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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: derekb.lowe@gmail.com Twitter: Dereklowe

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January 23, 2014

Alzheimer's Therapies: A Reasonably Gloomy Update

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Posted by Derek

The New England Journal of Medicine has publications from Pfizer / J&J and Lilly on their multiple phase III trials of anti-amyloid antibodies (bapineuzumab and solanezumab, respectively). As the world knows, neither of them hit their primary endpoints. How optimistic one can be after that is a matter for fine distinctions.

Medscape has a look-on-the-bright-side article here. There's some evidence that the antibodies were affecting amyloid, which is (presumably) at least a start:

. . .an analysis of apolipoprotein E (APOE) 4 carriers found a decreased rate of accumulation of amyloid in the brain in a subset of patients taking bapineuzumab who had positron emission tomography (PET) imaging using Pittsburgh compound B, although the difference was smaller than that seen in phase 2 studies using a higher dose of the drug. And, among carriers, bapineuzumab was associated with reduced concentrations of cerebrospinal fluid (CSF) phospho-tau, a marker of neurodegeneration.

"We were getting some target engagement and that's encouraging," said Dr. Salloway. "But we were limited in our ability to lower amyloid because of the dose-related side effects."

Those side effects were signs of edema in the brain imaging of the bapineuzumab patients who carried the APOE4 gene. Their dose was lowered to half a milligram per kilo, while the other patients got up to 1 mpk. The Phase II trials had gone up to 2 mpk, but that dose was dropped completely. At any rate, I think that bapineuzumab has also been dropped completely; I'm unaware of any further work with it. That's as opposed to solanezumab, where Lilly is famously pressing on.

It's at least better-tolerated than bapineuzumab, perhaps because it doesn't specifically target amyloid fibrils, but goes more after the soluble forms. And that, conceivably, is connected with the hints of efficacy that were seen in the patients with milder forms of Alzheimer's, and on this outcropping of solid bedrock rests Eli Lilly's Alzheimer's strategy. It's a tough place to be, but Lilly is already in a tough place, so a roll of the dice like this might be their best shot at this point.

There's a quote in the Medscape piece saying that we've "entered the era of prevention studies" in the disease, but that's too sunny even for an optimistic guy like me. We still have no clear idea of that actual early mechanisms that lead to Alzheimer's. The amyloid hypothesis, though it has a fair amount of evidence on its side, remains unproven, and every attempt to target it pharmacologically has either failed or (if you squint hard) just about failed. The only reason we're running prevention trials with the agents we have is that they failed to do anything in treatment trials. We have staggered into an era of prevention trials because we have nothing else to offer.

That doesn't mean I'm hoping for solanezumab or anything else to fail - far from it. A preventative agent for Alzheimer's would be a great advance. It's just that I'm not hopeful that any of the current therapies will work that way. If one does, it'll be a real long shot bet that's come through, and it's going to be five to ten years before we'll even know enough to say that. So I hope that I don't see too many "Alzheimer's Prevention Trials Underway!" headlines in the general press. The occasional mentions of a "cure by 2025" make a person wonder, though.

There's also a lot of talk about combination therapies, a monoclonal antibody, plus a secretase inhibitor, plus something for tau, and so on. That may well be the way to go, eventually. But it's worth remembering that previous cocktail regimens like this, in other disease areas, combined agents that showed much more robust effects than anything has in Alzheimer's so far. They were good enough, usually, to be approved on their own. In Alzheimer's, as it stands now, we'd be looking at combining two or three drugs that have all struck out in the clinic, and maybe one or two that we don't even have yet, and hoping for the best. I don't see that as a realistic strategy until something works a bit better. Or works at all.

Comments (24) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


COMMENTS

1. Anonymous on January 23, 2014 9:19 AM writes...

I'd like to see a drug to prevent gambling addiction, it might help the guys at Lilly.

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2. Anonymous on January 23, 2014 9:40 AM writes...

YES

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3. anonymous on January 23, 2014 10:02 AM writes...

Just give them a whiff of a selenium compound every time they want to gamble.

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4. Curryworks on January 23, 2014 10:04 AM writes...

Recent studies have shown peroxynitro radicals are not implicated in AD and may be a natural defense mechanism utilized by the body. This new research flies in contrast to prior research.

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5. bhip on January 23, 2014 10:22 AM writes...

The difficulty in treating advanced disease is akin to trying to reverse COPD in an elderly patient- the damage has been done before the patient ever sees their doctor. It makes sense that success of any therapeutic agent is more likely if screening can identify Alzheimer’s (& COPD) in its early stages.
That said, attempting to effectively decrease amyloid deposition in the CNS with a peripheral antibody seems like such a long shot (I am being kind) & I don’t believe that their failure in Alzheimer’s patients really addresses the hypothesis that amyloid is a/the underlying cause of the disease (cue Lane Simonian). The direct inhibition of BACE seems to be a more straightforward approach if any potential/probable mechanism-based side effects are tolerable with chronic dosing.

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6. Anchor on January 23, 2014 10:34 AM writes...

It is against this gloomy forecast, am curious about Merck's analog that is going through clinical trials. Do they know something the rest of us do not?

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7. Lane Simonian on January 23, 2014 11:53 AM writes...

The surest way to go down with the ship is to believe that it can still float.

I would be surprised if anti-amyloid strategies ever produced any significant results no matter when they were started. Amyloid is likely on the periphery of Alzheimer's disease, neither a symptom nor a cause but somewhere in between.

Amyloid by attracting copper and zinc initially increase the production of hydrogen peroxide which combines with a nitrite anion (a product of peroxynitrite scavenging) to reform peroxynitrites. Amyloid later entombs copper and zinc which increases levels of superoxide anions and decreases levels of hydrogen peroxide. But if inducible nitric oxide levels are lower than superoxide anion levels than this would not increase the level of peroxynitrites. This might explain why metal chelators and amyloid antibodies don't seem to have any effectiveness at all when given late.

Curryworks what recent studies show that peroxynitrites are not implicated in Alzheimer's disease? Peroxynitrites may be part of the body's defense mechanisms against viruses and bacteria. This may help explain why certain chronic viral and bacterial infections increase the risk of Alzheimer's disease. There are a number of studies linking peroxynitrites to the hyperphosphorylation of tau proteins, the aggregation of amyloid plaques, and the decreased synthesis and release of acetylcholine. I am interested, though, also in the contrary evidence.

I am going to try a separate post showing the possible pathways to Alzheimer's disease to show just how intertwined peroxynitrite production and amyloid is.

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8. Lane Siimonian on January 23, 2014 12:23 PM writes...

I would start with the Kegg pathway for Alzheimer's disease--not perfect but a reasonable approximation of the pathways to Alzheimer's disease.

Then the phospholipase C signalling pathway from biocarta.

The likely pathway to amyloid then: high levels of myo-inositol, decreased activation of the phosphatidylinositol 3-kinase, activation of tryosine receptor kinases and/or g proteins (either via g protein-coupled receptors or independently of g protein-coupled receptors), phospholipase C, intracellular calcium release (which activates the y secretase), protein kinase C, src kinase (which regulates the beta secretase), amyloid.

The likely pathway to peroxynitrites: high levels of myo-inositol, decreased activation of the phosphatidylinositol 3 kinase, activation of tyrosine receptor kinases and/or g proteins (either via g protein-coupled receptors or independent of g protein-coupled receptor), protein kinase C and src kinases, p38 MAPK, peroxynitrites. Nearly the same pathways. Protein kinase C results in the release of the amyloid precursor protein and src activation, but if some factor is limiting the release of intracellular calcium (caffeine, heparin, etc.), you get few or any plaques. Alternatively if you have a good antioxidant system, you may get many plaques but few peroxynitrites. Or in other words, you can have Alzheimer's disease without plaques or plaques without Alzheimer's disease.

J Neurosci. 1998 Apr 15;18(8):2907-13.
Protein kinase C activation increases release of secreted amyloid precursor protein without decreasing Abeta production in human primary neuron cultures.
LeBlanc AC, Koutroumanis M, Goodyer CG.
Author information

Abstract
Overexpression and altered metabolism of amyloid precursor protein (APP) resulting in increased 4 kDa amyloid beta peptide (Abeta) production are believed to play a major role in Alzheimer's disease (AD). Therefore, reducing Abeta production in the brain is a possible therapy for AD. Because AD pathology is fairly restricted to the CNS of humans, we have established human cerebral primary neuron cultures to investigate the metabolism of APP. In many cell lines and rodent primary neuron cultures, phorbol ester activation of protein kinase C (PKC) increases the release of the secreted large N-terminal fragment of amyloid precursor protein (sAPP) and decreases Abeta release (; ; ). In contrast, we find that PKC activation in human primary neurons increases the rate of sAPP release and the production of APP C-terminal fragments and 4 kDa Abeta. Our results indicate species- and cell type-specific regulation of APP metabolism. Therefore, our results curtail the use of PKC activators in controlling human brain Abeta levels.

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.
Author information
Abstract
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.

One more post on the prevention and treatment of Alzheimer's disease.

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9. Lane Simonian on January 23, 2014 12:59 PM writes...

First of all there is no absolutely way to prevent Alzheimer's disease, only ways to potentially reduce the risk. The pathways described above can be activated (or deactivated in the case of the phosphatidylinostiol 3-kinase) by dozens of factors ranging from genetic, to diet, to environmental toxins, to drugs. That is why Alzheimer's disease is such a prevalent disease.

A Mediterranean or Indian diet contains many phenolic compounds that inhibit tyrosine receptor kinases which in some people would limit the production of both amyloid and peroxynitrites. The pathways described above work best in lipid rafts high in low density lipids and saturated fats. Omega 3-fatty acids partially alter the lipid balance. So a diet high in polyphenols and omega 3-fatty acids may reduce the risk of Alzheimer's disease for some people.

Neurobiol Aging. 2005 Dec;26 Suppl 1:133-6. Epub 2005 Nov 2.

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions.
Cole GM, Lim GP, Yang F, Teter B, Begum A, Ma Q, Harris-White ME, Frautschy SA

The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.).

I have seen speculation that Merck's beta secretase inhibitor is a curcumin analog. If so it may work because it inhibits tyrosine receptor kinases. All the methoxyphenols such as curcumin, ferulic acid, and eugenol are beta secretase inhibitors for this reason.

In regards to treatment of Alzheimer's disease methoxyphenols through their superior peroxynitrite scavenging abilities have partially ameliorated Alzheimer's disease in small-scale clinical trials.

Eugenol (in rosemary and lemon balm essential oils)

J Agric Food Chem. 2005 Jun 15;53(12):4762-5.
In vitro activity of the essential oil of Cinnamomum zeylanicum and eugenol in peroxynitrite-induced oxidative processes.
Chericoni S, Prieto JM, Iacopini P, Cioni P, Morelli I.
Author information

Abstract
The essential oil obtained from the bark of Cinnamomum zeylanicum Blume (Lauraceae) and three of its main components, eugenol, (E)-cinnamaldehyde, and linalool (representing 82.5% of the total composition), were tested in two in vitro models of peroxynitrite-induced nitration and lipid peroxidation. The essential oil and eugenol showed very powerful activities, decreasing 3-nitrotyrosine formation with IC50 values of 18.4 microg/mL and 46.7 microM, respectively (reference compound, ascorbic acid, 71.3 microg/mL and 405.0 microM) and also inhibiting the peroxynitrite-induced lipid peroxidation showing an IC50 of 2.0 microg/mL and 13.1 microM, respectively, against 59.0 microg/mL (235.5 microM) of the reference compound Trolox. On the contrary, (E)-cinnamaldehyde and linalool were completely inactive.

Effects of Eugenol on the Central Nervous System: Its Possible Application to Treatment of Alzheimer's Disease, Depression, and Parkinson's Disease
Author: Irie, Yoshifumi

Abstract:
Eugenol (4-allyl-2-methoxyphenol) is a fragrant compound that is commonly contained in various sorts of plants, especially in spices and medicinal herbs. Eugenol has been used for dental analgesic, which also has anticonvulsive and anti-microbial activities. Besides, anti-inflammatory and antioxidative activities of eugenol are known. A body of evidence suggests that eugenol can be used as a drug for treatment of Alzheimer's disease (AD). According to recent reports, the extract of a medicinal plant Rhizoma Acori Graminei (RAG) alleviates neurotoxicity induced by amyloid beta peptides (Aβ) in vitro and the active constituent of RAG is eugenol. Eugenol inhibits Aβ-induced excessive influx of calcium ion into neurons that causes neuronal death. Moreover, eugenol possesses an antidepressant-like activity. Eugenol, like other antidepressants, increases expression of brain-derived neurotrophic factor (BDNF) gene in the hippocampus, which is necessary for an antidepressant to exhibit its activity. Furthermore, eugenol inhibits monoamine oxidase A (MAO-A) and may restore monoamines that are decreased in the brain of patients with depression. Thus, eugenol can be a good medicine for AD and depression. Here we suggest that eugenol and its analogs can be used also for other diseases of the central nervous system (CNS) including Parkinson's disease (PD). This article reviews the previous investigations concerning effects of eugenol including its analogs on the CNS and describes perspectives of this highly potential compound.

Psychogeriatrics. 2009 Dec;9(4):173-9. doi: 10.1111/j.1479-8301.2009.00299.x.
Effect of aromatherapy on patients with Alzheimer's disease.
Jimbo D, Kimura Y, Taniguchi M, Inoue M, Urakami K.
Author information

Abstract
OBJECTIVE:
Recently, the importance of non-pharmacological therapies for dementia has come to the fore. In the present study, we examined the curative effects of aromatherapy in dementia in 28 elderly people, 17 of whom had Alzheimer's disease (AD).

METHODS:
After a control period of 28 days, aromatherapy was performed over the following 28 days, with a wash out period of another 28 days. Aromatherapy consisted of the use of rosemary and lemon essential oils in the morning, and lavender and orange in the evening. To determine the effects of aromatherapy, patients were evaluated using the Japanese version of the Gottfries, Brane, Steen scale (GBSS-J), Functional Assessment Staging of Alzheimer's disease (FAST), a revised version of Hasegawa's Dementia Scale (HDS-R), and the Touch Panel-type Dementia Assessment Scale (TDAS) four times: before the control period, after the control period, after aromatherapy, and after the washout period.

RESULTS:
All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.

CONCLUSIONS:
In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind, randomised, placebo controlled trial
S Akhondzadeh, M Noroozian, M Mohammadi, S Ohadinia, A Jamshidi, and M Khani
Author information

Abstract
Objective: To assess the efficacy and safety of Melissa officinalis extract using a fixed dose (60 drops/day) in patients with mild to moderate Alzheimer's disease.

Design: A four month, parallel group, placebo controlled trial undertaken in three centres in Tehran, Iran.

Methods: Patients with mild to moderate Alzheimer's disease aged between 65 and 80 years (n = 42; 18 women, 24 men) with a score of ≥ 12 on the cognitive subscale of Alzheimer's disease assessment scale (ADAS-cog) and ≤ 2 on the clinical dementia rating (CDR) were randomised to placebo or fixed dose of Melissa officinalis extract. The main efficacy measures were the change in the ADAS-cog and CDR-SB scores compared with baseline. Side effects were systematically recorded.

Results: At four months, Melissa officinalis extract produced a significantly better outcome on cognitive function than placebo (ADAS-cog: df = 1, F = 6.93, p = 0.01; CDR: df = 1, F = 16.87, p

Conclusions: Melissa officinalis extract is of value in the management of mild to moderate Alzheimer's disease and has a positive effect on agitation in such patients.

Ferulic acid

J Med Food. 2009 Feb;12(1):124-30. doi: 10.1089/jmf.2007.0646.
Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.
Kang KS, Tanaka T, Cho EJ, Yokozawa T.
Author information

Abstract
To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.

Nutr Neurosci. 2012 Jul 9. [Epub ahead of print]
Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.
Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.

Abstract
OBJECTIVES:
Ginseng has been reported to improve cognitive function in animals and in healthy and cognitively impaired individuals. In this study, we investigated the efficacy of a heat-processed form of ginseng that contains more potent ginsenosides than raw ginseng in the treatment of cognitive impairment in patients with moderately severe Alzheimer's disease (AD).

METHODS:
Forty patients with AD were randomized into one of three different dose groups or the control group as follows: 1.5 g/day (n = 10), 3 g/day (n = 10), and 4.5 g/day (n = 10) groups, or control (n = 10). The Alzheimer's Disease Assessment Scale (ADAS) and Mini-Mental State Examination (MMSE) were used to assess cognitive function for 24 weeks.

RESULTS:
The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up.

DISCUSSION:
These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

Geriatr Gerontol Int. 2011 Jul;11(3):309-14. doi: 10.1111/j.1447-0594.2010.00687.x. Epub 2011 Jan 28.

Effect of ferulic acid and Angelica archangelica extract on behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.
Kimura T, Hayashida H, Murata M, Takamatsu J.
Author information

Abstract
AIM:
The behavioral and psychological symptoms of dementia place a heavy burden on caregivers. Antipsychotic drugs, though used to reduce the symptoms, frequently decrease patients' activities of daily living and reduce their quality of life. Recently, it was suggested that ferulic acid is an effective treatment for behavioral and psychological symptoms. We have also reported several patients with dementia with Lewy bodies showing good responses to ferulic acid and Angelica archangelica extract (Feru-guard). The present study investigated the efficacy of Feru-guard in the treatment of behavioral and psychological symptoms in frontotemporal lobar degeneration and dementia with Lewy bodies.

METHODS:
We designed a prospective, open-label trial of daily Feru-guard (3.0 g/day) lasting 4 weeks in 20 patients with frontotemporal lobar degeneration or dementia with Lewy bodies. Behavioral and psychological symptoms of dementia were assessed at baseline and 4 weeks after the start of treatment, using the Neuropsychiatric Inventory. The Neuropsychiatric Inventory scores were analyzed using the Wilcoxon rank sum test.

RESULTS:
Treatment with Feru-guard led to decreased scores on the Neuropsychiatric Inventory in 19 of 20 patients and significantly decreased the score overall. The treatment also led to significantly reduced subscale scores on the Neuropsychiatric Inventory ("delusions", "hallucinations", "agitation/aggression", "anxiety", "apathy/indifference", "irritability/lability" and "aberrant behavior"). There were no adverse effects or significant changes in physical findings or laboratory data.

CONCLUSION:
Feru-guard may be effective and valuable for treating the behavioral and psychological symptoms of dementia in frontotemporal lobar degeneration and dementia with Lewy bodies.

Curcumin

Phytother Res. 2003 May;17(5):481-4.
In vitro peroxynitrite scavenging activity of diarylheptanoids from Curcuma longa.
Kim JE, Kim AR, Chung HY, Han SY, Kim BS, Choi JS.

Ayu. 2012 Oct;33(4):499-504. doi: 10.4103/0974-8520.110524.
Effects of turmeric on Alzheimer's disease with behavioral and psychological symptoms of dementia.
Hishikawa N, Takahashi Y, Amakusa Y, Tanno Y, Tuji Y, Niwa H, Murakami N, Krishna UK.
Author information

Abstract
We describe here three patients with the Alzheimer's Disease (AD) whose behavioral symptoms were improved remarkably as a result of the turmeric treatment, which is the traditional Indian medicine. Their cognitive decline and Behavioral and Psychological Symptoms of Dementia (BPSD) were very severe. All three patients exhibited irritability, agitation, anxiety, and apathy, two patients suffer from urinary incontinence and wonderings. They were prescribed turmeric powder capsules and started recovering from these symptoms without any adverse reaction in the clinical symptom and laboratory data. After 12 weeks of the treatment, total score of the Neuro-Psychiatric Inventory-brief questionnaire decreased significantly in both acuity of symptoms and burden of caregivers. In one case, the Mini-Mental State Examination (MMSE) score was up five points, from 12/30 to 17/30. In the other two cases, no significant change was seen in the MMSE; however, they came to recognize their family within 1 year treatment. All cases have been taking turmeric for more than 1 year, re-exacerbation of BPSD was not seen. The present cases suggest a significant improvement of the behavioral symptoms in the AD with the turmeric treatment, leading to probable benefit of the use of turmeric in individuals with the AD with BPSD.

None of these are cures for Alzheimer's disease (or other forms of dementia), but they give a person a better life with the disease. I know that work is being done to improve the uptake of these compounds and to determine appropriate dosing. I am not a chemist, but if I were I would be interested in developing synthetic peroxynitrite scavengers to treat Alzheimer's disease.

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10. Joe on January 23, 2014 1:05 PM writes...

How about something simpler, Lane, and in the macro: a loss of cellular architecture from lysyl oxidase signaling errors resulting in a cross linked mess - renormalize the LOXL and see what lights up - in other words, maybe the brain is one big scar after awhile - like old wrinkled papery thin skin that has undergone cross linking to such an extent it is nonfunctional (check out grandma) - skin and brain evolved from the same - and you will notice that women who have applied the most wrinkle cream have the worst skin over time - the induced inflammatory histology shows up in undesirable cross linking - and all of your biochem scenarios would be in that cascade of inflammation for lack of a better descriptor. Renormalize LOXL - could be a bumper sticker.

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11. Anonymous on January 23, 2014 1:41 PM writes...

Peroxynitrate blah blah pap blah...(here we go again)

I used to be interested in AD.

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12. Anonymous on January 23, 2014 2:01 PM writes...

@3: May as well bolt it onto their nose, then.

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13. biotechtoreador on January 23, 2014 3:34 PM writes...

Well, if you assume the market potential for an Alzheimer's drug is $20 billion, and that odds of success of the study are 10%, that means the product has an nPV of $2 billion. Assuming LLY pays $100 million fore the study and another $100 million to launch the drug they've made a $800 million profit....

Seriously, that is how MBAs would view this.

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14. Anonymous on January 23, 2014 5:11 PM writes...

13: It's not the math that's the problem, it's the assumptions. The probability that Lilly's drug will succeed is precisely zero, because the drug has already failed in Phase 3, along with every other drug of its kind. Even if by some miracle it did succeed, the FDA would never believe it and call a "fix". Its credibility has gone, period.

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15. MoMo on January 23, 2014 6:00 PM writes...

Of course its a Gloomy Update on Alzheimers results!

2 weeks ago everyone couldn't contain themselves critiquing/bashing the academic group with the polyfunctional molecule.

As I stated then and I will restate- Pharma has done a poor job here, wasting billions and billions of dollars- being focused on A TARGET when in fact the disease is MULTIFACTORIAL.

Everyone of you who bashed the Academics go stand in the corner with a Dunce Cap on Now!

No Bread Pudding for You!

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16. biotechtoreador on January 23, 2014 7:03 PM writes...

"13: It's not the math that's the problem, it's the assumptions."

No no, there's a study from The Tufts Center for the Study of Drug Development showing that ~60% of phase 3 studies succeed. Using my massive MBA brain I've risk adjusted this to reflect the greater risk in neurology, and combined it with a holistic interpretation of the phase 2 data to come up with 10% (it was actually 10.487%, but i rounded off). Now scurry along back to the lab, I have some projections to make on 2026 sales of a group of molecules our chemists have proposed to start work on.

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17. MB on January 23, 2014 11:47 PM writes...

Once again mechanism based 'science' fails. How many more billions do we have to flush down the toilet before we get over the fact that we aren't as smart as we think we are and that the sum of all that defines life is greater than its parts. The fact that a cocktail is being talked about reiterates this.

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18. pete on January 24, 2014 12:47 AM writes...

@17 MB
"Once again mechanism based 'science' fails."

Dumb-de-dumb-dumb -- Book 'em, Danno.

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19. Lane Simonian on January 24, 2014 11:03 AM writes...

This is an interesting quote regarding Eli Lilly's earlier trials with solanezumab:

Looking back at the data, researchers learned that as many as 25 percent of the people they were studying likely did not have Alzheimer's disease but some other form of de