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Alzheimer’s

Antibody-Based Therapeutics To Watch In 2011

Reichert JM. Antibody-based therapeutics to watch in 2011. MAbs;3(1):76-99. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038014/pdf/mabs0301_0076.pdf

This overview of 25 monoclonal antibody (mAb) and 5 Fc fusion protein therapeutics provides brief descriptions of the candidates, recently published clinical study results and on-going Phase 3 studies. In alphanumeric order, the 2011 therapeutic antibodies to watch list comprises AIN-457, bapineuzumab, brentuximab vedotin, briakinumab, dalotuzumab, epratuzumab, farletuzumab, girentuximab (WX-G250), naptumomab estafenatox, necitumumab, obinutuzumab, otelixizumab, pagibaximab, pertuzumab, ramucirumab, REGN88, reslizumab, solanezumab, T1h , teplizumab, trastuzumab emtansine, tremelimumab, vedolizumab, zalutumumab and zanolimumab. In alphanumeric order, the 2011 Fc fusion protein therapeutics to watch list comprises aflibercept, AMG-386, atacicept, Factor VIII and Factor IX-Fc. Commercially-sponsored mAb and Fc fusion therapeutics that have progressed only as far as Phase 2/3 or 3 were included. Candidates undergoing regulatory review or products that have been approved may also be in Phase 3 studies, but these were excluded. Due to the large body of primary literature about the candidates, only selected references are given and results from recent publications and articles that were relevant to Phase 3 studies are emphasized. Current as of September 2010, the information presented here will serve as a baseline against which future progress in the development of antibody-based therapeutics can be measured.
 
Alzheimer's Disease May Be Easily Misdiagnosed

Alzheimer's Disease May Be Easily Misdiagnosed
PRNewswire-USNewswire

02-25-11


ST. PAUL, Minn., Feb. 23, 2011 /PRNewswire-USNewswire/ -- New research shows that Alzheimer's disease and other dementing illnesses may be easily misdiagnosed in the elderly, according to early results of a study of people in Hawaii who had their brains autopsied after death. The research is being released today and will be presented as part of a plenary session at the American Academy of Neurology's 63rd Annual Meeting in Honolulu April 9 to April 16, 2011.

"Diagnosing specific dementias in people who are very old is complex, but with the large increase in dementia cases expected within the next 10 years in the United States, it will be increasingly important to correctly recognize, diagnose, prevent and treat age-related cognitive decline," said study author Lon White, MD, MPH, with the Kuakini Medical System in Honolulu.

For the study, researchers autopsied the brains of 426 Japanese-American men who were residents of Hawaii, and who died at an average age of 87 years. Of those, 211 had been diagnosed with a dementia when they were alive, most commonly attributed to Alzheimer's disease.

The study found that about half of those diagnosed with Alzheimer's disease did not have sufficient numbers of the brain lesions characterizing that condition to support the diagnosis. Most of those in whom the diagnosis of Alzheimer's disease was not confirmed had one or a combination of other brain lesions sufficient to explain the dementia. These included microinfarcts, Lewy bodies, hippocampal sclerosis or generalized brain atrophy.

However, diagnoses of Lewy body dementia and vascular dementia were more accurate. Misdiagnoses increased with older age. They also reflected non-specific manifestations of dementia, a very high prevalence of mixed brain lesions, and the ambiguity of most neuroimaging measures.

"Larger studies are needed to confirm these findings and provide insight as to how we may more accurately diagnose and prevent Alzheimer's disease and other principal dementing disease processes in the elderly," said White.

The study was supported by the National Institute on Aging and the Department of Veterans Affairs.

This research will be presented as part of the Contemporary and Clinical Issues and Case Studies Plenary Session on Wednesday, April 13, 2011, at the 2011 American Academy of Neurology's Annual Meeting in Honolulu.

The American Academy of Neurology, an association of more than 22,500 neurologists and neuroscience professionals, is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer's disease, stroke, migraine, multiple sclerosis, brain injury, epilepsy and Parkinson's disease. For more information about the American Academy of Neurology and its upcoming Annual Meeting, visit Home -- American Academy of Neurology.

American Academy of Neurology

CONTACT: Rachel Seroka, rseroka@aan.com, +1-651-695-2738, or Angela Babb,ababb@aan.com, +1-651-695-2789

Web site: Home -- American Academy of Neurology


Copyright PRNewswire-USNewswire 2011
 
This is an excellent book and the author is a recognized expert:

[ame=http://www.amazon.com/Brain-Trust-Program-Scientifically-EnhanceAttention/dp/0399534547/ref=sr_1_1?ie=UTF8&s=books&qid=1300111221&sr=8-1]Amazon.com: The Brain Trust Program: A Scientifically Based Three-Part Plan to Improve Memory, Elevate Mood, EnhanceAttention, Alleviate Migraine and Menopausal Symptoms, and Boost Mental (9780399534546): Larry McCleary: Books[/ame]


It suggests using MCT oil along with flaxseed oil and EPA, and a few other supplements like huperzine. Add this one to your booklist, zkt. Required reading.

My mother is up to half the equivalent full dose of Axona and she is clearly more alert; this began when she started taking coconut oil. No improvement in cognitive functions/memory just yet. However, her mood is better and she interacts more. I'm hoping to get her up to two tablespoons per day which is 50 % more than the Axona dose - one in the morning and one at night.:)
 
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Alzheimer's & Dementia: The Journal of the Alzheimer's Association - Elsevier


The Alzheimer’s Association Facts and Figures report details the growing prevalence and escalating impact of Alzheimer’s and dementia on individuals, caregivers, families, government and the nation’s healthcare system. http://www.alz.org/downloads/Facts_Figures_2011.pdf
 
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Re: Diabetes of the Brain

cvictorg said:
Is Alzheimer's disease actually a form of diabetes? - By Amanda Schaffer - Slate Magazine

Is Alzheimer's disease actually a form of diabetes?
Click to expand...

This is the idea behind Axona, MCT oil and ketone bodies as an alternate energy source for the brain that LW64 and I are exploring.
Rosiglitazone is certainly an interesting approach to the problem.
[ame="http://en.wikipedia.org/wiki/Rosiglitazone"]Rosiglitazone - Wikipedia, the free encyclopedia@@AMEPARAM@@/wiki/File:Rosiglitazone_Enantiomers_Structural_Formulae.png" class="image"><img alt="" src="http://upload.wikimedia.org/wikipedia/commons/thumb/0/01/Rosiglitazone_Enantiomers_Structural_Formulae.png/260px-Rosiglitazone_Enantiomers_Structural_Formulae.png"@@AMEPARAM@@commons/thumb/0/01/Rosiglitazone_Enantiomers_Structural_Formulae.png/260px-Rosiglitazone_Enantiomers_Structural_Formulae.png[/ame]
 
Insulin Could Be Alzheimer's Therapy
Insulin could be Alzheimer's therapy

ScienceDaily (Apr. 2, 2011) — A low dose of insulin has been found to suppress the expression in the blood of four precursor proteins involved in the pathogenesis of Alzheimer's disease, according to new clinical research by University at Buffalo endocrinologists. The research, published in March online in the Journal of Clinical Endocrinology and Metabolism, suggests that insulin could have a powerful, new role to play in fighting Alzheimer's disease.

"Our results show clearly that insulin has the potential to be developed as a therapeutic agent for Alzheimer's, for which no satisfactory treatment is currently available," says Paresh Dandona, MD, PhD, UB distinguished professor of medicine in the School of Medicine and Biomedical Sciences and senior author on the study.

One of the four proteins shown in the study to be suppressed by insulin is a precursor to beta amyloid, the main component of plaques considered the hallmark of Alzheimer's disease.

The findings also demonstrate for the first time that the four precursor proteins studied are expressed in peripheral mononuclear cells, white blood cells that are an important component of the immune system.

The paper builds on the UB researchers' earlier work showing that insulin has a potent and rapid anti-inflammatory effect on peripheral mononuclear cells. It also builds on the well-known association between obesity, type 2 diabetes and chronic low-grade inflammation, as well as insulin resistance, all conditions that manifest a significantly increased prevalence of Alzheimer's disease.

In the study, 10 obese, type 2 diabetic patients were infused with two 100 ml units of insulin per hour over a period of four hours. The patients were all taking oral drugs to treat their diabetes; none of them were taking insulin or any antioxidant or nonsteroidal anti-inflammatory drugs. The control group received 5 percent dextrose per hour or normal saline solution.

The low-dose insulin was found to suppress the expression of amyloid precursor protein, from which beta amyloid is derived. It also suppressed presenilin-1 and presenilin-2, the two subunits of an enzyme that converts amyloid precursor protein into beta amyloid, which forms the amyloid plaques. Insulin also suppressed glycogen synthase kinase, which phosphorylates, or adds on another phosphate group, to another neuronal protein, tau, to form the neurofibrillary tangles, the other important component of Alzheimer's disease in the brain.

"Our data show, for the first time, that the peripheral mononuclear cells express some of the key proteins involved in the pathogenesis of Alzheimer's disease," says Dandona. "They demonstrate that these cells can be used for investigating the effect of potential Alzheimer's disease therapies on key proteins involved in the disease.

"Even more importantly, it is likely that insulin has a direct cellular effect on these precursor proteins while also exerting its other anti-inflammatory actions," he continues. "If this effect of insulin proves, in larger studies, to be systemic, then insulin may well be a potential therapeutic agent in treating Alzheimer's disease. The challenge is to deliver insulin directly into the brain, thus avoiding its hypoglycemic effect."

Fortunately, Dandona says, a previous preliminary study has shown that intranasal delivery of insulin can lead to its entry into the brain along the olfactory nerves and that its administration may improve cognitive function in patients with Alzheimer's disease. However, he cautions, the mode of action is not known.

"Our study provides a potential rational mechanism," he says.


Dandona P, Mohamed I, Ghanim H, et al. Insulin Suppresses the Expression of Amyloid Precursor Protein, Presenilins, and Glycogen Synthase Kinase-3{beta} in Peripheral Blood Mononuclear Cells. J Clin Endocrinol Metab:jc.2010-961. Insulin Suppresses the Expression of Amyloid Precursor Protein, Presenilins, and Glycogen Synthase Kinase-3{beta} in Peripheral Blood Mononuclear Cells -- Dandona et al., 10.1210/jc.2010-2961 -- Journal of Clinical Endocrinology & Metabolism

Objective - Our objective was to determine whether peripheral blood mononuclear cells express amyloid precursor protein (APP) and other mediators involved in the pathogenesis of Alzheimer's disease and whether their expression is suppressed by insulin.

Research Design and Methods - Ten obese type 2 diabetic patients were infused with insulin (2 U/h with 100 ml 5% dextrose/h) for 4 h. Patients were also infused with 5% dextrose/h or normal physiological saline for 4 h, respectively, on two other days as controls. Blood samples were obtained at 0, 2, 4, and 6 h.

Results - Insulin infusion significantly suppressed the expression of APP, presenilin-1, presenilin-2, and glycogen synthase kinase-3{beta} in peripheral blood mononuclear cells. Dextrose and saline infusions did not alter these indices. Insulin infusion also caused significant parallel reductions in nuclear factor-{kappa}B binding activity and plasma concentrations of serum amyloid A and intercellular adhesion molecule-1.

Conclusions - A low dose infusion of insulin suppresses APP, presenilin-1, presenilin-2, and glycogen synthase kinase-3{beta}, key proteins involved in the pathogenesis of Alzheimer's disease, in parallel with exerting its other antiinflammatory effects.
 
Five new genes linked to Alzheimer's
Five new genes linked to Alzheimer's

Scientists said Sunday they had uncovered five genes linked to the onset of Alzheimer's disease, doubling the number of genetic variants known to favour the commonest form of dementia.

The findings, published in the journal Nature Genetics, may provide clues on the causes of this incurable and complex disease and help doctors predict who is most at risk, they said.
In the largest such studies to date, some 300 scientists in two consortia combed the genomes of 54,000 people -- some afflicted, others not -- to tease out the newly identified genetic variations.

The two projects started out independently but later swapped their data, enabling each group to confirm the overall findings.

"Prior to these studies, there were five accepted late-onset genes," said Gerard Schellenberg, a researcher at the University of Pennsylvania School of Medicine and the main architect of one of the studies.

"Now there are five more -- MS4A, ABCA7, CD33, EPHA1 and CD2AP," he said in an email exchange.

Identifying which snippets of DNA contribute to Alzheimer's boosts our understanding of the role of inheritance in its onset, Schellenberg said, adding that others surely remained to be found.

But, he added, "the biggest contribution will be in helping to understand the underlying mechanism that causes Alzheimer's. These genes highlight new pathways that are critical to the disease process."

Over the course of the illness, unwanted proteins form plaque in some areas of the brain, ultimately destroying neurons and leading to irreversible brain damage. Typically, symptoms include memory loss, erratic behaviour and eventually full-on dementia.

The ultimate aim, said Schellenberg, is creating drugs that can stop or even prevent this progression.

Toward that goal, "molecular biologists who work on disease mechanisms now need to figure out exactly how these new genes plug into the Alzheimer's process," he said.

Current treatments, he added, are only "marginally effective" in masking symptoms or slowing the disease's inexorable advance.

Alzheimer's affects 13 percent of people over 65, and up to 50 percent of those over 85.

As populations in rich countries age, the number of sufferers worldwide is set to double to more than 65 million by 2030, placing a huge burden on health care systems, experts forecast.

Ninety percent of Alzheimer's cases are so-called "late-onset", affecting people over the age of 65. The likelihood of developing this form doubles every five years.


Naj AC, Jun G, Beecham GW, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease : Nature Genetics : Nature Publishing Group


Hollingworth P, Harold D, Sims R, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease : Nature Genetics : Nature Publishing Group
 
This just goes to show you how complicated the problem is.
If you want a big insulin spike just eat a lot of sugar; but that doesnt seem to be beneficial.


Michael Scally MD said:
Insulin Could Be Alzheimer's Therapy
Insulin could be Alzheimer's therapy

ScienceDaily (Apr. 2, 2011) — A low dose of insulin has been found to suppress the expression in the blood of four precursor proteins involved in the pathogenesis of Alzheimer's disease, according to new clinical research by University at Buffalo endocrinologists. The research, published in March online in the Journal of Clinical Endocrinology and Metabolism, suggests that insulin could have a powerful, new role to play in fighting Alzheimer's disease.

"Our results show clearly that insulin has the potential to be developed as a therapeutic agent for Alzheimer's, for which no satisfactory treatment is currently available," says Paresh Dandona, MD, PhD, UB distinguished professor of medicine in the School of Medicine and Biomedical Sciences and senior author on the study.

One of the four proteins shown in the study to be suppressed by insulin is a precursor to beta amyloid, the main component of plaques considered the hallmark of Alzheimer's disease.

The findings also demonstrate for the first time that the four precursor proteins studied are expressed in peripheral mononuclear cells, white blood cells that are an important component of the immune system.

The paper builds on the UB researchers' earlier work showing that insulin has a potent and rapid anti-inflammatory effect on peripheral mononuclear cells. It also builds on the well-known association between obesity, type 2 diabetes and chronic low-grade inflammation, as well as insulin resistance, all conditions that manifest a significantly increased prevalence of Alzheimer's disease.

In the study, 10 obese, type 2 diabetic patients were infused with two 100 ml units of insulin per hour over a period of four hours. The patients were all taking oral drugs to treat their diabetes; none of them were taking insulin or any antioxidant or nonsteroidal anti-inflammatory drugs. The control group received 5 percent dextrose per hour or normal saline solution.

The low-dose insulin was found to suppress the expression of amyloid precursor protein, from which beta amyloid is derived. It also suppressed presenilin-1 and presenilin-2, the two subunits of an enzyme that converts amyloid precursor protein into beta amyloid, which forms the amyloid plaques. Insulin also suppressed glycogen synthase kinase, which phosphorylates, or adds on another phosphate group, to another neuronal protein, tau, to form the neurofibrillary tangles, the other important component of Alzheimer's disease in the brain.

"Our data show, for the first time, that the peripheral mononuclear cells express some of the key proteins involved in the pathogenesis of Alzheimer's disease," says Dandona. "They demonstrate that these cells can be used for investigating the effect of potential Alzheimer's disease therapies on key proteins involved in the disease.

"Even more importantly, it is likely that insulin has a direct cellular effect on these precursor proteins while also exerting its other anti-inflammatory actions," he continues. "If this effect of insulin proves, in larger studies, to be systemic, then insulin may well be a potential therapeutic agent in treating Alzheimer's disease. The challenge is to deliver insulin directly into the brain, thus avoiding its hypoglycemic effect."

Fortunately, Dandona says, a previous preliminary study has shown that intranasal delivery of insulin can lead to its entry into the brain along the olfactory nerves and that its administration may improve cognitive function in patients with Alzheimer's disease. However, he cautions, the mode of action is not known.

"Our study provides a potential rational mechanism," he says.


Dandona P, Mohamed I, Ghanim H, et al. Insulin Suppresses the Expression of Amyloid Precursor Protein, Presenilins, and Glycogen Synthase Kinase-3{beta} in Peripheral Blood Mononuclear Cells. J Clin Endocrinol Metab:jc.2010-961. Insulin Suppresses the Expression of Amyloid Precursor Protein, Presenilins, and Glycogen Synthase Kinase-3{beta} in Peripheral Blood Mononuclear Cells -- Dandona et al., 10.1210/jc.2010-2961 -- Journal of Clinical Endocrinology & Metabolism

Objective - Our objective was to determine whether peripheral blood mononuclear cells express amyloid precursor protein (APP) and other mediators involved in the pathogenesis of Alzheimer's disease and whether their expression is suppressed by insulin.

Research Design and Methods - Ten obese type 2 diabetic patients were infused with insulin (2 U/h with 100 ml 5% dextrose/h) for 4 h. Patients were also infused with 5% dextrose/h or normal physiological saline for 4 h, respectively, on two other days as controls. Blood samples were obtained at 0, 2, 4, and 6 h.

Results - Insulin infusion significantly suppressed the expression of APP, presenilin-1, presenilin-2, and glycogen synthase kinase-3{beta} in peripheral blood mononuclear cells. Dextrose and saline infusions did not alter these indices. Insulin infusion also caused significant parallel reductions in nuclear factor-{kappa}B binding activity and plasma concentrations of serum amyloid A and intercellular adhesion molecule-1.

Conclusions - A low dose infusion of insulin suppresses APP, presenilin-1, presenilin-2, and glycogen synthase kinase-3{beta}, key proteins involved in the pathogenesis of Alzheimer's disease, in parallel with exerting its other antiinflammatory effects.
Click to expand...
 
Lack of Evidence for the Efficacy of Memantine in Mild Alzheimer Disease

Memantine, indicated for moderate to severe Alzheimer disease (AD), is frequently prescribed off-label either alone or with a cholinesterase inhibitor for mild AD and mild cognitive impairment. In 2006, it was prescribed to 19% of patients with mild AD in the United States. In the mainly academic centers that comprise the Alzheimer Disease Neuroimaging Initiative, 45.7% of patients with mild AD were receiving memantine, and 25.0% of patients with mild AD who were registered in 2009 in the National Institutes of Health National Alzheimer Coordinating Center were receiving it. In mild to moderate AD clinical trials conducted from 2003 to 2009, 13.5% to 63.4% of patients received memantine. Similarly, 11.4% and 11.1% of patients with mild cognitive impairment who were in the Alzheimer Disease Neuroimaging Initiative and the National Alzheimer Coordinating Center, respectively, were receiving memantine. Nearly 40% of US neurologists surveyed reported prescribing memantine at least sometimes to patients with mild cognitive impairment.

The European Medicines Agency approved memantine in May 2002 for use in "moderately severe to severe" AD, and the US Food and Drug Administration (FDA) approved it in October 2003 for "moderate to severe dementia of the Alzheimer type." The "moderate to severe" FDA indication is based on 2 clinical trials that included patients with AD on the basis of their receiving a Mini-Mental State Examination (MMSE) score of 14 or less as described in the "clinical studies" section of the prescribing information.

In July 2005, the FDA did not approve a supplemental new drug application by the manufacturer to expand marketing approval for memantine from "moderate to severe" to "mild to severe" AD. The supplemental new drug application included 3 placebo-controlled clinical trials that enrolled patients with mild to moderate AD, defined on the basis of the patient having an MMSE score of 10 to 23. Two of the 3 trials did not show statistical significance on the primary end points. Because the trials included both patients with mild and moderate AD, specific evidence for memantine's efficacy in the mild AD subgroup is lacking.

In November 2005, the European Medicines Agency expanded its indication to "moderate to severe" AD. This expanded indication was based on pooled analyses of "moderate" subsets of patients with MMSE scores of 10 to 19; these pooled analyses were derived from the same 3 clinical trials of mild to moderate AD reviewed by the FDA.

Subsequently, similar meta-analyses of memantine were published by the US manufacturer and the European manufacturer. Each included the same 6 trials, comprising the 3 trials of mild to moderate AD already mentioned and 3 other trials of moderate to severe AD. The European meta-analysis specifically excluded patients with mild AD who had MMSE scores of 20 to 23 and claimed only "clinically relevant efficacy in patients with moderate to severe AD." Notwithstanding the FDA's prior rejection of a mild AD indication, the US authors claimed that memantine was beneficial for patients with AD "across the spectrum of the disease, from mild to severe cases." These 2 meta-analyses, one a subset of the other and using the same data sets, allowed for the opportunity to directly assess the effects of memantine in mild AD and in moderate AD.


Schneider LS, Dagerman KS, Higgins JPT, McShane R. Lack of Evidence for the Efficacy of Memantine in Mild Alzheimer Disease. Arch Neurol:archneurol.2011.69. Arch Neurol -- Abstract: Lack of Evidence for the Efficacy of Memantine in Mild Alzheimer Disease, April 11, 2011, Schneider et al. 0 (2011): archneurol.2011.69v1

Objective We directly assessed the clinical trials' evidence for memantine's efficacy in mild Alzheimer disease (AD). Memantine is indicated in the United States and Europe for moderate to severe AD, which is diagnosed if a patient has a Mini-Mental State Examination (MMSE) score of less than 15 or less than 20, respectively. Yet memantine is very frequently prescribed for mild AD and mild cognitive impairment, and a manufacturer-sponsoredmeta-analysis claimed its efficacy in mild AD.

Data Sources, Study Selection, and Data Extraction Manufacturer-sponsored meta-analyses, registries, presentations, and publications were systematically searched for randomized placebo-controlled, parallel-groupclinical trials of memantine in patients with mild to moderate AD. The trials' characteristics and outcomes were extracted by one reviewer and checked by another. Meta-analyses were performed as inverse variance–weighted averages of mean differences using fixed-effects models. Summary results for patients with mild AD were obtained by contrasting the summary results for patients with mild or moderate AD with the summary results for the subset of patients with moderate AD.

Data Synthesis Three trials were identified that included 431 patients with mild AD (ie, with MMSE scores of 20-23) and 697 patients with moderate AD (ie, with MMSE scores of 10-19). There were no significant differences between memantine and placebo on any outcome for patients with mild AD, either within any trial or when data were combined: mean differences (95% confidence intervals [CIs]) on the Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus caregiver's input (CIBIC-plus), the Alzheimer Disease Cooperative Study–activities of daily living (ADCS-ADL) scale, and the Neuropsychiatric Inventory (NPI) were –0.17 (95% CI, –1.60 to 1.26), –0.09 (95% CI, –0.30 to 0.12), 0.62 (95% CI, –1.64 to 2.71), and 0.09 (95% CI, –2.11 to 2.29), respectively. For patients with moderate AD, there were small differences on the ADAS-cog and the CIBIC-plus, –1.33 (95% CI, –2.28 to –0.38) and –0.16 (95% CI, –0.32 to 0.00), respectively, but no differences on the ADCS-ADL scale (–0.57 [95% CI, –1.75 to 0.60]) or the NPI (0.25 [95% CI, –1.48 to 1.99]).

Conclusions Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild AD, and there is meager evidence for its efficacy in moderate AD. Prospective trials are needed to further assess the potential for efficacy of memantine either alone or added to cholinesterase inhibitors in mild and moderate AD.
 
New Diagnostic Criteria and Guidelines for Alzheimer's Disease
New Diagnostic Criteria and Guidelines for Alzheimer's Disease

Accelerating scientific discovery has sharpened our understanding of Alzheimer's disease. In response to the pace of insight, the National Institute on Aging (NIA) and the Alzheimer's Association convened three workgroups to explore the need for new diagnostic criteria that reflect the full clinical continuum of the disease from its earliest effects to its eventual impact on mental and physical function.

Each workgroup released its proposed recommendations at the 2010 Alzheimer's Association International Conference on Alzheimer's Disease (AAICAD). Following release, these recommendations were posted here until October 2010 for public comment. The new guidelines, revised to reflect input from the professional community at large, are now published as free-access papers in Alzheimer's and Dementia: The Journal of the Alzheimer's Association and are available as PDFs below.
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Ineresting read from a first hand early onset victim;

Are You at Increased Risk if Alzheimer’s Runs in Your Family?
http://www.everydayhealth.com/blog/dealing-with-dementia-at-an-early-age/are-you-at-increased-risk-if-alzheimers-runs-in-your-family/

“Alzheimer’s runs in my family.” I hear this in support groups sometimes, but more often I read it online in forums or hear it from friends. I rarely press for further information because the statement is broad and the specifics can be very tedious. Some people believe that if they have one relative who developed any type of dementing illness, they have a greater chance of developing the disease than others. Discovering if you are at increased risk, and if so, how to find out if there is any early intervention is what we’ll dive into today.

When I was finally diagnosed with early-onset (or what is now called young-onset) dementia, all the limited research said early onset meant rapid decline. It was depressing and scary! When the latest research was released saying they could diagnose early onset before people had symptoms, I came out heartily against it, despite the fact that a clinical trial I had been a part of was used to develop the test. But I truly do not have a family history of Alzheimer’s or any type of dementing illness. I would not have thought twice about getting tested before symptoms. If you think your family has a greater risk, you may feel differently.

If first-degree relatives in your family have had memory loss, or even confirmed diagnosis of a dementing illness before 65 (some are now saying 60 or even 55), then you may be at a true higher risk. I have a friend who has traced his family’s incidence of Alzheimer’s, and he and his relatives are part of a study . Knowing, loving, and ultimately meeting Chuck’s daughter has been a great part of my Alzheimer’s journey. We were all in Washington, D.C., for a forum one year and spoke privately about whether or not his daughter would get tested. Even knowing the distinct family history and sitting through a Senate hearing, at the time she said she would not choose testing.

Unlike HIV, a condition where testing can mean quicker treatment and a healthy normal life, at this point there is no hope for a healthy, normal lifespan with dementia. There is the elusive hope, a researcher’s dream, but there is nothing tangible. The best argument seems to be that with early testing, before symptoms, people would be able to get their affairs in order and make decisions. I hope everyone has their personal affairs in order no matter what. I made decisions early in my illness that I have now changed. I’m sure I’ll change my mind more as I progress.

Also unlike HIV or cancer, this terminal illness is difficult to diagnose. I applaud the new tests in that they may alleviate the long and convoluted way that Alzheimer’s has been diagnosed for years, which has been a “rule out” method. Rule out means simply that: All other possible causes of cognitive loss are tested for. If those tests are negative, then neuropsychological testing is indicated and the final diagnosis comes from those results. I often hear that if the cognitive decline happens in those after 65, certainly in those in their late 70s or older, that few tests are done and simple observation by a close caregiver is used to diagnose. Caregivers are still given a greater influence on diagnosis and decline than the person affected. With early onset, I find that dismissive, and I hope the medical community moves away from that model.

Only you know if early testing is right for you. Even those at greater risk may choose not to test. If the onset of Alzheimer’s or another dementing illness is after 65, then it is unlikely that the cause is genetic. New tests can diagnose illnesses earlier, but unless you are willing or able to be a part of a drug study, no further treatment is available. Most research is limited to those older than 55. However, if your relative developed a type of dementia related to an underlying health problem such as drinking, a head injury, or a developmental delay, then your risks are not the same. Similarly, if your family members with dementia are not first-degree relatives, your risks are not as great.
 
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Public Citizen to FDA: Dangerous Alzheimer’s Drug Should Be Pulled Immediately From Market
Higher Dose of Aricept Has Serious Adverse Effects, Isn’t Effective
http://www.citizen.org/petition-to-fda-to-ban-23-mg-dose-of-donepezil-aricept-2011
http://www.citizen.org/documents/1950.pdf

Public Citizen, representing more than 225,000 members and supporters nationwide, hereby petitions the Food and Drug Administration (FDA), pursuant to the Federal Food, Drug, and Cosmetic Act 21 U.S.C. Section 355(e)(3), and 21 C.F.R. 10.30, to immediately remove from the market the 23 milligram (mg) dose of Aricept (donepezil; Eisai Co., Ltd; Pfizer Inc.) because in the primary clinical trial:

1) The 23 mg dose of Aricept failed to meet the two efficacy criteria required by FDA as a condition of approval of drugs for dementia, specifically required for Aricept 23 in this case.

2) The 23 mg dose of Aricept significantly increased adverse events compared with the previously approved 10 mg dose, including increased risks for nausea, vomiting, diarrhea, anorexia, and confusion.

3) The 23 mg dose of Aricept received negative reviews from both the FDA clinical and statistical reviewers.
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Caffeine Synergizes with Another Coffee Component For Protection Against Alzheimer's Disease


Mystery Ingredient in Coffee Boosts Protection Against Alzheimer's Disease, Study Finds
Mystery ingredient in coffee boosts protection against Alzheimer's disease, study finds

ScienceDaily (June 21, 2011) — A yet unidentified component of coffee interacts with the beverage's caffeine, which could be a surprising reason why daily coffee intake protects against Alzheimer's disease. A new Alzheimer's mouse study by researchers at the University of South Florida found that this interaction boosts blood levels of a critical growth factor that seems to fight off the Alzheimer's disease process.

The findings appear in the early online version of an article to be published June 28 in the Journal of Alzheimer's Disease. Using mice bred to develop symptoms mimicking Alzheimer's disease, the USF team presents the first evidence that caffeinated coffee offers protection against the memory-robbing disease that is not possible with other caffeine-containing drinks or decaffeinated coffee.

Previous observational studies in humans reported that daily coffee/caffeine intake during mid-life and in older age decreases the risk of Alzheimer's disease. The USF researchers' earlier studies in Alzheimer's mice indicated that caffeine was likely the ingredient in coffee that provides this protection because it decreases brain production of the abnormal protein beta-amyloid, which is thought to cause the disease.

The new study does not diminish the importance of caffeine to protect against Alzheimer's. Rather it shows that caffeinated coffee induces an increase in blood levels of a growth factor called GCSF (granulocyte colony stimulating factor). GCSF is a substance greatly decreased in patients with Alzheimer's disease and demonstrated to improve memory in Alzheimer's mice. A just-completed clinical trial at the USF Health Byrd Alzheimer's Institute is investigating GCSF treatment to prevent full-blown Alzheimer's in patients with mild cognitive impairment, a condition preceding the disease. The results of that trial are currently being evaluated and should be known soon.

"Caffeinated coffee provides a natural increase in blood GCSF levels," said USF neuroscientist Dr. Chuanhai Cao, lead author of the study. "The exact way that this occurs is not understood. There is a synergistic interaction between caffeine and some mystery component of coffee that provides this beneficial increase in blood GCSF levels."

The researchers would like to identify this yet unknown component so that coffee and other beverages could be enriched with it to provide long-term protection against Alzheimer's.

In their study, the researchers compared the effects of caffeinated and decaffeinated coffee to those of caffeine alone. In both Alzheimer's mice and normal mice, treatment with caffeinated coffee greatly increased blood levels of GCSF; neither caffeine alone or decaffeinated coffee provided this effect. The researchers caution that, since they used only "drip" coffee in their studies, they do not know whether "instant" caffeinated coffee would provide the same GCSF response.

The boost in GCSF levels is important, because the researchers also reported that long-term treatment with coffee (but not decaffeinated coffee) enhances memory in Alzheimer's mice. Higher blood GCSF levels due to coffee intake were associated with better memory. The researchers identified three ways that GCSF seems to improve memory performance in the Alzheimer's mice. First, GCSF recruits stem cells from bone marrow to enter the brain and remove the harmful beta-amyloid protein that initiates the disease. GCSF also creates new connections between brain cells and increases the birth of new neurons in the brain.

"All three mechanisms could complement caffeine's ability to suppress beta amyloid production in the brain" Dr. Cao said, "Together these actions appear to give coffee an amazing potential to protect against Alzheimer's -- but only if you drink moderate amounts of caffeinated coffee."

Although the present study was performed in Alzheimer's mice, the researchers indicated that they've gathered clinical evidence of caffeine/coffee's ability to protect humans against Alzheimer's and will soon publish those findings.

Coffee is safe for most Americans to consume in the moderate amounts (4 to 5 cups a day) that appear necessary to protect against Alzheimer's disease. The USF researchers previously reported this level of coffee/caffeine intake was needed to counteract the brain pathology and memory impairment in Alzheimer's mice. The average American drinks 1½ to 2 cups of coffee a day, considerably less than the amount the researchers believe protects against Alzheimer's.

"No synthetic drugs have yet been developed to treat the underlying Alzheimer's disease process" said Dr. Gary Arendash, the study's other lead author. "We see no reason why an inherently natural product such as coffee cannot be more beneficial and safer than medications, especially to protect against a disease that takes decades to become apparent after it starts in the brain."

The researchers believe that moderate daily coffee intake starting at least by middle age (30s -- 50s) is optimal for providing protection against Alzheimer's disease, although starting even in older age appears protective from their studies. "We are not saying that daily moderate coffee consumption will completely protect people from getting Alzheimer's disease," Dr. Cao said. "However, we do believe that moderate coffee consumption can appreciably reduce your risk of this dreaded disease or delay its onset."

The researchers conclude that coffee is the best source of caffeine to counteract the cognitive decline of Alzheimer's because its yet unidentified component synergizes with caffeine to increase blood GCSF levels. Other sources of caffeine, such as carbonated drinks, energy drinks, and tea, would not provide the same level of protection against Alzheimer's as coffee, they said.

Coffee also contains many ingredients other than caffeine that potentially offer cognitive benefits against Alzheimer's disease. "The average American gets most of their daily antioxidants intake through coffee," Dr. Cao said. "Coffee is high in anti-inflammatory compounds that also may provide protective benefits against Alzheimer's disease."

An increasing body of scientific literature indicates that moderate consumption of coffee decreases the risk of several diseases of aging, including Parkinson's disease, Type II diabetes and stroke. Just within the last few months, new studies have reported that drinking coffee in moderation may also significantly reduce the risk of breast and prostate cancers.

"Now is the time to aggressively pursue the protective benefits of coffee against Alzheimer's disease," Dr. Arendash said. "Hopefully, the coffee industry will soon become an active partner with Alzheimer's researchers to find the protective ingredient in coffee and concentrate it in dietary sources."

New Alzheimer's diagnostic guidelines, now encompassing the full continuum of the disease from no overt symptoms to mild impairment to clear cognitive decline, could double the number of Americans with some form of the disease to more than 10 million. With the baby-boomer generation entering older age, these numbers will climb even more unless an effective preventive measure is identified.

"Because Alzheimer's starts in the brain several decades before it is diagnosed, any protective therapy would obviously need to be taken for decades," Dr. Cao said. "We believe moderate daily consumption of caffeinated coffee is the best current option for long-term protection against Alzheimer's memory loss. Coffee is inexpensive, readily available, easily gets into the brain, appears to directly attack the disease process, and has few side-effects for most of us."

According to the researchers, no other Alzheimer's therapy being developed comes close to meeting all these criteria.

"Aside from coffee, two other lifestyle choices -- physical and cognitive activity -- appear to reduce the risk of dementia. Combining regular physical and mental exercise with moderate coffee consumption would seem to be an excellent multi-faceted approach to reducing risk or delaying Alzheimer's," Dr. Arendash said. "With pharmaceutical companies spending millions of dollars trying to develop drugs against Alzheimer's disease, there may very well be an effective preventive right under our noses every morning -- caffeinated coffee."


Cao C, Wang L, Lin X, et al. Caffeine Synergizes with Another Coffee Component to Increase Plasma GCSF: Linkage to Cognitive Benefits in Alzheimer's Mice. J Alzheimers Dis. Caffeine Synergizes with Another Coffee Component ... [J Alzheimers Dis. 2011] - PubMed result

Retrospective and prospective epidemiologic studies suggest that enhanced coffee/caffeine intake during aging reduces risk of Alzheimer's disease (AD). Underscoring this premise, our studies in AD transgenic mice show that long-term caffeine administration protects against cognitive impairment and reduces brain amyloid-beta levels/deposition through suppression of both beta- and gamma-secretase.

Because coffee contains many constituents in addition to caffeine that may provide cognitive benefits against AD, we examined effects of caffeinated and decaffeinated coffee on plasma cytokines, comparing their effects to caffeine alone. In both AbetaPPsw+PS1 transgenic mice and non-transgenic littermates, acute i.p. treatment with caffeinated coffee greatly and specifically increased plasma levels of granulocyte-colony stimulating factor (GCSF), IL-10, and IL-6. Neither caffeine solution alone (which provided high plasma caffeine levels) or decaffeinated coffee provided this effect, indicating that caffeine synergized with some as yet unidentified component of coffee to selectively elevate these three plasma cytokines.

The increase in GCSF is particularly important because long-term treatment with coffee (but not decaffeinated coffee) enhanced working memory in a fashion that was associated only with increased plasma GCSF levels among all cytokines. Since we have previously reported that long-term GCSF treatment enhances cognitive performance in AD mice through three possible mechanisms (e.g., recruitment of microglia from bone marrow, synaptogenesis, and neurogenesis), the same mechanisms could be complimentary to caffeine's established ability to suppress Abeta production.

We conclude that coffee may be the best source of caffeine to protect against AD because of a component in coffee that synergizes with caffeine to enhance plasma GCSF levels, resulting in multiple therapeutic actions against AD.
 
Thanks Mike, good to know there is a definite benefit in coffee for MCI and AD.
Coffee consumption just doubled here. :)
 
Pramipexole prevents neurotoxicity induced by oligomers of beta-amyloid

Pramipexole prevents neurotoxicity induced by oligomers of beta-amyloid


Daniela Ubertia, Irene Bianchia, Luca Olivaria, Giulia Ferrari-Toninellia, PierLuigi Canonicob and Maurizio Memoa, ,

aDepartment of Biomedical Sciences and Biotechnologies, University of Brescia, Viale Europa 11, 25124 Brescia, Italy

bDFB Center, DISCAFF Department, University of Piemonte Orientale, Novara, Italy

Received 7 February 2007; revised 26 April 2007; accepted 3 May 2007. Available online 13 May 2007.

Abstract
Here we demonstrate that pramipexole, an antiparkinsonian dopamine receptor agonist drug, exerts neuroprotective effects against beta-amyloid neurotoxicity. Using a specific protocol to test individually oligomers, fibrils, or unaggregated amyloid beta-peptide, we found pramipexole able to protect cells against oligomers and fibrils. Unaggregated amyloid beta-peptide was found unable to cause cell death. Fibrils and oligomers were also found to produce elevated amount of free radicals, and this effect was prevented by pramipexole. We propose pramipexole may become in the future a coadjuvant in the treatment of neuropathologies, besides Parkinson's disease, where amyloid beta-peptide-mediated oxidative injury exerts a relevant role.
 
Alzheimer's Disease

From dancing to drugs, research on Alzheimer's disease is moving apace. Our improved understanding of the role that amyloid-? plays is uncovering new ways to treat and perhaps prevent the disease. Imaging the brain is improving diagnosis, and better biomarkers to track disease progression are sought. Could we soon lift the spectre of Alzheimer's disease?

Free full access - Nature Outlook : Alzheimer's Disease
 
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