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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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December 11, 2013

David Cameron, The Press, Alzheimer's, and Hope

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Posted by Derek

One should be cheering the news that Great Britain will double funding for Alzheimer's and dementia research. But there's something odd about the way it's being presented, at least to my eyes. Here's a story from the Guardian that might illustrate what I mean:

The health secretary, Jeremy Hunt, said he hoped the dementia summit would have the same effect as the G8 summit in Gleneagles on HIV/Aids in 2005.

"Today should be an optimistic day," he told BBC Breakfast. "Tony Blair had the G8 summit in Gleneagles in 2005 on HIV/Aids and actually that did turn out in retrospect to be a turning point in the battle against Aids.

"I think if you bring the world's leaders together, health ministers from across the world, and we are all resolved that we really are going to do something about this as we face up to an ageing society."

If 2005 was some sort of widely-recognized turning point in HIV control, I must have missed it. I'll be glad to be corrected, but the last sentence in that quote makes me wonder, because it isn't a sentence. Try it out: the first part isn't connected with the second. He thinks that if you bring the world's leaders together, then. . .what will happen? "If" implies some sort of resolution in a sentence, and there isn't any. How about the second part? They're all resolved that they're really going to do something - fine, but isn't that the easiest part? The simplest part? I mean, coming out and saying that you'd like to "do something" about a problem that everyone would like to see solved is not that big a step, is it?

Well, doubling research funding is certainly doing something, there's no taking away from that. Much is made in the various press articles about Lilly's Alzheimer's scan, which Britain's National Heath Service is going to make available to some patients. Now, Lilly has been talking bravely about Alzheimer's for some time now, and to be fair to them, they've been spending pretty bravely, too. No doubt their hope has been that their imaging agent would match up with some successful therapy they'd develop, but the "successful therapy" part has been the hard one.

But British Prime Minister David Cameron has also been talking about finding a cure by 2025. I hope we do - I may need it by then - but it's going to take a generous slug of luck for that to happen. I don't hold out much hope for anything currently in development as a cure, although I'd like to be wrong about that. And something that's not in development would barely make it through, on an optimistic timetable, by 2025. We certainly don't know enough about Alzheimer's to say that we're on track, so someone will have to get lucky. You wouldn't know that from the British newspapers, though. They've also been excited about the potential of Eli Lilly's solanezumab, which must make the UK the only area outside of Indianapolis where that state of mind obtains.

That's the part that worries me about the public statements in this area. Politicians (and CEOs) are prone to ringing declarations that make it sound as if all that's really needed is gumption and willpower - good faith will carry the day. But that just isn't true in research. It really isn't. Nerve and perseverance are necessary, and how, but they're nowhere near sufficient. To pretend otherwise is to engage in magical thinking, and the history of Big Proclamations in the biomedical field should be enough to prove that to anyone.

Back in 2003, we were supposedly going to eliminate death and suffering from cancer by 2015 (and Senator Arlen Spector asked if maybe we couldn't move the timetable up to 2010). On a lesser level, back in 2009, there were statements that a cure for the common cold was at hand. Sorry about that. The British press has a particular weakness for proclaimed Alzheimer's cures, not that the US press doesn't go for them, too.

No, saying it will not make it so. I don't know how to make it so, other than by spending a lot of money and a lot of time, and working really hard, and hoping for the best. But that's not the stuff of headlines.

Comments (60) + TrackBacks (0) | Category: Alzheimer's Disease | Cancer


1. Anonymous on December 11, 2013 12:50 PM writes...

"The British press has a particular weakness for proclaimed Alzheimer's cures".

Especially the BBC - every time someone publishes a paper testing a molecule on some cells, the BBC has heralded a major breakthrough in AD and a cure on the horizon. Even if the cells have nothing to do with AD!

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2. bank on December 11, 2013 1:22 PM writes...

I would say that there is some additional benefit to Big Proclamations such as Cameron's one on Alzheimer's disease, and that is how it affects the attitude of the public.

Alzheimer's disease is sometimes regarded as a natural consequence of ageing, and therefore inevitable. This leads to a defeatist attitude among the public and even those who care for people with dementia, with a knock-on effect of reducing support from government and donations to non-profits.

"A cure by [whenever]" is a rhetorical device and shouldn't be taken any more seriously, in a scientific sense, than Richard Nixon's War on Cancer in 1971.

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3. MoMo on December 11, 2013 1:25 PM writes...

Sure, it sounds good and is the kind of sensationalism that gets the British all worked up, but at that rate of investment, over 11 years it represents a measly 7% increase per year. Subtract 3% for inflation and it is back to square one with a 4% increase in funding, yearly.

It would be better to spend the extra money on more potent antioxidants and teas research.

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4. Anonymous on December 11, 2013 1:36 PM writes...

"Cameron said he would double funding research from £66m in 2015 to £122m in 2025"

Given that AD costs the US alone $100 Billion per year (and I assume at least £10 Billion per year to the UK), and these costs are expected to DOUBLE by 2025, £122 million is really quite pathetic! Talk about cracking a nut with a sledge hammer, this is like trying to crack a coconut with a toffee hammer.

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5. DrugA on December 11, 2013 1:40 PM writes...

Other than a few specific types of cancer, has any non-infectious disease ever been cured by drugs? I can't think of any.

That doesn't mean that pharmacotherapy hasn't been highly successful for a lot of conditions, but suggests that talk of "cures" may be a bit optimistic.

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6. Lane Simonian on December 11, 2013 1:50 PM writes...

I am going to try to state this as calmly as possible: there will be no cure for Alzheimer's disease until the right target is found. Amyloid is not the right target. Approximately a third of autopsies find significant buildup of amyloid in people without Alzheimer's disease. And even by Eli Lilly's admission about 20 percent of the people they thought had Alzheimer's disease in their studies did not have amyloid.

Everyone with Alzheimer's disease will have one of the following: the amyloid precursor protein, amyloid oligomers, or amyloid plaques. All you need for Alzheimer's disease is the precursor protein because the same pathways (the activation of tyrosine kinase receptors and protein kinase C alpha)that lead to the precursor protein also lead to the cause of Alzheimer's disease (peroxynitrites).

J Neurochem. 2001 Jul;78(1):109-20.
C-terminal fragment of amyloid precursor protein induces astrocytosis.
Bach JH, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS.
Department of Anatomy, College of Medicine, BioGrand Inc., and MRC, Chung-Ang University, 221 Huksuk-dong, Dongjak-ku, Seoul 156-756, Korea.

One of the pathophysiological features of Alzheimer's disease is astrocytosis around senile plaques. Reactive astrocytes may produce proinflammatory mediators, nitric oxide, and subsequent reactive oxygen intermediates such as peroxynitrites. In the present study, we investigated the possible role of the C-terminal fragment of amyloid precursor protein (CT-APP), which is another constituent of amyloid senile plaque and an abnormal product of APP metabolism, as an inducer of astrocytosis. We report that 100 nM recombinant C-terminal 105 amino acid fragment (CT105) of APP induced astrocytosis morphologically and immunologically. CT105 exposure resulted in activation of mitogen-activated protein kinase (MAPK) pathways as well as transcription factor NF-kappaB. Pretreatment with PD098059 and/or SB203580 decreased nitric oxide (NO) production and nuclear factor-kappa B (NF-kappaB) activation. But inhibitors of NF-kappaB activation did not affect MAPKs activation whereas they abolished NO production and attenuated astrocytosis. Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.

Amyloid oligomers and plaques additionally require the release of intracellular calcium and this does not always happen (caffeine and heparin, for instance, inhibit the release of intracellular calcium). On the other hand, with a good antioxidant system one may have plaques without Alzheimer's disease.

The peroxynitrite hypothesis for Alzheimer's disease was offered 15 years ago by the late Mark A. Smith, who liked to remark that lots of people liked to poke a stick in his eye but none were ever able to prove him wrong.

And just one last anonymous quote on this subject:

[Clinical trials with over-the-counter supplements have concentrated either on items which suppress inflammation, or on antioxidants which scavenge oxygen derived free radicals. Most of these items have proved to be worthless in the treatment of Alzheimer's disease. Similarly most drugs used to treat Alzheimer's disease do little to slow the deterioration, but instead offer a mild temporary
symptom relief. However, evidence has been accumulating that the primary driver of Alzheimer's disease is a nitrogen derived free radical called peroxynitrite, which may mediate both amyloid and tau accumulation as well as their toxicity. Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer's disease in human clinical trials being repeatedly demonstrated. IMHO, the only thing which may be preventing the abolition of
Alzheimer's disease is the mental inertia of scientists, as well as the bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful ones. Common sense is anything but...]

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7. Chris on December 11, 2013 1:51 PM writes...

It is good that Cameron has shone the spotlight on the issues of AD, and as others have said the amount of money is not sufficient to realistically find a cure. I can't help but feel that some of the charities in the UK should look at Cancer Research UK who have built a pretty impressive machine to fund Cancer research.
I'm not convinced that governments focus on things that will become a problem for the next generation.

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8. luigi on December 11, 2013 2:11 PM writes...

@4 - being pathetic must be contagious - Cameron's comments are no less pathetic and misplaced than those of Obama's 2012 funding of AD at the NIH for a cure - again by 2025. Being vague, delusional and dismissing the really hard part is a characteristic of politicians. Many may also remember Monty Python's Blue Peter sketch where John Cleese's advice on getting really rich was to "think of something interesting"

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9. Jed on December 11, 2013 2:57 PM writes...

"I don't hold out much hope for anything currently in development as a cure, although I'd like to be wrong about that."

What do you think about the Merck (Schering) BACE inhibitor MK-8931 in PhII/III? The APP mutation that prevents BACE cleavage and protects against AD seems like excellent target validation. The question seems to be whether a drug can get to the target and whether it will be safe. Another issue is clinical trial design and choosing the right patient population. I really hope this one works!

This is coming from someone who spent over 4 years working unsuccessfully on gamma secretase modulators. I still believe the amyloid pathway is critical, the problem is finding the right drug.

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10. Anonymous on December 11, 2013 2:58 PM writes...

That will be this Jeremy Hunt then ...

Early Day Motion signed in 2007:

That this House welcomes the positive contribution made to the health of the nation by the NHS homeopathic hospitals; notes that some six million people use complementary treatments each year; believes that complementary medicine has the potential to offer clinically-effective and cost-effective solutions to common health problems faced by NHS patients, including chronic difficult to treat conditions such as musculoskeletal and other chronic pain, eczema, depression, anxiety and insomnia, allergy, chronic fatigue and irritable bowel syndrome; expresses concern that NHS cuts are threatening the future of these hospitals; and calls on the Government actively to support these valuable national assets.

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11. Anonymous on December 11, 2013 3:00 PM writes...

David Cameron is a chicken hawk.

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12. Lane Simonian on December 11, 2013 3:25 PM writes...

Jed, early on the beta secretase is a good target. This secretase is controlled by tyrosine receptor kinases and protein kinase C alpha.

Platelet-derived growth factor induces the beta-gamma-secretase-mediated cleavage of Alzheimer's amyloid precursor protein through a Src-Rac-dependent pathway.

Mol Cell Biol. 2004 Sep;24(17):7578-97.
Protein kinase Calpha activates c-Src and induces podosome formation via AFAP-110.

The key to preventing Alzheimer's disease is to inhibit tyrosine kinase receptors and protein kinase C. Once the disease has progressed, in most cases, tyrosine kinase receptors and protein kinase C are already inhibited due to nitration and oxidation and then the main problem becomes the activation of NMDA receptors.

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13. Morten G on December 11, 2013 4:34 PM writes...

So Lilly has a diagnostic? That's pretty encouraging. What's the patent limit on diagnostics?

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14. DrSnowboard on December 11, 2013 4:48 PM writes...

If one were cynical, one could argue that Cameron is attempting to offset the removal of benefits and increased taxation that his fiscal policies are / are about to inflict on the aging baby boomer generation. Make a grand gesture towards a great fear of a rapidly ageing segment of the electorate, they may forgive you pilfering the benefits they paid in for.

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15. AndrewD on December 11, 2013 4:49 PM writes...

If I was being cynical, which I am, I would observe that in June 2015, there is a general election in the UK. The older generations tend to suffer from dementia and vote in Elections, I suspect vote getting

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16. milkshaken on December 11, 2013 6:00 PM writes...

faith-based medicine and drug development by a summit of government officials will revolutionize Alzheimer research. Just imagine the time and cost savings if the governments could waive the required proof of long term safety and efficacy...

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17. Lest we forget on December 11, 2013 6:06 PM writes...

Anno domini.

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18. Anonymous on December 11, 2013 6:25 PM writes...

16# I assume by 'faith-based' medicine you mean solanezumab! It is worth noting the Brit quoted in the Telegraph article used to work for Lilly. Therefore the exictement is principally in Indianapolis and a small village in the UK called Windlesham were the Lilly Research Centre is located.

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19. Nick K on December 11, 2013 6:48 PM writes...

#10: Agreed. This is a terrible indictment of the scientific illiteracy of British politicians. And these people are running the country!

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20. BTDT on December 11, 2013 8:05 PM writes...

Not to be picky, but the "war on cancer" goes much farther back than 2003. Just search for: The National Cancer Act of 1971

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21. whirlygig on December 11, 2013 10:54 PM writes...

Dat last sentence... @@@@@@

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22. Anonymous BMS Researcher on December 12, 2013 12:03 AM writes...

Seems to me we need fundamental new ideas for AD. Old sayings come to mind:

"Nine women cannot produce a baby in one month"

"You can't win the high jump with eight guys who can each jump one foot, you need one guy who can jump eight feet."

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23. Dr Jimbo on December 12, 2013 12:28 AM writes...

I saw a chicken hawk on the bayou today (doing some touristing after ASH), and it's a magnificent bird that I'm sure would take exception to your comparison to that worm Cameron.

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24. Hotdog Jack on December 12, 2013 3:14 AM writes...

Cameron is scum, but there _is_ some room for government to help. This era's pharmaceutical giants are extremely slow, conservative, and risk-averse -- and the regulatory agencies that oversee them are much, much worse. With the proper development incentives, and with regulatory 'fast tracking' and leniency taken to an absolute extreme, it's possible that some headway can be made before 2025. The disease would instantly become a much more attractive target to companies of all sizes, and the market can then sort out which treatment is most effective, as has happened many times in the past.

Alzheimer's is just about as bad as it gets. I'd argue that almost no side effect is too severe. The current drug-approval model fails miserably for diseases such as this.

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25. petros on December 12, 2013 3:17 AM writes...

And the Health Secretary, over whom one BBC interviewer had a slip of the tongue to start his name with a C, is one of the less inspiring Cabinet Ministers in the UK Government

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26. james on December 12, 2013 3:32 AM writes...

It was not one BBC presenter but two in a row in the space of a few hours, I remember that morning well!

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27. Leedschemist on December 12, 2013 4:22 AM writes...

yeah J Hunt is almost the definition of a useless cabinet minister; he also believes in homeopathy just what you want from your Health Secretary! The idea is laudable though and any increase in funding for UK science has to be welcomed in the current climate.

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28. Anonymous on December 12, 2013 6:37 AM writes...

@6, 12 (Lane Simonian): "The key to preventing Alzheimer's disease is to inhibit tyrosine kinase receptors and protein kinase C. Once the disease has progressed, in most cases, tyrosine kinase receptors and protein kinase C are already inhibited due to nitration and oxidation and then the main problem becomes the activation of NMDA receptors." blah blah blah

You should read a few articles about how hubris (people such as yourself thinking they know more than they really do) is killing drug development in the pharma industry.

Here is one that you should take lessons from, ideally before posting more crap as if you are an absolute authority on the field, while everyone else is stupid:

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29. Project Osprey on December 12, 2013 7:47 AM writes...


Cures? Not many no. But perhaps that's a unfair area to pick on. Non-communicable diseases are normally the result of some sort of permament damage to the body, which makes them tricky to treat. It's like trying to cure someone from having lost a arm.
There are a lot of sucessful treatments though. Think of asthma, diabetes, certain autoimune disorders: A generation ago these were dibilitating, even lethal. Now you can live a long life with them. It's not perfect but things are improving.

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30. MTK on December 12, 2013 8:02 AM writes...


Agree. Modern medicine, and the drugs used, has taken many conditions which were once fatal or debilitating and turned them into manageable chronic conditions with acceptable minimal impact on life expectancy and quality. That's a real win and should not be discounted.


Actually in the late 60's and early 70's a "cure" for cancer was actually thought within reach by many scientists. Certainly not all, but quite a few. Nixon's War on Cancer was more than just a rhetorical device. America had just gone to the moon, for pete's sake. We sort of thought we could accomplish anything if we put our mind to it.

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31. johnnyboy on December 12, 2013 10:02 AM writes...

I've been looking into moving to the UK at some point in the future (for personal, rather than work reasons), but frankly, at the salaries that are on offer for life sciences researchers, it's a wonder there's any research still going on there at all. Cameron's 66 million is a case in point: they seem to expect such crumbs to actually make a difference, when it won't even make a dent.

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32. NC on December 12, 2013 12:31 PM writes...

They don't expect these crumbs to make a difference - they expect the public to read about it and think "oh! How marvellous the Tories are for science and the economy". The public are not typically scientists!

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33. Lane Simonian on December 12, 2013 2:23 PM writes...

#28 It has nothing to do with hubris or blah, blah, blah. It is about trying to move away from pious announcements, miracles of the month, and repeated failures based on an entrenched but largely incorrect hypothesis of the disease. BACE inhibitors if they do not produce major side effects offer some hope, not because they stop the production of amyloid plaques but because if you start far enough upstream they slow down the production of peroxynitrites. Gamma secretases do not work because they slow down the production of amyloid but not of peroxynitrites.

The critical point is that one can have Alzheimer's disease without amyloid plaques. In some people with Alzheimer's disease removing amyloid plaques may help somewthat, but in people who have Alzheimer's disease without the plaques it is not going to help at all.

Alzheimer’s Disease Without Amyloid Plaque

Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease. Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death.

It is not hubris to point out that certain peroxynitrite scavengers have partially reversed Alzheimer's disease in human clinical trials--they just did. The hubris comes in ignoring these studies because you expect/want a different result.

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34. Anonymous on December 12, 2013 2:50 PM writes...

@33, Lane: Did it ever occur to you that a completely different form of amyloid might be the main culprit? There are now hundreds, if not thousands of research papers showing that soluble oligomeric forms of amyloid, not the insoluble plaques are inherently toxic and kill cells, apparently by forming holes in cell membranes, and (in many cases) without the formation of peroxynitrites. You are about 15 years and several hundred papers behind in your thinking.

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35. Morten G on December 12, 2013 3:14 PM writes...

@23 a chicken hawk is a (middle aged) gay man who preys on guys around 18-21 yo. I haven't heard this before so I'm not sure if it's being used as a nonce which can both be literal and just an insult.

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36. a. nonymaus on December 12, 2013 3:34 PM writes...

Re: 35
I think that in this context, the term Chickenhawk refers to the political creature that engages in warmongering but is not in any danger of being sent abroad.

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37. Lane Simonian on December 12, 2013 3:42 PM writes...

#34 Yes, amyloid comes in different forms and yes various forms of amyloid can do damage to the brain, but the failure of amyloid antibodies cannot simply be explained by going after the wrong form of amyloid or starting too late. Damage to neurons can occur well before the formation of either amyloid oligomers or plaques.

If you look at the general and specific damage done in the brain of people with Alzheimer's disease: nitration, oxidation, lipid peroxidation, inflammation, DNA damage, inhibition of neurotransmitter release and synthesis, mitochondrial failure, misfolded proteins, vascular dysfunction, disruption of transport systems, inhibition of the regeneration of neurons, and death of neurons it is all directly or indirectly connected to peroxynitrites. That is why peroxynitrite scavengers likely provide the critical therapeutic strategy for the treatment of Alzheimer's disease.

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38. Torson on December 13, 2013 12:40 AM writes...

For all guys above that already have figured out how to cure Alzheimer. The quote is from April 2013.

"Sanofi (SAN), won’t push hard to find an Alzheimer’s treatment because the science isn’t advanced enough to justify the costs to develop a drug, Chief Executive Officer Chris Viehbacher said."

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39. Torson on December 13, 2013 12:41 AM writes...

For all guys above that already have figured out how to cure Alzheimer. The quote is from April 2013.

"Sanofi (SAN), won't push hard to find an Alzheimer's treatment because the science isn't advanced enough to justify the costs to develop a drug, Chief Executive Officer Chris Viehbacher said."

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40. Anonymous on December 13, 2013 8:36 AM writes...

@37: Complete rubbish. Amyloid antibodies don't work simply because they can't get into the brain and within the brain cells. Their failure to work has nothing to do with amyloid.

And you're wrong about amyloid not forming early enough, because again you are thinking about the visible insoluble plaques which only form later, rather than invisible soluble oligomers. Read some papers, or even better, go out and cure the disease if you already know everything. Either way, shut up until you have a clue.

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41. Anonymous on December 13, 2013 9:10 AM writes...

How hard can it be to find political leaders able to string a logical sentence together? At least Jeremy Hunt isn't the secretary for education, I suppose.

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42. Lane Simonian on December 13, 2013 10:04 AM writes...

#40 Whether this is true or not, by some means they are reducing amyloid levels to some degree. More importantly let me repeat two findings above regarding the amyloid precursor protein.

Alzheimer’s Disease Without Amyloid Plaque

Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease. Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death.

Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.

And this one on rosmarinic acid (there are a couple dozen other peroxynitrite scavengers that have produced the same results).

Behav Brain Res. 2007 Jun 18;180(2):139-45. Epub 2007 Mar 12.
A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).

Think people, think. If you have the death of neurons simply in the presence of the amyloid precursor protein, amyloid cannot be the sole cause of Alzheimer's disease. It can be a contributor but it cannot be a sole cause. And if peroxynitrite scavengers attenuate the cytotoxicity of both the amyloid precuror protein and amyloid beta, the most effective peroxynitrite scavengers should be able to partially ameliorate the disease (which they have already done in small-scale clinical trials). It is not hard to put together for someone who is willing to do so.

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43. Anonymous on December 13, 2013 11:26 AM writes...

"Think people, think. If you have the death of neurons simply in the presence of the amyloid precursor protein, amyloid cannot be the sole cause of Alzheimer's disease."

That makes no sense at all. If neurons are present, then by definition they are not "simply in the presence of the amyloid precursor protein". Neurons themselves are very complex, comprising millions of compounds. How can you be sure they don't contain *any* amyloid, or even secretase.

Think, Lane, think! Because I'm sick of trying to think for you, you're a waste of space.