Current Alzheimer's Drugs Research
- Published on Tuesday, 24 June 2008 02:53
- Written by Stanton O. Berg
In July 2009, Dr. Knopman was quoted in the Minneapolis Star-Tribune as stating: "Despite years of research, drug companies have struggled to find an effective treatment. Part of the problem, Dr. Knopman of Mayo says, is timing: Symptoms only surface 20 to 30 years after patients develop the disease. By then, it's too late"
Current Alzheimer's Cause/Cure Theories
Beta-Amyloid Protein plaques: At the present time it appears that most of the research is directed towards the Beta-Amyloid Protein plaques found in the brains of Alzheimer’s victims. It is not currently known if the plaque found in the Alzheimer’s brain is the “cause of” or the “result of” Alzheimer’s. Some people have been found to have Beta-Amyloid plaques in their brains but did not show symptoms of Alzheimer’s. Also found in the Alzheimer’s brain are tangles of a protein called Tau. This Tau is also a suspect in the search for the cause of Alzheimer’s. Initially Amyloid plaques appear in the disease followed by Tau neurofibrillary tangling and its associated neurotoxicity.
AOL Health News 6/23/2008 reports findings of Dr. Ganesh M. Shankar and Dr. Dennis J. Selkoe of Harvard Medical School. “Researchers have caused Alzheimer’s symptoms in rats by injecting them with one particular form of Beta-Amyloid. ...other forms of Beta-Amyloid did not cause illness, which may explain why some people have Beta-Amyloid plaque in their brains but do not show disease symptoms.”
(1.)“Two-molecule form of soluble Beta-Amyloid produced characteristics of Alzheimer’s in the rats.
(2.) There was no detectable effect from the (a.) insoluble plaque or the (b.) soluble one-molecule or (c.) soluble three molecule forms. The question is why one has the damaging effect and not others.”
(Note: Four varieties of plaque are involved here.)
Vacination strategies for Azlheimer's disease remain an area of intense interest. But some critics have questioned whether amyloid-B vacination was simply a way to reverse cerebral amyloidosis without affecting other componetns of Azlheimer's disease....
We have learned a great deal about the possible pathogenic role that amyloid in its various forms might play in Alzheimer's disease pathogenesis, but the final demonstration that reversing amyloid pathology ameliorates the disease itself is still lacking."
Lancet Magazine for July 19th 2008: In a study, British researchers led by Dr. Clive Holmes, from the Memory Assessment and Research Centre at Moorgreen Hospital in Southampton, analyzed data on 80 Alzheimer's patients who were treated with an experimental vaccine that for now is dubbed AN1792. The vaccine is targeted at the removal of amyloid protein plaques that clump around brain cells in increasing numbers as Alzheimer's progresses. The theory was that dementia could be slowed or reversed once the plaques were cleared, and experiments in animals have shown that removing these plaques improves brain function. But there was a catch. "Crucially, there was no evidence that the patients benefited by the removal of plaques and even those subjects with virtually complete removal continued to deteriorate and had severe end-stage dementia prior to their death," Holmes said….Based on these results, the researcher now believes that removing plaques -- at least by this method -- is unlikely to make a significant difference to the clinical outcome of patients with established Alzheimer's disease. "In addition, it strongly suggests that plaques are not sufficient on their own to account for disease progression," Holmes said.
AMDA "Caring for the Ages" April 2009 contains a guest editorial by Dr. Richard J. Caselli, MD. (Chair of Neurology at Mayo Clinic, Scottsdale, AZ and professor of neurology at Mayo Medical School, Rochester, MN)
"There is widespread belief that amyloid neurotoxicity is at the heart of Alzheimer's disease pathogenesis, yet trials of very sophisticated and effective antiamyloid strategies have failed to halt, reverse, or even convincingly slow the disease in patients. These findings have caused some experts to reconsider whether we may have misunderstood amyloids's role in Alzheimer's pathogenesis. While we all are familiar with the pathologic hallmark of amyloid plaques, we may be less aware that neuronal disyfunction more likely reflects soluble amyloid oligomers, rather than insoluble plaques...
AMDA "Caring for the Ages" September 2009 suggests further confusion in the Protein Plaques theories. "Oldest Brains Can Belie Dementia Status." This article states: "In some patients who die very old, the brain might show the classic pathologic features of Alzheimer's disease even though the patient did not exhibit dementia, according to a report in the New England Journal of Medicine. Assessment of 426 brains donated to the United Kingdom's Cognitive Function and Ageing Study (CFAS) showed that characteristic Alzheimer's pathology did not always correspond with dementia among the "oldest old."... "In an editorial comment accompanying this report, Douglas C. Ewbank, PhD, and Steven E. Arnold, MD of the University of Pennsylvania, Philadelphia said it is essential to understand why some elderly people fail to develop dementia when their brains show the same number of plaques and tangles seen in Alzhiemer's disease."
Note: "In recent years, however, some researchers have questioned whether Beta-amyloid plaque even leads to Alzheimer's. The brain is such a complicated system that it's hard to pin down one primary cause of the disease, Dr. Knopman of Mayo said."
"Both plaques and tangles can occur as part of the normal aging process of the brain, but they are much more abundant in individuals with symptoms of Alzheimer's. It is yet unknown whether these structures are causes or symptoms of Alzheimer's disease." (2011)
Recent Research on the Spread of Alzheimer's - February 2012
The New York Times on February 2nd, 2012 had an article “Path is Found for the Spread of Alzheimer’s”
“Alzheimer’s disease seems to spread like an infection from brain cell to brain cell, two new studies in mice have found. But instead of viruses or Bacteria, what is being spread is a distorted protein known as tau.”
Since the research was findings in Mice and not Humans…they go on to say “perhaps in humans as well”.
Note: I do not know anyone that ever thought it was spread by viruses or bacteria.
"Alzheimer’s researchers have long known that dying, tau filled cells first emerge in a small area of the brain where Memories are made and stored. The disease then slowly moves outward to larger areas that involve remembering and reasoning.”
“Researchers knew that something set off Alzheimer’s disease. The most likely candidate is a protein known as bet amyloid, which accumulates in the brain of Alzheimer’s patients, forming hard, barnacle like plaques. But beta amyloid is very different from tau. It is secreted and clumps outside cells. Although researchers have looked, they have never see evidence that amyloid spreads from cell to cell in a network. Still, amyloid creates what amounts to a bad neighborhood in memory regions of the brain. Then tau comes along – some researchers call it “the executioner” – piling up inside cells and killing them… But if tau spreads from neuron to neuron…it may be necessary to block both beta amyloid production, which seems to get the disease going and the spread of tau, which continues it, to bring Alzheimer’s to a halt.”…It was concluded that: “It is contagion from one neuron to another.”
“It may be possible to bring Alzheimer’s diseases to an abrupt halt early on by preventing cell-to-cell transmission, perhaps with an antibody that blocks tau.”
(Referenced research by Columbia and Harvard Universities in regard to the mice studies.)
Rudolph E. Tanzi, Ph.D. Professor of Neurology, Harvard Medical School, Director, Genetics and Aging Research Unit, Massachusetts General Hospital discusses Alzheimer’s genes and the present state of this research (April 2011. This update by Dr. Tanzi follows his participation in the 10th Annual International Conference on Alzheimer’s Disease/Parkinson’s Disease (AD/PD) held in March 2011 in Barcelona:
“There are approximately 25,000 genes in the human genome. A gene’s job is to either make proteins or control the activity of other genes. In the perfect biological system, genes make proteins that allow the system to run smoothly and normally. But, over time, genes can change or mutate from their original function and, for example, produce proteins that are variations of the original form. Or, mutations can cause genes to produce the wrong amounts of proteins. Genes of all kinds can carry several mutations or variants, many of which are harmless and simply help engender subtle differences among humans. Trouble arises when a gene mutation (or variant) causes or predisposes to disease. It should also be mentioned that some gene mutations and variants can instead confer protection from disease.
Therefore, an Alzheimer’s Gene is a normal gene that when inherited with certain mutations or variants can either increase risk for or provide protection against the onset of Alzheimer’s disease.
Note: Current technology facilitates gene discovery through Genome Wide Association Screens or GWAS. The DNA purified from the genomes of Alzheimer’s patients and non-Alzheimer’s patients are screened via sophisticated equipment and chips and then analyzed statistically to find mutations and variants in our genome that differ in the prevalence between AD patients and unaffected elderly subjects.
Four “established” AD genes have been known to the Alzheimer’s research field for over 20 years
Three of these genes --- amyloid precursor protein (APP), Presenilin 1 and Presenilin 2 (PSEN1 and 2) --- were co-discovered by Tanzi and his colleagues and all of these Alzheimer’s genes are strongly penetrant and essentially guarantee the onset of early-onset Alzheimer’s disease (usually under 60 years old)
The fourth gene, APOE, was discovered by a group from Duke University led by Dr. Allen Roses. APOE has been the grand daddy of regular or late onset genes. It contains a variant called epsilon 4 that is present in about 20% of the population in general and in >50% of AD cases. Unlike the early-onset AD gene mutations, this variant does not guarantee AD, but serves to increase risk. Inheriting one copy of the variant increases risk 4-fold versus the general population and two copies, >10-fold. However, a person can carry the APOE gene variant and not have or get Alzheimer’s in a normal lifetime.
Most recently, the Cure Alzheimer’s Fund Alzheimer’s Genome Project has identified two rare pathological mutations in the gene, ADAM10. These mutations were found in only 7 of 1000 AD families tested and appear to strongly increase risk for AD at about 70 years old. Based on these finding, ADAM10 has been proposed as the 5th established AD gene
In 2008, Dr. Tanzi and the Alzheimer’s Genome Project reported the first four newly identified and confirmed AD candidate genes from a family-based GWAS in a paper lauded by TIME/CNN as among the Ten Best Medical Research Breakthroughs of 2008.
These genes included the following ATXN1, CD33, GWA14Q34, and DLGAP1. All four are being analyzed in AD families to identify the disease-causing gene defects. CD33 is perhaps the most interesting as it is not only associated with Alzheimer’s disease risk, but also controls the brain’s innate immune system. Interestingly, in another recent Cure Alzheimer’s Fund project, the amyloid beta protein, which makes up the senile plaques in AD patients’ brains, was found to play a role in the brain’s innate immunity system
In 2009-2010, four more confirmed AD genes were found in case-control GWAS. These included PICALM, CLU, CR1, and BIN1. Most recently in April, 2011, the American and European Consortia reported the results of large case-control GWAS. They confirmed CD33 as an AD gene. CD33 was originally described in the Cure Alzheimer’s Fund Alzheimer’s Genome Project screen in 2008 in a paper from Dr. Tanzi’s laboratory. They consortia also confirmed the genes, PICALM1, CLU, CR1 and BIN1. They have also found four more confirmed: AD genes including: MS4A4/MS4A6E, CD2AP, EPHA1, and ABCA7
So how many confirmed AD genes are there now and how strong an effect do they have on AD pathology? There are arguably five established AD genes plus the four confirmed candidate genes published by Tanzi as part of the Cure Alzheimer’s Fund Alzheimer’s Genome Project screen in 2008 plus the eight from the case-control consortia. So the actual new total is 17 confirmed or established AD genes: 3 genes for early-onset AD and 14 genes for late-onset AD
Note: The reports from the recent case-control GWAS for the U.S. and European consortia claim that the number of AD genes has been doubled from five to ten. This number only referred to the late-onset gene, APOE and the four case-control derived confirmed genes, PICALM, CLU, CR1, and BIN1 to be the original 5 followed by MS4A4/MS4A6E, CD2AP, EPHA1, ABCA7, and CD33 as the next five that were either newly discovered or confirmed (in the case of CD33) in the new studies published on April 4, 2011. It is important to note that APOE and CD33 are the only confirmed AD genes that have been shown to be significantly associated with AD in both family-based and case-control genome studies
Most Alzheimer’s researchers agree that Alzheimer’s is largely a genetically driven disease
Environmental factors such as age, gender, stroke and head injury have profound influence on when the disease becomes manifest, but a person’s genetic make-up greatly influences risk for the disease usually by working together with one’s life exposure factors. Therefore, knowing ALL the genes that contribute to AD risk or protection, and especially which ones contribute the most to risk are essential clues for researchers developing therapies to effectively treat or prevent the disease
So far, all the drug therapies that have been developed or are in the pipeline to combat the disease have been based on knowledge learned from those first four genes (mainly the three early-onset AD genes) discovered over 25 years ago. Now, with more targets affecting more and different biological pathways, researchers can take many more shots on goal to come up with truly effective therapies to stop the disease from progressing, reversing its progress, or prevent it from occurring in the first place.”
Mayo Clinic on 18 January 2011 has the following to say about Gene's as a risk factor compared to age:
""Increasing age is the greatest known risk factor for Alzheimer's. Alzheimer's is not a part of normal aging, but your risk increases greatly as you grow older. After you reach age 65, your risk of developing the disease doubles about every five years. Nearly half of those over age 85 have Alzheimer's.
People with rare genetic changes that guarantee they'll develop Alzheimer's often begin experiencing symptoms in their 40s or 50s.
Family history and genetics - Your risk of developing Alzheimer's appears to be somewhat higher if a first-degree relative — your parent, sibling or child — has the disease. Scientists have identified rare changes (mutations) in three genes that guarantee a person who inherits them will develop Alzheimer's. But these mutations account for less than 5 percent of Alzheimer's disease. Most genetic mechanisms of Alzheimer's among families remain largely unexplained. The strongest risk gene researchers have found so far is apolipoprotein e4 (APOE-e4). Other risk genes have been identified but not conclusively confirmed."
Stem Cell Research and Therapy Potentials
The Alzheimer's Association Newsletter for Summer 2009 discusses this exciting area of research and theory. "Stem Cell therapy has not only the potential to introduce cells into the brain to replace cells that have degenerated or died but also to introduce cells that can function as small factories to produce natural substances, such as powerful nerve growth factors, that the brain needs to protect itself and to regenerate damaged parts.".Until recently it was thought that the only means of introducing stems cells into the brain was to:
(1.) perform "Neurosurgery and implant the cells in the brain. (This method would be very expensive and also potentially dangerous because of the risk of injury to the brain in the implantation process or the causing of an infection in the brain.)
(2.) Recently a method has been discovered that will permit stem cells to be non-invasively delivered to the brain using an intranasal delivery method developed by Dr. William H. Frey, Director of the Alzheimer's Research Center at Regions Hospital in St. Paul, MN.(While this method would suggest great future potential, obviously much more research and testing will be necessary and required before this method and treatment is ready for the FDA approval process.)
Washington Post June 10,2004: “Stem Cells an Unlikely Therapy for Alzheimer’s” ...“But the infrequently voiced reality, stem cell experts confess, is that, of all the diseases that may someday be cured by embryonic stem cell treatments, Alzheimer's is among the least likely to benefit.
"I think the chance of doing repairs to Alzheimer's brains by putting in stem cells is small," said stem cell researcher Michael Shelanski, co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at the Columbia University Medical Center in New York, echoing many other experts. "I personally think we're going to get other therapies for Alzheimer's a lot sooner."
Albert, a Johns Hopkins University researcher who chairs the Medical and Scientific Advisory Council of the Alzheimer’s Association, says there are more promising efforts to treat the disease than waiting on the decades it could take to see results from embryonic stem cells. Marcelle Morrison-Bogorad, associate director of the National Institute on Aging’s neuroscience and neuropsychology of aging program, concurs. (January 2009)
Detection using Functional Magnetic Resonance Imaging - fMRI
Time Magazine for Wednesday 26 August 2009 contained an article by Alice Park on work now being conducted by researchers at Cleveland Clinic into a new method of early detection of Alzheimer's. "What Britney Spears Can Reveal About Alzheimer's"
The article says "they may have found a way to identify those most at risk of developing the neurological disorder long before symptoms develop - simply by asking them whether they recognize celebrities such as Britney Spears and Johnny Carson. It turns out that when people who are at highest risk of Alzheimer's try to recognize a famous name, their brains activate in very different ways from those of people who aren't at risk...scientists can actually see this difference using functional magnetic resonance imaging, or fMRI."
The research was reported in the journal "Neurology". "team led by Stephen Rao, a brain imaging specialist...study of 69 healthy men and women aged 65 to 85...Rao's team found that when volunteers saw names such as Britney Spears, George Clooney, Albert Einstein and Marilyn Monroe, those who were at the highest risk of developing Alzheimer's - those with the genetic makeup (Version of gene for a protein called apolipoprotein E4..(ApoE4) and a family history - showed high levels of activity in the hippocampus, posterior cingulate and regions of the frontal cortex, all areas involved in memory. The control group showed the opposite pattern. Their brains became more excited when they saw unfamiliar names, which included Irma Jacoby, Joyce O'Neil and Virginia Warfield....This could mean that the at risk people were working harder to recognize the well known celebrities, compensating for already damaged or destroyed neurons that were no longer functioning, while the control group had to struggle only when trying to place the names of noncelebrities."
"The idea is not necessarily to diagnose Alzheimer's earlier, says Rao. But imaging studies can help to identify those most vulnerable to cognitive decline so they can participate in clinical trials of new drugs designed to postpone or reduce symptoms."
Note: I doubt very much that clinical trials will ever be based on pools of individuals that have been detected through the large numbers of testing needed for such a selection process...At the present time there are no drugs available to postpone or effectively reduce symptoms. Would the average person care to know this information if at the same time nothing can be done but worry...The early part of the article stated: "the disease has already been ravaging the brain for a decade or more, causing irreversible damage...However, .according to Knopman of the Mayo Alzheimer's research department, it is far longer than a decade...(He talks of 2-3 decades.) In July 2009, Dr. Knopman was quoted in the Minneapolis Star-Tribune as stating: "Despite years of research, drug companies have struggled to find an effective treatment. Part of the problem, Dr. Knopman says, is timing: Symptoms only surface 20 to 30 years after patients develop the disease. By then, it's too late" This is certainly an interesting development but does it have practical value. We need more attention to finding a cure and less to early detection.
SEE: Article this section "A New Direction for Alzheimer's Research" that discusses brain cells called GLIA or click on this link:
Current Clinical Trials
Caring for the Ages, (AMDA Journal) October 2009 has a dreary report under the title "Failed Drug Trials Suggest Alzheimer's Shift." An article by Michele G. Sullivan reported the bad news. "Vienna - Alzheimer's drug researchers served up a string of bad news at the International Conference on Azlheimer's Disease, presenting one failed trial after another...None of these strategies tested - such as blocking amyloid, improving insulin sensittivity in the brain, or even doubling up on agents that improve synaptic signaling - was able to alter the steady rate of cognitive and functional decline in patients with mild to moderate Azlheimer's...No effect seen with Rosiglitazone...end of the road for Tarenflurbil...combo no better than one...Divalporoex treatment over 2 years didn't delay onset of agitation or psychosis in patients with Alzheimer's disease , and patents taking the anticonvulsant showed significantly more brain volume loss on MRI at year 1 than did those taking placebo."
“2010 Wasn’t Good Year on Alzheimer’s Front” This is a lead article headlined in the December 2010 issue of the Medical Director’s Association (AMDA) journal “Caring for the Ages” “With more dashed hopes for drug therapies, next likely FDA review isn’t until end of 2011.”
“This summer, another potential Alzheimer’s drug failed with Eli Lilly & Co. pulling the plug on its phase III study of Semagacestat, a gamma secretase inhibitor designed to reduce the aggregation of beta-amyloid into brain plaques….this is the latest in a long string of Alzheimer’s drug flops…
Earlier this year, the investigational drug Dimebon failed to show any benefit over placebo for patients with mild to moderate Alzheimer’s disease on any of the efficacy end points in a 6 month, phase III trial, drug manufacturers Medivation Inc. and Pfizer Inc. announced.
The rise and apparent fall of Dimebon and Semagacestat through the clinical drug development process has mirrored the recent history of Tramiprosate and Tarenflurbil for AD, both of which initially had positive results in phase II trials that were not replicated in phase III trials.
It could be near the end of 2011 before another drug for AD comes through the Food and Drug Administrations review process for potential approval. The most promising candidate, in terms of how chronologically close it might be to an FDA review, now appears to be Bapineuzumab, a monoclonal antibody against amyloid-beta. This drug was reported to have failed the FDA Phase III trials. (7/25/2012)
24 August 2012 - Eli Lilly's experimental Alzheimer's drug Solanezumab fails study but said to show potential.
(AP) INDIANAPOLIS - A possible Alzheimer's disease treatment from drugmaker Eli Lilly missed the main goals of two late-stage studies, but the treatment showed some potential for slowing memory decline in patients with mild cases…Lilly said Friday that its treatment, solanezumab, failed to slow cognitive decline, which involves a person's ability to remember things, in two late-stage studies of about 1,000 patients each. But when data from the trials were combined, scientists saw a statistically significant slowing of the rate of cognitive decline in that bigger population. . The studies focused on patients with mild to moderate Alzheimer's cases. It's unclear how the Food and Drug Administration will view the results, given that the drug missed its main goals. If you look through "rose-colored glasses" at the results, there may be a sign of potential benefit on cognitive tests, but it is not clear whether that is enough to make a real difference clinically in how patients do, said Dr. Ronald Petersen, director of the Mayo Clinic's Alzheimer's Disease Research Center.
Science Express: 9 February 2012 – In Mice, Cancer Drug Reduces Beta-Amyloid and Helps Memory..
Report describes a research study in mouse models of Alzheimer’s disease of a FDA-approved cancer therapy called Bexarotene. (Used to treat cutaneous T-cell Lymphoma) The researchers believe that drug will enhance clearance of an abnormal protein associated with Alzheimer’s (beta amyloid protein) from the brain by increasing levels of another protein, know as ApoE. The scientists found that the orally administered drug rapidly lowered levels of soluble beta amyloid and amyloid plaques in both young and older test animals, and also improved some cognitive and behavioral deficits. This study is exciting because it instigates a possible new approach to treating Alzheimer’s disease. This study while very interesting, is also very preliminary. Mouse models of Alzheimer’s are limited in how closely they represent human Alzheimer’s. We are still far away from knowing if this has potential as a therapy for people with Alzheimer’s. However, it is intriguing preliminary research that deserves further study.
Note: "Phase I studies are early-stage human clinical trials, Phase II are midstage and Phase III are late stage trials designed to demonstrate treatment efficacy."
“Campaign Urges Quick End to Alzheimer’s”…Medical Directors Association in their publication: “Caring for the Ages” headlined a new campaign to end Alzheimer’s in 10 years…”A new national campaign will promote more federal funding of research on Alzheimer’s disease, with a strikingly ambitious goal. “USAgainstAllzheimer’s” is committed to “stop Alzheimer’s disease by 2020” according to the political and academic celebrities introducing it at a Washing, D.C., press conference.
“Goal to stop disease by 2020 isn’t realistic without major research changes, says LTC expert….Nobel Prize winner Stanley B. Prusiner, MD, of the Institute for Neurodegenerative Diseases at the University of California, San Francisco…”Alzheimer’s is a “cancer-size problem”, Dr.. Prusiner said, yet cancer receives 15 times as much funding as Alzheimer’s does…Congress must address this funding disparity and create an innovative, well funded strategic plan…Science cannot do this alone.”:
.Editorial Note: My wife June was diagnosed with Alzheimer’s in January 1998. Later during June’s visit as a patient at the Mayo Clinic, one of the clinic doctors advised us that with all the Alzheimer’s research taking place, they expected a cure would be found in 5-10 years. June died in October 2008 (almost 11 years later) and we were no closer to a cure than the day that she was diagnosed.
The problem is that there is actually very little research that has been done compared to the research that is going on in the areas of other diseases. The disparity in funding for cancer research compared to Alzheimer’s is pointed out by Dr. Prusiner above.
Another glaring area of disparity is research for AIDS. Alzheimer’s is presently the 5th leading cause of disease death while AIDS is not even one of the 15 leading causes of death in the US. AIDS However it receives 6 times more funding than does Alzheimer’s...
This Government’s inappropriate disparity in previous years funding may have effectively sentenced my wife to death as well as my mother Ellen and the other over 200 daily Alzheimer’s deaths. This has been happening year after year for the last 12 plus years.