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DBL%20Hendrix%20small.png College chemistry, 1983

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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« The Supreme Court Rules on Myriad | Main | One. . .Million. . .Pounds (For a New Antibiotic?) »

June 14, 2013

A Beta-Secretase Inhibitor Hits the Skids in Alzheimer's

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Posted by Derek

The brutal drumbeat of Alzheimer's clinical failure continues at Eli Lilly. After the Phase III failure of their gamma-secretase inhibitor semagacestat, and a delusional attempt to pretend that the anti-amyloid antibody solanezumab succeeded, now comes word that the company has halted studies of a beta-secretase inhibitor.

This one wasn't for efficacy, but for tox. The company says that LY2886721 led to abnormalities in liver function, which is the sort of thing that can happen to anyone in Phase II. There is that thioamidine thing in it, but overall, it's not a bad-looking compound, particularly by the standards of beta-secretase inhibitors. But what does that avail one? We'll never find out what this one would have done in a real Phase III trial, although (unfortunately) I know how I'd lay the odds, considering what we know about Alzheimer's drug in the clinic. Beta-secretase inhibitors are an even higher-stakes bet than usual in this field, because mechanistically they have pretty strong support when it comes to inhibiting the buildup of amyloid protein, but they also have clear mechanistic liabilities: the enzyme seems to be important in the formation of myelin sheaths, which is not the sort of thing you'd want to touch in a patient population that's already neurologically impaired. Which effect wins out in humans? Does a BACE inhibitor really lower amyloid in the clinic? And does lowering amyloid in this way really affect the progression of Alzheimer's disease? Extremely good questions, all of those, and the only way to answer them is to round up a plausible drug candidate (not so easy for this target), half a billion dollars (for starters) and try it out.

This failure makes Lilly perhaps the first company to achieve a dread milestone, the Amyloid Trifecta. They have now wiped out on beta-secretase, on gamma-secretase, and on antibody therapy. And you know, I have to salute them for it. They've been making a determined effort against a terrible disease, trying all the most well-founded means of attack, and they're getting hammered into the ground like a tent peg for it. Alzheimer's. At the rate things are going, Lilly is going to end up in a terrible position, and a lot of it has to do with battering themselves against Alzheimer's. Remember this next time someone tells you about how drug companies are just interested in ripping off each other's baldness cures or something.

Comments (30) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


COMMENTS

1. rab on June 14, 2013 7:51 AM writes...

The problem is the mechanistic black hole at the heart of AD. Without an idea of the biology, there are no reliable surrogate markers, and therefore no reliable clinical trials.
For all we know, by the time that symptoms become clinically apparent, the therapeutic window of opportunity might be long closed.
It's difficult to think of a logical way forward without massive, longitudinal human studies and some major effort to find an animal model.

I agree with Derek that Lilly needs to be applauded for taking this on, but if I were a shareholder, perhaps I wouldn't have this view.

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2. The Aqueous Layer on June 14, 2013 8:20 AM writes...

Like repeatedly trying to take a Medieval fortress with only infantry, there is a fine line between bravery and stupidity.

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3. PPedroso on June 14, 2013 8:23 AM writes...

Excellent post Derek!

I will use it in my discussions with non-pharma colleagues! :)

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4. Z on June 14, 2013 8:23 AM writes...

What did Derek mean when he said "There is that thioamidine thing in it ..."?

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5. Puff the Mutant Dragon on June 14, 2013 8:42 AM writes...

Second #1. You can't make any progress with Alzheimer's until you have a solid idea what's actually going on biologically. Nobody does. Mounting a drug discovery program against Alzheimer's at this point (where we still don't understand the biology) makes as much sense to me as mounting a manned expedition to the Andromeda Galaxy. Heroic, but unlikely it'll get there anytime soon...

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6. Carlos on June 14, 2013 9:07 AM writes...

Totally agree. We should be applauding pharma for even trying. We've made the same point on our blog as well.

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7. Cesare Ragazzi on June 14, 2013 9:09 AM writes...

What if amyloid buildup is a beneficial adaptive response that keeps the brain working long after its time is past due in face of something else going wrong (aging, cholesterol dishomeostasis)? Amyloid buils up 20 yearsbefore clinical onset! I wonder if the liver tests problems were due to lipid accumulation (like they see in the retina with this class of compounds)

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8. Lane Simonian on June 14, 2013 10:46 AM writes...

Three great myths about Alzheimer's disease. First after three decades of research we know nothing about the disease. Second past a certain point it is irreversible. Third amyloid oligomers or plaques are the cause of Alzheimer's disease.

Alzheimer's is caused by a potent oxidant called peroxynitrite. The oxidative and nitrative damage caused by peroxynitrites is partially reversible. Peroxynitrite scavengers convert peroxynitrites into a nitrite anion and water (water is a de-nitrating agent). The nitrite anion combines with hydrogen peroxide to form more peroxynitrites and water. Eventually, the body's antioxidant systems become exhausted in this cycle.

Amyloid oligomers increase the conversion of superoxide anions to hydrogen peroxide by attracting copper and zinc (the enzyme which converts superoxide anions into hydrogen peroxide depend upon copper and zinc). The iron ions in the oligomers can convert nitrite anions into nitrite which can directly nitrate critical proteins in the brain. As plaques aggregate they entomb copper and zinc, so that nearly all of the superoxide anions combine with inducible nitric oxide to form peroxynitrites. So amyloid oligomers and plaques may play some role in peroxynitrite-mediated damage, they are neither the main cause of peroxynitrite formation (which is p38 MAPK)and thus they are not the main cause of Alzheimer's disease.

All peroxynitrite scavengers ever studied have to one degree or another ameliorated Alzheimer's disease either in vitro, in animals, or in human beings. The ones that have done so in human beings are eugenol in rosemary essential oil (via aromatherapy), eugenol and ferulic acid in a lemon balm (Melissa officinalis) extract, and ferulic acid, syringic acid, and vanillic acid in heat-processed ginseng.

Go after the right target and Alzheimer's disease becomes much easier to treat.

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9. Lane Simonian on June 14, 2013 10:46 AM writes...

Three great myths about Alzheimer's disease. First after three decades of research we know nothing about the disease. Second past a certain point it is irreversible. Third amyloid oligomers or plaques are the cause of Alzheimer's disease.

Alzheimer's is caused by a potent oxidant called peroxynitrite. The oxidative and nitrative damage caused by peroxynitrites is partially reversible. Peroxynitrite scavengers convert peroxynitrites into a nitrite anion and water (water is a de-nitrating agent). The nitrite anion combines with hydrogen peroxide to form more peroxynitrites and water. Eventually, the body's antioxidant systems become exhausted in this cycle.

Amyloid oligomers increase the conversion of superoxide anions to hydrogen peroxide by attracting copper and zinc (the enzyme which converts superoxide anions into hydrogen peroxide depend upon copper and zinc). The iron ions in the oligomers can convert nitrite anions into nitrite which can directly nitrate critical proteins in the brain. As plaques aggregate they entomb copper and zinc, so that nearly all of the superoxide anions combine with inducible nitric oxide to form peroxynitrites. So amyloid oligomers and plaques may play some role in peroxynitrite-mediated damage, they are neither the main cause of peroxynitrite formation (which is p38 MAPK)and thus they are not the main cause of Alzheimer's disease.

All peroxynitrite scavengers ever studied have to one degree or another ameliorated Alzheimer's disease either in vitro, in animals, or in human beings. The ones that have done so in human beings are eugenol in rosemary essential oil (via aromatherapy), eugenol and ferulic acid in a lemon balm (Melissa officinalis) extract, and ferulic acid, syringic acid, and vanillic acid in heat-processed ginseng.

Go after the right target and Alzheimer's disease becomes much easier to treat.

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10. anon on June 14, 2013 10:48 AM writes...

Just for the record, you don't need to do a half-billion dollar study to tell if these drugs reduce aB plaque, or if aB is correlated with dementia. Lilly owns the IP for doing PET scans to detect the levels of both aB and tau in the human brain. I expect that Lilly will soon have a huge advantage over the competition in terms of data...

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11. NMH on June 14, 2013 11:05 AM writes...

Is there a reference for nitrosylation of neuronal proteins in Alzheimers patients?

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12. drug_hunter on June 14, 2013 11:38 AM writes...

Just to put my biases on the table, I notice that Lane Simonian is also a fan of aromatherapy, which makes me a tad more skeptical of anything else he says...

Having said that, I echo #11 (NMH) -- I would like to know more about the evidence for the role of peroxynitrite. Certainly an interesting hypothesis.

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13. Hap on June 14, 2013 12:53 PM writes...

@4: The core of LY2886721 is a furo[3,4-d]thiazinone imine - the thiazinone imine can also be seen as an amidine with the C-alkyl group replaced with an alkylthio group (sometimes it's also called an isothiourea).

If peroxynitrite is causing also Alzheimer's (which seems like a pretty strong statement with the current evidence), wouldn't one expect that Alzheimer's would be associated with other diseases involving oxidative damage?

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14. Anonymous on June 14, 2013 2:50 PM writes...

Just to point out, there was a time when drug discovery was done without any knowledge of the biological target. Heck, there was a time when effective treatments were identified without even knowing what was in the extract. Insulin comes to mind. Lithium is still one of te best treatments for bipolar disorder and the mechanism/target is not fully understood. Lilly and all the other players are testing or at least attempting to test a valid hypothesis. I am sure their shareholders are aware of this.

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15. Marc on June 14, 2013 3:15 PM writes...

They could be forgiven if it was the first time the amyloid hypothesis had failed. I don't think they deserve any credit for being so hell bent on beating a dead horse.

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16. bank on June 14, 2013 4:55 PM writes...

Lilly also has a long-standing program investigating apoE4 in Alzheimer's disease. Some of the people involved in ReXceptor (which is investigating bexarotene) are funded by Lilly. The recent reports in Science on that approach didn't look very encouraging either.

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17. Starlie Wiggel on June 14, 2013 7:17 PM writes...

Never underestimate a McCarthyite. It's cheap to live like a king in Indy, and nobody in bldg 73 wants to give up being the smartest person in the neighborhood, which is what would happen if they had to leave flyover land.

Big Red is undoubtedly working like hell in D.C. to get the FDA to redefine success in a phIII AD trial. After that, a certain ineffective/potentially dangerous antibody will be just one wobbly set of clinical trial endpoints away from approval.

Anyone else remember the "Lilly amendment" in the Homeland security act? Nothing is impossible when you own a few congressmen.


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18. 5-ht on June 14, 2013 8:44 PM writes...

For heaven's sake, this isn't an indictment of the amyloid hypothesis or anything near to it. It failed because of liver tox... Another failure, yes, and the drumbeat continues. But it doesn't have anything to do with the target.

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19. Anonymous BMS Researcher on June 14, 2013 8:44 PM writes...

I recall at a Keystone Conference on AD and related diseases one speaker's first slide had boxes with labels like "Amyloid plaque," "mitochondrial dysfunction," "loss of synapses," etc., etc.

He said "I think we have many of the BOXES, but we still don't have the ARROWS," by which he meant although we know the pathological effects in considerable detail we still know far too little about cause and effect.

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20. 5-ht on June 14, 2013 8:45 PM writes...

For heaven's sake, this isn't an indictment of the amyloid hypothesis or anything near to it. It failed because of liver tox... Another failure, yes, and the drumbeat continues. But it doesn't have anything to do with the target.

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21. Nick K on June 14, 2013 10:56 PM writes...

Could someone translate what #17 Starlie Wiggel posted?

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22. Starlie Wiggel on June 15, 2013 12:33 AM writes...

http://www.nytimes.com/2013/03/14/health/fda-to-ease-alzheimers-drug-approval-rules.html?pagewanted=all&_r=0

Indianapolis is closer to D.C. than you think, and a certain antibody program is closer to approval than it appears.

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23. Oligodendrocyte expert on June 15, 2013 3:14 AM writes...

@14 (and @18): Calling the Amyloid Hypothesis "valid" is charitable, at best.

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24. TX raven on June 15, 2013 8:07 AM writes...

So, for how many CNS diseases can we say we understand their mechanisms?

I think the answer is: "not too many".

Should we then give up the search for a treatment?

In the end, these are all expensive experiments. If we get lucky, we can help patients and investors.
If we don't get lucky, but do good science, we may just learn something so that the next drug might, maybe, have a better chance to work.

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25. Lane Simonian on June 15, 2013 10:28 AM writes...

I apologize for the late response,as I have been on the road. Here are three of the most important citations for peroxynitrites and Alzheimer's disease:

Mark A. Smith, et al. Widespread-peroxynitrite mediated damage in Alzheimer's disease.

YJ Zhang, et al. Peroxynitrite induces Alzheimer's-like tau modifications in rat brain and underlying mechanisms.

T Alkam, et al. A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta 25-35.

Oxidation or nitration by peroxynitrites also contributes to tissue damage, inflammation, poor glucose transport, damage to g protein-coupled receptors involved in short-term memory, sleep, mood, smell, social recognition, and alertness, decreased synthesis of neurotransmitters such as acetylcholine,dopamine, and serotonin,and the efflux of glutamate and the influx of calcium which kills brain cells.

Many other other diseases have been linked to peroxynitrites, including several other neurodegenerative diseases. They differ in part because peroxynitrites target different parts of the body and based on the protein or proteins targeted such as diabetes outside of the brain and the nitration of the insulin receptor substrate.

The number of studies on peroxynitrites and Alzheimer's disease pale in comparison to the studies on amyloid but in the end these studies may turn out to be much more important.

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26. Anonymous on June 16, 2013 3:04 AM writes...

Poor Lilly... Even more to the point, poor AD patients. Still not sure about this amyloid thing. There is some work in yeast in which switching to an amyloidogenic state confers resistance against various anti-fungals.
Also the role of APP in general is not well understood: it is up-regulated in various cancers, has 3 splice variants and the non-amyloid part acts as a gene transcription factor after cleavage.....

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27. expert on June 16, 2013 9:55 AM writes...

This post is not up to Derek's standard - informed, balanced, thoughtful. Some of the comments on this post belong on Café Pharma. The fact that Lilly's BACE inhibitor failed due to liver toxicity (likely off target) has absolutely nothing to do with the hypothesis that Abeta accumulation plays an early and critical role in the pathogenesis of AD, which cannot be disproved by testing drugs that lower Abeta generation in patients whose brains are already full of amyloid.

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28. Tim Bates on September 28, 2013 11:34 AM writes...

A beta secretase inhibitor is a rational thing to try for AD therapy. We showed a concentration specific inhibition of mitochondrial cytochrome c oxidase activity (Canevari, Laura and Clark, John B. and Bates, Timothy E. (1999) Beta-amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria. FEBS Letters, 457 (1). pp. 131-134). Decreased complex IV activity is seen in AD brain in regions of pathology, linking mitochondrial dysfunction and amyloid toxicity (cited 129 times). I wish AD research was as advanced in the UK then (1999) as it was in the USA. I wanted to continue this work but could not get funding! Kids at School and a Mother with AD have prevented me moving countries to pursue this work.

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29. London Fields on March 16, 2014 3:42 PM writes...

Lane Simonian shows up on Alzheimer forums all over the web with the same shtick….reeling off a list of putative chemical reactions and doing so in an utterly mind-numbing, apoplexy-inducing way seeming to know chemistry but in fact knowing nothing of it. (One does not describe chemical reactions with dense run-on sentences). He does an intellectual rain dance always to lead to the same upshot….the magic potions are the cure for Alzheimers. Whiff of rosemary, a pinch of snorted lemon balm. This is exquisite poppycock and total nonsense. Either he believes it, in which case he cannot be taken seriously, or else he does not believe it and should not be listened to. He is not a scientist or clinician. He is a pseud masquerading as an intellectual. He is a single issue advocate who surfaces everywhere with the same refrain….peroxynitrite blah blah blah,….kinase ahem….scavengers…….cell damage….uhh….more peroxynitrite….superoxide….yeah, that sounds right….rosemary! Aromatherapy! He lulls the reader into boredom with his chemical incantations and just when he has lost them and caused them to want to skip on, prescribes eye of newt. Shame on forums for leaving his fatuous musings posted, and shame on American minds for letting themselves be scammed by pseudoscience.

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30. Lane Simonian on May 3, 2014 12:18 AM writes...

Mostly wrong. Once again someone with a supposedly scientific mind takes pot shots at a hypothesis that has the support of some of the best Alzheimer's researchers of the past twenty years. They don't believe the science, they through red herrings at the clinical trials, they hurl insults at me because they cannot constructively argue with the science itself.

Let's do it sequentially and see if you can follow along.

High levels of myo-inositol levels lead to high levels of phosphatidylinositol 3,4 biphosphate. The conversion of phosphatidylinositol 3,4 biphosphate into phosphatidylinositol 3,4,5 biphosphate leads to the neuroprotective Akt pathway. Otherwise it is converted by phospholipase C into a pathway that leads to Alzheimer's disease. Ok, the proof of this so far:

Comparison of patients with progressive disease versus those who developed AD for the cingulate gyrus showed the increased myo-inositol-to-water ratio to be 72% predictive for dementia; similarly for the hippocampus, it was 70% predictive for dementia.

The researchers also suspect that high levels of myo-inositol could play a role in predisposing people with Down syndrome to early-onset Alzheimer's disease.

The molecule is known to promote the formation of amyloid plaques - a hallmark of Alzheimer's.

Together, our data indicate that the neuroprotective role of PS1
depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote
neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling
may be beneficial to FAD patients.

These results suggest that the increased levels of PLCgamma, by increasing the hydrolysis of PIP2 in the hippocampus and SMTG, may contribute to pathophysiology of AD. These results also support a role for excitatory neurotransmitters and their receptors in AD.

Step two: phospholipase C leads to the production of diacylglycerol which activates protein kinase C which leads to the activation of p38 MAPK. P38 MAPK generates superoxide anions and inducible nitric oxide which combine to produce peroxynitrites. Peroxynitrites stimulate beta secretase which leads to the c-terminal fragment of the amyloid precursor protein (the phospholipase C stimulation of inositol 1,4,5 triphosphate leads to the release of intracellular calcium which induces the next cut in the amyloid precursor protein leading to amyloid oligomers and plaques). Now the simple evidence for this.


Protein Kinase C Activation Increases Release of Secreted Amyloid Precursor Protein without Decreasing Ab Production in Human Primary Neuron Cultures.

Our results suggest that activated p38 MAPK may serve as a potential signaling molecule in ONOO(-) generation through dual regulatory mechanisms, involving iNOS induction and NADPH oxidase activation.

These novel NO-mediated regulatory mechanisms likely protect BACE1 from being further oxidized by excessive oxidative stress, as from H2O2 and peroxynitrite which are known to upregulate BACE1 and activate the enzyme, resulting in excessive cleavage of APP and Aβ generation; they likely represent the crucial house-keeping mechanism for BACE1 expression/activation under physiological conditions.

Peroxynitrites nitrate NMDA receptors leading to an influx in calcium which activates p38 MAPK which leads to the further production of peroxynitrites.

These data demonstrate that PN-mediated apoptosis depends on the p38 pathway and that p38 mediates deactivation of AKT survival pathways possibly by the involvement of PP2A.

Now stay with me through the evidence that compounds that inhibit the formation and scavenge peroxynitrites treat Alzheimer's disease.

Brains from subjects who have Alzheimer's disease (AD) express inducible nitric oxide synthase (iNOS). We tested the hypothesis that iNOS contributes to AD pathogenesis. Immunoreactive iNOS was detected in brains of mice with AD-like disease resulting from transgenic expression of mutant human beta-amyloid precursor protein (hAPP) and presenilin-1 (hPS1). We bred hAPP-, hPS1-double transgenic mice to be iNOS(+/+) or iNOS(-/-), and compared them with a congenic WT strain. Deficiency of iNOS substantially protected the AD-like mice from premature mortality, cerebral plaque formation, increased beta-amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of beta-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

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.


Now specific compounds that inhibit peroxynitrite formation.

Eugenol in various essential oils and plants.

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.


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.

Ferulic acid, syringic acid, and vanillic acid in heat-processed ginseng.

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.

Now you tell me where the pseudoscience is in any of this. Either people have a financial stake in the amyloid hypothesis of Alzheimer's disease or they are unable being highly-trained scientists (and thus ideologically shaped)to accept the capacity of natural products to treat Alzheimer's disease or they are extreme skeptics for which no amount of evidence is sufficient. All I can do is to present the evidence. If people don't like the evidence shame on them, not shame on me.


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