Tag: Alzheimer’ Disease

Innovation Radar: Approved Drug Counters Effects of Alzheimer’s in Mice

An FDA-approved drug called bexarotene counters many of the effects of Alzheimer’s disease in mouse models, researchers report. The build-up of protein fragments called amyloid-beta is a key feature of the disease; everyone’s brain produces amyloid-beta, but in healthy individuals, enzymes break the fragments down, with help from a protein called ApoE. Paige Cramer and colleagues knew that bexarotene activates a protein that helps switch on the ApoEgene, and they hypothesized that the drug might therefore enhance the clearance of amyloid-beta in the brain. They gave the drug to mice engineered to have an Alzheimer’s-like condition and observed that levels of the protein fragments in the mice’s brains dropped substantially within just a few days. The mice also showed improvements in their cognitive, social and olfactory performance. Bexarotene, also known as Targretin, is currently used to treat a form of skin cancer and has a favorable safety profile, the authors note. The drug activates the nuclear receptor protein known as RXR, which binds one of two other nuclear receptors, PPAR and LXR. These receptor pairs then activate the transcription of the ApoE gene.

The research is published online by the journal Science at this week’s Science Express website.

Food for Thought: “Forget Alzheimer’s”? – A Book Review

“Forget Alzheimer’s” is the title and the message of a book by German journalist Cornelia Stolze who is claiming to tell the “truth about a disease which isn’t one” (Cornelia Stolze, Vergiss Alzheimer. Die Wahrheit über eine Krankheit, die keine ist, Köln/Cologne 2011: Kiepenheuer & Witsch).

The book is strongly criticizing the handling of dementia, in particular Alzheimer’s disease (AD) in today’s medicine, pointing out the lack of adequate diagnostics and therapies and contrasting this sad reality with the often exaggerated promises of imminent breakthroughs by experts.

Stolze starts by explaining that to date, it is extremely difficult to diagnose Alzheimer’s disease. Most claims about new methods to confirm a diagnosis or, even better, to predict the onset have turned out to be false. She also points out that about 50 diseases and at least 150 medications may cause dementia symptoms. She concludes that most physicians are overextended to differentiate and often too early and too easily put the patient down as having Alzheimer’s, thereby impeding a causal treatment and condemning the patient to unnecessary mental derangement.

Examples are cognitive impairments associated with dehydration and depression, but also a variety of drugs, in particular, if patients take cocktails of drugs prescribed by different specialists who neglected potential interactions and side effects. Complications during surgery or anesthesia, too, can cause dementia symptoms. Stolze summarizes that about 75% of all dementia diagnoses are false.

She also points out that most medications on the market for the treatment of AD are ineffective, do not provide causal therapy and may at best slow down disease progression for a limited period of time.

These chapters are a strength of the book and can be read as a roll call to relatives, patient advocacy groups and the health care system in general to raise awareness about the various forms of dementia and to demand better diagnosis and better drugs.

Stolze then tells the 1970s story of how Alzheimer’s disease was put on the agenda of the then newly founded US National Institute on Aging (NIA). Back then, little was known about Alzheimer’s disease, but using a fancy name describing a threatening disease was way more efficient in raising awareness and money from governments and private sponsors than by talking in general terms about senility or dementia.

Subsequently, Stolze’s story gets astray as she tries to convince the reader that AD has been and still is a mere invention by the medical industry, and that every scientific description of the disease – whether in terms of pathology, biochemistry or cellular and molecular biology – is full of errors, inconsistencies and contradictions.

The author makes no efforts to go into the details to substantiate this claim. As an example, Stolze writes that plaques – long viewed as the hallmarks of AD – can be found in the brains of mentally wide awake elderly as well. She ignores that this fact has puzzled researchers since long and that there is an explanation to it already: plaques in the brain of healthy people do have a different molecular composition than those in people with AD, in which they predominantly consist of a certain, very toxic variant of the A beta peptide. The details have been elucidated by researchers from the German biotech company Probiodrug, with the first publications appearing in the late 1990s. The hypothesis meanwhile has been confirmed independently by various research groups around the world and a first drug addressing the underlying mechanism already has reached clinical stage.

Moreover, Stolze completely ignores that there are inherited forms of AD such as Familial Alzheimer’s disease (FAD) or Early Onset Familial Alzheimer’s disease (EOFAD), uncommon forms of Alzheimer’s disease which usually strike quite early in life. They are inherited in an autosomal dominant fashion and the genes involved have been characterized years ago. Moreover, studies in these inherited forms have revealed further details of the pathophysiological mechanisms involved in AD in general.

Further parts of the book deal with selected German Alzheimer specialists and their connections to industry and politics, raising questions about conflict of interest disclosures. This is an ongoing debate in medicine in general, and Stolze seems to share the widely held beliefs in Germany that a researcher or medical doctor, who files for a patent, already has crossed the line to unethical behavior.

Most regrettable about the book is that it shakes the confidence in medicine of patients, relatives and people involved in the care of dementia patients without providing any valuable guidance what to do and whom to trust if a loved one is showing signs of confusion, disorientation or loss of memory.

Food for Thought: Weekly Wrap-Up

Joachim Müller-Jung in Frankfurter Allgemeines Zeitung (FAZ) this week deals with the ethic implications of non-invasive prenatal diagnosis, describing that a huge number of tests based on fetal DNA entering the mother’s blood stream is ready to enter the market. His recommendation is to start an immediate discussion about which tests should be applied and which ones should not.

Ulrich Bahnsen in Die ZEIT interviews Norbert Donner-Banzhoff, Professor at the University of Marburg’s Department of General Practice, Preventive and Rehabilitative Medicine. Donner-Banzhoff conducted a study published in the Canadian Medical Association Journal CMAJ investigating the influence of pharmaceutical advertising on the drug recommendations made in articles in 11 German journals that focus on medical education. Donner-Banzhoff and his team come to the conclusion that journals financed by advertisement from the pharma industry and given away for free almost exclusively recommended the use of specified drugs, whereas journals financed entirely with subscription fees tended to recommend against the use of the same drugs. In the interview, Donner-Banzhoff suggests that a lot of articles published in the free journals have been written by ghost writers and/or members of the pharmaceutical industry.

Matthew Herper in Forbes this week deals with the latest setback in developing drugs to treat Alzheimer’s Disease (AD). He features the failure of Eli Lilly’s semagacest in a Phase III trial in more than 2,600 patients with mild-to-moderate AD. According to an interim analysis, patients receiving the drug, a gamma secretase blocker, worsened to a statistically significant greater degree than those treated with placebo. In addition, the drug was associated with an increased risk of skin cancer. Herper concludes that there is something fundamentally wrong with current hypotheses on the onset of AD and that the failure of the drug may set AD drug development back by many years (see also akampioneer’s recent comment on Probiodrug’s AD hypothesis).

While William Pentland, also in Forbes, reports a potential biofuel breakthrough in producing isobutanol directly from cellulose by using a microbe thriving in decaying grass, Josh Wolfe, co-founder and managing partner of Lux Capital Management, in Forbes states it is time to realize that investing in biofuels may be foolish. He states that while it is hyped as biotech 2.0, there is in fact a fundamental difference to biotech 1.0 which is often overlooked. While biotech 1.0 drugs and molecules can be protected by IP, biofuels cannot. In addition, the marginal cost of producing IP-protected molecules is really low once you did the discovery and first synthesis work (as compared to your margins) – so you can make big profits. Biofuel molecules however have to compete from the onset with the generic fuels already on the market. Biofuel is a commodity, he states, and instead of going back to an agrarian-based economy we should focus on materials and processing based on high energy density, such as uranium.

Donald G. McNeil jr in The New York Times reports on a panel of independent experts from 24 countries that reviewed the handling of the swine flu by the World Health Organization (WHO) in 2009. The draft report – “posted in an obscure corner of the W.H.O.’s Web site” – criticizes the WHO’s “needlessly complex” definition of a pandemic, its inability to deploy 78 million doses donated by rich nations for use in poor ones and its “clumsy communications”.

Colin Barras in New Scientist writes about the origin of cancer and features recent contributions by astrobiologists. While many researchers think that cancer is triggered by a malfunction of the genes trying to control replication which needs to be limited in multicellular organisms, some astrobiologists think a tumor is switching back to some forms of basic cellular cooperation found in the earliest ancestors of multicellular organisms. The distinction is far from being academic: if cancer is some sort of “living fossil” revived it would have only a limited set of survival strategies. In contrast, contemporary medicine regards a tumor as independently evolving cells with nearly unlimited evolutionary potential to escape treatment strategies. The hypothesis explains the co-ordinated survival strategies of cancer, such as angiogenesis and metastasis, and will be further tested soon by genetic profiling.


Food for Thought: Weekly Wrap-Up

In Frankfurter Allgemeine Zeitung (FAZ), Manfred Lindinger takes up the issue whether nanotechnology poses danger to human health and the environment in an article and an interview with Jochen Flasbarth, president of the German Federal Environment Agency (Umweltbundesamt – UBA). Flasbarth points out that UBA’s nanotechnology study published last year, highlighting gaps in knowledge about potential health hazards, was misunderstood by the media and the public as a sweeping warning of all things nano. He also dismisses calls for introducing a label for products containing nanotechnology: “If there is no risk, we don’t need to put up a warning sign.”

Several German papers feature and discuss an ad-hoc statement on preimplantation diagnosis  issued January 18 by the German National Academy of Sciences Leopoldina and Berlin-Brandenburgische Akademie der Wissenschaften. It was drafted by 13 eminent German academians from biology, medicine, law and philosophy & ethics, among them nobelist Christiane Nuesslein-Volhard. The statement calls for admission of PID under narrowly defined circumstances (high risk of serious monogenic disorder, chromosomal dysfunction, miscarriage or stillbirth). The parliament needs to to regulate PID after the German Federal Supreme Court last year ruled that Germany’s ban on PID was based on misinterpretation of the country’s Embryo Protection Law.

John Tierney in The New York Times provides new insights on people who underwent personal genetic testing to learn about their risk for conditions from obesity to cancer and Alzheimer’s. It is widespread belief among experts and politicians that personal DNA testing needs careful supervision and cannot be offered without expert guidance. The NYT introduces two studies – one follow-up study of about 2,000 people who had a genomewide scan by Navigenics  and one representative sample of 1,500 people – and found that the medical field overestimates the level of psychological anxiety or trauma caused by the results and is way too paternalistic about the tests. One researcher is quoted by saying: “We should recognize that consumers might reasonably want the information for nonmedical reasons. People value it for its own sake, and because they feel more in control of their lives.”

Gardiner Harris reports that the Obama administration has become so concerned about the slowing pace of new drugs coming out of the pharma industry that it has decided to start a federal billion-dollar drug development center. The “National Center for Advancing Translational Sciences” will open in October this year and will beef up early research results by finding leads against new targets or even perform preclinical studies so that projects become attractive to the pharma industry. NIH director Francis S. Collins who is behind the idea, is quoted by NYT as saying: “I am a little frustrated to see how many of the discoveries that do look as though they have therapeutic implications are waiting for the pharmaceutical industry to follow through with them.” In a first step, more than $700 million in research projects from other NIH institutes will be brought together at the new center.

Gina Kolata reports on an FDA advisory committee recommending approval of a new brain scan that can detect the typical plaques in the brains of living Alzheimer disease patients. The test has been developed by Avid Radiopharmaceuticals, now a subsidiary of Eli Lilly (see akampioneer, June 24, 2010).

In the New Scientist, Anil Ananthaswamy features findings from Australian researchers suggesting that Parkinson’s disease, Multiple Sclerosis and maybe other, more common diseases such as rheumatoid arthritis or diabetes, might be cured by antibiotics and subsequent (re-)colonization of the colon with bacteria from healthy people. The hypothesis was derived from case studies of Parkinson’s patients treated for colon infections, in which the treatment also abated the Parkinson’s symptoms. The researchers from the Center of Digestive Diseases in New South Wales are now planning a pilot study in Parkinson’s patients. Already, neuroanatomists from German Ulm University have suggested in 2003 that Parkinson’s might be caused by a bug that breaks through the mucosal barrier of the GI tract and enters the central nervous system via the vagus nerve (Journal of Neural Transmission, DOI: 10.1007/s00702-002-0808-2).

Linda Geddes reports on how cytokines associated with inflammation can enter the brain under certain circumstances and cause depression. Unfortunately, the article fails to mention German biotech company Affectis which already has Cimicoxib, an anti-inflammatory COX-2 inhibitor, in Phase II trials for the treatment of depression, after researchers discovered that COX-2 inhibitors can alleviate depression.

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