Alzheimer's disease. Treatment with a synthetic compound similar to marijuana (WIN-55212-2) reduced inflammation in older rats and substantially improved their memories.
The researchers presented their findings October 18 at the annual Society for Neuroscience meeting in Atlanta.
http://www.eurekalert.org/pub_releases/2006-10/osu-lb101206.htm
http://www.sciencedaily.com/releases/2006/10/061018151055.htm

February 2006

New drug reduces plaque and tangles in Alzheimer's mice

Alzheimer's mice that received a compound known as AF267B for eight weeks performed significantly better on a spatial memory test than untreated mice did. A different memory test that involved associating a place with a shock was not affected. The drug was found to reduce plaques and tangles in the hippocampus but not in the amygdala. AF267B seems to work in part by enhancing the activity of receptors for the neurotransmitter acetylcholine, and boosting the levels of an enzyme called alpha secretase, which blocks the production of beta-amyloid proteins. Suppressing the M1 receptors worsened the condition and performance of Alzheimer’s mice, confirming the important role of M1 receptors in modulating the plaques and tangles characteristic of Alzheimer’s.
The report appeared in the March 2 issue of Neuron. Full reference
http://www.sciam.com/article.cfm?chanID=sa003&articleID=000332CA-2F01-1405-AE5A83414B7F4945

January 2006

New compound stops brain cell degeneration in Alzheimer's disease

A new orally administered compound specifically targeted to suppress brain cell inflammation and neuron loss associated with Alzheimer's disease has been developed. The compound, MW01-5-188WH, is rapidly absorbed by the brain and is non-toxic. It selectively inhibits production of pro-inflammatory proteins called cytokines by glia, giving it relevance for several neurodegenerative disorders. The compound suppressed brain inflammation and neuron dysfunction in the hippocampus and protected against cognitive decline in genetically engineered mice. The compound also restored normal levels of markers of synaptic dysfunction in the hippocampus and attenuated Alzheimer's-like behavioral deficits. The compound represents a new approach to Alzheimer’s therapy.
The report appeared in the January 11 issue of the Journal of Neuroscience. Full reference
http://www.eurekalert.org/pub_releases/2006-01/nu-ncs011906.htm

December 2005

Testosterone improves quality of life

A 24-week study involving 16 male patients diagnosed with mild Alzheimer disease and 22 healthy male controls found that Alzheimer’s patients who received daily testosterone treatment showed significant improvement on a quality-of-life instrument that encompasses memory, interpersonal relationships, physical health, energy, living situation and overall well-being, however improvement in memory or other cognitive skills using cognitive tests did not reach significance. Among healthy controls, those receiving testosterone showed a non-significant trend toward greater improvement in self-rated quality of life.
The study was published December 12 in an early online release of Archives of Neurology. Full reference
Full text at http://archneur.ama-assn.org/cgi/content/full/63.2.nct50002v1
http://www.eurekalert.org/pub_releases/2005-12/uoc--apt120805.htm

Natural compound from 'pond scum' shows potential activity against Alzheimer's

A compound isolated from a cyanobacterium, a type of blue-green algae (‘pond scum’) shows promise of becoming a natural drug candidate for fighting Alzheimer's. Nostocarboline (the newly isolated compound) is a potent inhibitor of cholinesterase, with a potency comparable to galanthamine.
The study was published in the December 26 issue of the Journal of Natural Product. Full reference
http://www.eurekalert.org/pub_releases/2005-12/acs-ncf122705.htm

October 2005

Gas-blockers might slow down Alzheimer's disease

Beta-amyloid is known to cause brain cells to make an inhibitor of an enzyme that triggers the production of nitric oxide (iNOS). This enzyme is normally turned on during infection and is needed to help immune cells destroy invading pathogens, but it is not normally found in the brain, where it may cause cellular damage that destroys neurons. Although it’s long been known that iNOS is present in the brain lesions of Alzheimer’s patients, it hasn’t been known whether its presence makes things worse. A new study has now shown that Alzheimer's-prone mice that lack iNOS live twice as long and develop fewer brain lesions than iNOS-expressing mice. The researchers suggest that iNOS inhibitors might turn out to be an effective in slowing the progression of Alzheimer's disease.
The study appeared in the November 7 issue of the Journal of Experimental Medicine. Full reference
http://www.eurekalert.org/pub_releases/2005-10/joem-gms102005.htm

June 2005

New memory drug works best in combination with older drug

An experimental drug – a compound known as SGS742 – has been successful in animal studies in improving memory, and is now in human clinical trials. The drug works by blocking certain chemicals that interfere with memory formation, thus enabling better acquisition and retention of new information. It alters the activity of gene control machinery that is important for memory consolidation. It was most effective when used in conjunction with Aricept, an established Alzheimer’s drug.
The findings were described in the June issue of Neuropharmacology. Full reference
http://www.eurekalert.org/pub_releases/2005-06/jhu-nmd060905.htm

March 2005

Chemical decoy shows promise for slowing Alzheimer's

A chemical polymer shows promise in cell culture studies of slowing Alzheimer’s by blocking the toxic brain proteins thought to cause the disease. The likely candidate for any drugs developed from this approach would be people at increased risk of Alzheimer’s, who haven’t yet developed signs of the disease.
The finding was presented on March 17 at the 229th national meeting of the American Chemical Society. Reference
http://www.eurekalert.org/pub_releases/2005-03/acs-ds030705.htm

January 2005

Antibody treatment partially reverses nerve damage in Alzheimer disease

A mouse study has had success in significantly decreasing structural nerve damage in the brains of mice with Alzheimer’s, by administering an beta amyloid antibody treatment to the brain surface.
The study appeared online on January 20 in advance of print publication in the February 1 issue of the Journal of Clinical Investigation. Full reference
http://www.eurekalert.org/pub_releases/2005-01/joci-atp011305.htm
http://news.bbc.co.uk/go/pr/fr/-/1/hi/health/4188677.stm

December 2004

Rolipram - a potential new treatment

In a mouse study, a phosphodiesterase 4 inhibitor, rolipram, was found to improve memory in both long-term potential and contextual learning. Rolipram's protective effect is due to its ability to modify gene expression, making brain synapses more resistant to the insult caused by the accumulation of Ab. The beneficial effect of rolipram treatment was found to extend for at least 2 months after the end of one course of the treatment, and was more effective in the later stages of the disease.
The study appeared in the December 1 issue of the Journal of Clinical Investigation. Full reference
http://www.eurekalert.org/pub_releases/2004-12/joci-r-a111804.htm

Keeping blood pressure & cholesterol low may help some dementia patients more than Alzheimer's drugs

A comprehensive review of all recent medical studies on mixed dementia, vascular dementia and Alzheimer's suggests that efforts to treat cardiovascular risk factors, especially high blood pressure, may be more effective for many than memory drugs in protecting brain function.
The study was published in the December 15 issue of the Journal of the American Medical Association. Full reference
http://www.eurekalert.org/pub_releases/2004-12/uomh-thy120904.htm

November 2004

New type of Alzheimer's drug on trial

A clinical trial is commencing to test the effectiveness of a new type of drug, called Alzhemed, that attacks amyloid. The trial will last 18 months and will enroll about 950 Alzheimer's patients with a mild-to-moderate form of the disease, from centers around the United States and Canada. The drug actually physically combines with amyloid to prevent plaque formation, and is also expected to inhibit the inflammatory response associated with amyloid buildup in Alzheimer's.
http://www.eurekalert.org/pub_releases/2004-11/tju-jns110204.htm

October 2004

Blood pressure drugs may slow deterioration of Alzheimer's

A study involving 162 people in Japan living in long-term care facilities with mild to moderate Alzheimer's disease and high blood pressure has found that certain blood pressure drugs may slow the deterioration of Alzheimer's disease. The results, while interesting, will need to be replicated in carefully controlled, randomized, blinded studies
The study was published in the October 12 issue of Neurology. Full reference
http://www.eurekalert.org/pub_releases/2004-10/aaon-bpd100404.htm

Anti-cholesterol drug treats Alzheimer's disease in mice

A drug that jams a key enzyme regulating cholesterol (CP-113,818) has been found to drastically reduce the levels of amyloid plaque in genetically engineered mice. The drug has not been tested in clinical trials, but another ACAT inhibitor, avasimibe, is now in final clinical trials as a treatment for vascular disease and atherosclerosis.
The study was reported in the October 14 issue of Neuron. Full reference
http://www.eurekalert.org/pub_releases/2004-10/cp-adt101204.htm

May 2004

Protein found that dissolves amyloid fibers

Amyloid plaque is extremely tough — so tough researchers have been unable to find a means to attack them. A new study suggests that yeast may be the means. Oddly, the yeast protein seems to be involved both in making amyloid fibers, and in dissolving them. The yeast protein Sup35 sometimes forms amyloid fibers in yeast cells — this is part of the cell's normal biology, changing the types of proteins that the cell makes. Another protein — Hsp104 — appears to affect Sup35's ability to form amyloid fibers. When a yeast cell contained either high amounts of Hsp104 or none at all, amyloid fibers never formed. But when Hsp104 levels were small, the fibers flourished. In the latest study, researchers found that small amounts of Hsp104 catalyzed the formation of amyloid fibers, but large levels of the protein actually caused the fibers to dissolve. Interestingly, Hsp104 belongs to a class of proteins that sometimes are influenced by environmental factors.
The study was published online 20 May in Science.
http://www.eurekalert.org/pub_releases/2004-05/wifb-rdp052004.htm

December 2003

Clioquinol slowed progression of cognitive decline in Alzheimer's patients

A new clinical trial has found that the drug Clioquinol slowed the progression of cognitive decline in a group of 36 patients with moderate to severe Alzheimer’s, over a period of 24 weeks. PBT-1 (Clioquinol) is a chemical that binds zinc and copper, and has been shown to lower the levels of beta-amyloid and the associated toxicity in the brains of transgenic mice used as a model of Alzheimer's disease.
The trial was reported in the December 15 issue of the Archives of Neurology. Full reference
http://www.eurekalert.org/pub_releases/2003-12/aaft-cto121503.htm

September 2003

Cancer drug may help against Alzheimer's too

The drug Gleevec, approved for treatment of chronic myelogenous leukemia (CML) over two years ago, has been found to reduce the level of beta-amyloid in immature rat neurons and cultured human cells. The drug also significantly reduced the levels of amyloid peptides in live guinea pigs (who have amyloid peptides comparable to those found in humans). While still preliminary, the work may indicate a new approach to treating Alzheimer’s.
The report was published in the Proceedings of the National Academy of Sciences. Full reference
http://www.sciam.com/article.cfm?chanID=sa003&articleID=00014A83-AC91-1F78-AC9183414B7F0000

April 2003

New Drug for Moderate-to-Severe Alzheimer's

Four drugs — donepezil, galantamine, rivastigmine, and tacrine — are approved for treatment of mild-to-moderate Alzheimer's disease in the U.S., but there are no approved treatments for severe AD. Now an industry-sponsored study has examined memantine for this use. The study involved 252 patients with moderate-to-severe AD, over a period of 28 weeks. Patients were evaluated on 7 tests of cognition, functional capacity, and behavior. Outcomes were significantly better with memantine than with placebo on 4 of these scales, and no significant adverse events were noted. It is not clear yet how clinically meaningful these small improvements are. Memantine has been approved for use in Europe.
The report appeared in the April 3 issue of the New England Journal of Medicine. Full reference
http://www.eurekalert.org/pub_releases/2003-04/nyum-dsp032603.htm

DHEA supplement shows no effect on Alzheimer's

The supplement dehydroepiandrosterone, or DHEA, had no effect on Alzheimer's patients who took the supplement for six months. A transient benefit on cognitive performance occurred at three months, but was not statistically significant. Of the 58 people who started the study, 46 completed three months of treatment and 33 completed six months of treatment. The small size of the study and the high number of people who dropped out may limit the findings of the study.
The study was published in the April 8 issue of Neurology. Full reference
http://www.eurekalert.org/pub_releases/2003-04/aaon-dss033103.htm

August 2001

Designer chemical offers Alzheimer's hope

Researchers at the University of Illinois at Chicago have designed and synthesized highly potent inhibitor compounds that could lead to an effective treatment for Alzheimer’s disease.In earlier work, the researchers had designed an inhibitor that blocks the action of one of two enzymes thought to be responsible for Alzheimer’s disease. This enzyme, called memapsin 2, is responsible for producing beta-amyloid, which forms the plaques so characteristic of Alzheimer’s disease. The inhibitor was reported in the Journal of the American Chemical Society last year and was shown to be effective in test tube experiments. However, while useful as a model, the inhibitor was too big to be effective in drug therapy. What is needed is a compound small enough to cross the blood-brain barrier. This latest paper reports on a new, smaller, generation of inhibitors designed and tested in the laboratory.
The work was reported in the American Chemical Society’s Journal of Medicinal Chemistry.
http://www.eurekalert.org/pub_releases/2001-08/uoia-dco080201.htm

April 2001

Naturally occurring protein could slow Alzheimer's disease

A cholesterol-lowering protein produced by the body, Apolipoprotein A-1, might be able to slow the progression of Alzheimer's disease.
Everyone has some quantity of Apo-A, in their body. It is produced in the small intestine and the liver and is known to help prevent coronary heart disease. At normal levels, the protein clears cholesterol throughout the body, including in the brain. The scientists speculate that boosting Apo-A levels may also help clear beta amyloid, an important part of the Alzheimer's disease plaques that strangle normal brain cells. Further testing is needed to confirm the role of Apo-A in animals and its relation with Alzheimer's, before any human trials could begin.
The findings are reported in the March 27 issue of Biochemistry, a journal of the American Chemical Society.
http://www.eurekalert.org/pub_releases/2001-04/ACS-Nopc-0104101.htm

December 2000

Why Vitamin E might slow the progress of Alzheimer's

A chemical called methionine (an amino acid found in beta-amyloid) may be the source of the toxic free radicals produced by the amyloid-beta peptide. Recent studies have demonstrated that higher than normal doses of vitamin E may slow the advance of Alzheimer's in some people with late stages of the disease. The current study provides a possible explanation for this link. Vitamin E, an antioxidant, appears to work by destroying free radicals (oxidants) produced by amyloid.
The study was presented at the 2000 International Chemical Congress of Pacific Basin Societies.
http://www.eurekalert.org/pub_releases/2000-12/ACS-Ript-1712100.htm

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Vaccines

January 2007

Transdermal vaccine effective in treating Alzheimer's disease in mice

Previous research on an Alzheimer's vaccine proven safe and effective in an animal model was suspended when the initial clinical trial caused brain inflammation and death in a small percentage of patients. A new mouse study has now had success with a transdermal method of delivery (a skin patch), that doesn’t appear to trigger the toxic reaction of past immunization strategies. Further research is needed to assess whether the transdermal vaccine can curb memory loss as well as reduce Ab plaque.
The study was published online before print on January 30 in the Proceedings of the National Academy of Sciences. Full reference
http://www.eurekalert.org/pub_releases/2007-01/uosf-tve011807.htm

May 2005

Hopeful results from interrupted Alzheimer's vaccine study

Phase 2 of a human clinical trial vaccinating patients with beta-amyloid was halted in 2002 when some participants developed brain inflammation. Participants continued to be monitored, however, and results show that participants whose immune systems mounted a response against beta amyloid performed significantly better on a series of memory tests than those who received a placebo injection (but not on 5 tests often used to diagnose dementia). There were also signs of reduced levels of tau protein (a protein considered a sign of cell death) in those who had an immune response. As a result, new trials are underway, this time using humanized antibodies rather than beta amyloid itself. The antibodies should help trigger the immune system to attack beta amyloid, but will be cleared by the body soon after injection.
Two papers were published in the May 10 issue of Neurology. Full reference 1 Full reference 2
http://www.eurekalert.org/pub_releases/2005-05/uomh-hrf050505.htm

June 2004

Progress on Alzheimer's vaccine

Efforts to create a vaccine for Alzheimer’s have been hindered by potential side effects — some human participants in an earlier trial developed severe inflammation in the brain. A mouse study has now substantially increased the safety of the vaccine by including a tetanus toxin to alter the immune response. Future studies are planned using the herpes virus.
The work was published on-line June 25 in Neurobiology of Aging. Reference
http://www.eurekalert.org/pub_releases/2004-06/uorm-hta062904.htm

August 2001

Mice immunized against Alzheimer's

Using a new vaccine, NYU School of Medicine researchers have prevented the development of Alzheimer's disease in mice genetically engineered with the human gene for the disease. The researchers are optimistic that this new vaccine is safer than one already being tested in early human clinical trials. The new vaccine, modeled on a fragment of a protein called amyloid, which is most frequently implicated in causing Alzheimer's, reduced the amount of amyloid plaque in the brains of mice by 89 percent. At the same time, the vaccine reduced the amount of soluble amyloid beta in the brain by 57 percent. Early clinical trials of the new vaccine could begin within one year.
The study is published in the August 2 issue of the American Journal of Pathology.
http://www.eurekalert.org/pub_releases/2001-08/nyum-nrs080101.htm

December 2000

A vaccine for Alzheimer's

A vaccine may help prevent and treat the disabling memory loss and cognitive impairment of Alzheimer's disease. Alzheimer's occurs when amyloid-beta peptides accumulate in the brain, forming plaque. While previous studies have shown that vaccinating mutated mice with this amyloid-beta peptide could remove the plaque deposits, there was never any evidence of improvement in brain function, until now. The researchers also believe this study provides the final element of proof that Alzheimer's is initiated by amyloid-beta peptides. The researchers believe clinical trials could begin on human subjects within the year.
The study was published in the Dec. 21-28 issue of Nature.
http://www.eurekalert.org/pub_releases/2000-12/UoT-UoTr-1912100.htm

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