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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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April 9, 2014

The State of Alzheimer's Research, 2014

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Posted by Derek

Via Bernard Munos on Twitter, here's a report from the New York Academy of Sciences looking at the current state of Alzheimer's research. Those various tabs are all live; you can get summaries of each one by clicking.

Looking them over breeds a mixture of hope and despair. The whole thing is themed around the 2025 target that many in the Alzheimer's world have been talking about. And while I understand the need for goals, etc., that year seems way too close. If a promising new compound were to be discovered this afternoon, it wouldn't make it. That brings up another point - many of the speakers at this meeting were talking about moving away from a "compound-centric" point of view. I can see (some of) the point, because there may well be other things to do for Alzheimer's patients. But it's also worth remembering that the reason people are talking like this is that no compounds have worked. This outlook is a second choice driven by necessity, not by some sort of obvious first principle.

And I think that, in the end, Alzheimer's will be arrested by compounds - more than one, most likely, and some of them are quite possibly going to be biomolecules, but compounds all the same. Reading the recommendations about adaptive clinical trials (good idea), broader cooperation and use of common clinical standards (another good idea), and all the others just make me wonder: clinical trials of what? That's the real stumper in this field; where to go next. How to go there is a topic that it's easier to reach agreement on.

Comments (42) + TrackBacks (0) | Category: Alzheimer's Disease


COMMENTS

1. Anonymous on April 9, 2014 11:28 AM writes...

DL - What are your thoughts on the current state of the amyloid theory ? Jury still out? Is beta/gamma secretase inhibitor development tail chaising?

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2. Cato the Elder on April 9, 2014 12:51 PM writes...

"the worldwide costs of AD and related disorders (ADRD) were estimated at $604 billion, or 1% of GDP".

what? this number seems waaay to high. I'm curious what all they have lumped in with Alzheimer's to reach this number.

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3. Cato the Elder on April 9, 2014 12:52 PM writes...

*too

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4. Imaging guy on April 9, 2014 1:14 PM writes...

#Cato the Elder
These numbers are highly conjectural. If you sum the economic costs attributed to different diseases, the total would be 20 to 30 times higher than the combined GDP of the world. They are generally used in constructing a sentence for the introductory section of the manuscripts.

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5. exGlaxoid on April 9, 2014 1:48 PM writes...

Wait until you have a parent or loved one with it. The minimum cost of the simplest care for someone with early Alzheimer's is about $2000 / month, once they get less able to care for themselves, it can rise to $4000-6000 per month. I have known quite a few people that needed that level of care for 2-5 years. That adds up fast and uses up people's savings quickly, and medicaid spending is going up rapidly due to it as well. It could easily cost that much worldwide, although much of that cost is likely in the US.

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6. Chemjobber on April 9, 2014 2:21 PM writes...

@4: So true.

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7. Anonymous on April 9, 2014 3:43 PM writes...

Indeed, lost productivity of full time care workers is by far the biggest cost. Consequently AD can easily cost USD 200,000 per patient per year, often for 5 to 10 years per patient. I'd rather die from cancer (or euthanasia) than inflict this kind of burden on my family and society when I go...

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8. Lane Simonian on April 9, 2014 3:52 PM writes...

I am going to repeat my favorite quote about peroxynitrites and Alzheimer's disease and then present the results of clinical trials using peroxynitrite scavengers to treat Alzheimer's disease.

[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...]

Ferulic acid, syringic acid, vanillic acid, maltol, and p-coumaric acid in Panax ginseng (most highly concentrated in heat-processed ginseng).

Abstract
A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer’s disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer’s Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer’s disease.

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.

Eugenol in rosemary and lemon balm essential oil and geraniol in lemon essential oil for cognition, and linalool in orange, lavender, and lemon balm essential oil (for behavior)

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 aromatherpay 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 aromatherpay, 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 aromatherpay, 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.


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.

These are among the only clinical trials in which cognitive decline in Alzheimer's patients have been partially reversed and in which that reversal has been sustained. We can spend several more decades working on amyloid or tau or we can begin attacking what causes the disease.

Permalink to Comment

9. emjeff on April 9, 2014 5:39 PM writes...

Your statement about a compound discovered today not making the 2025 goal is an indictment of the current state of drug development. It's too damn complicated and takes far too long.

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10. Mike C on April 9, 2014 6:33 PM writes...

@ #9: An 11 year development period is optimistic even in an ideal environment when you consider the drug may have to be administered several years in advance of symptoms for it to show efficacy. 10 year trials anyone?

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11. Anonymous on April 10, 2014 2:42 AM writes...

Why do we continue to research target specific small molecules for systems biology problems like AD? We need molecules that target critical signaling or metabolic bottlenecks. Inhibiting something like oglcnacase (thiamet G) is going to be much more powerful than any molecule that only targets one pathway/cascade/protein. AD has been labeled as type 3 diabetes, and I'd bet everything from amyloid plaques, taus, etc etc are all secondary to one of the real primary drivers of AD- altered state of metabolism - that is a near universal feature of AD. DNA meh. Proteome meh. The next 100 years of biology are going to be focused on post translational modifications which take such a small genome and small proteome to generate the millions and millions of distinct molecular species that truly define the complexity of life. Ptm patterns, virtually all of them, are very reflective of cellular metabolic state. In a disease like AD, which is almost always accompanied by impaired glucose metabolism, you can therefore expect systems wide changes to occur in ptms which will profoundly alter pretty much every protein and genetic event in a cell with AD. Targeting specific proteins, receptors, or cascades isn't going to work. You need a systems solution which is going to involve some aspect of metabolism. A lead like thiamet G has begun to address this.

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12. sepisp on April 10, 2014 3:27 AM writes...

Why Alzheimer isn't cured is a mystery to me. I can understand the victim blaming that went on for decades with Helicobacter pylori-induced ulcers, since the symptom was nonspecific and clinicians had no idea the cause could even come from that direction. But, in this case, we have patients that display obvious symptoms, and there is also a distinctive microscopic finding identifying the disease. When the cause is identified, I think the change will be as dramatic as with tuberculosis vs. antibiotics or even with smallpox vs. vaccine. The cause is what is missing, not new drugs, yet.

That said, very few mental disorders or diseases of the brain have actual cures, drugs being only for management of symptoms; for instance, schizophrenia.

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13. Morten G on April 10, 2014 4:15 AM writes...

@13 Off-topic but mental diseases aren't all chronic.

So what are the alternatives to small-molecule therapy?
Inducing autophagy?
The dietary interventions that improve glucose sensitivity?

Permalink to Comment

14. simpl on April 10, 2014 4:28 AM writes...

Quick non-compound solutions (i.e. before 2025)
#12 caffein as a matabolism booster is already available
For Derek's more ambitious program, heat seaweed in a wok with fish oil (not to excess, it doesn't taste too good), then quench with cola to phosphorylate the lipids. Now, who has a seaweed library, and is anybody hungry? More seriously, isn't this why epidemologists have been looking at the Mediterranean diet?

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15. UK Chemist on April 10, 2014 6:41 AM writes...

#9
So how do propose to speed it up exactly.

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16. Anonymous BMS Researcher on April 10, 2014 6:53 AM writes...

Imaging guy says "total..higher than the combined GDP of the world. They are generally used in constructing a sentence for the introductory section of the manuscripts..."

And we all quote each others' Intro sections!

I am reminded of the calculation some news reporter made during the 1973 Yom Kippur War -- he added up Arab claims for the numbers of Israeli aircraft shot down, pointing out that (1) the total vastly exceeded the number of planes Israel had when the war started and (2) Israeli planes were still flying.

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17. Lyle Langley on April 10, 2014 7:09 AM writes...

@12, sepisp...
"That said, very few mental disorders or diseases of the brain have actual cures, drugs being only for management of symptoms; for instance, schizophrenia."

I think you could make the argument that even management of symptoms in diseases such as SZ is not done well.

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18. exGlaxoid on April 10, 2014 9:19 AM writes...

#9, #11, #12, etc, Would all of the people complaining that drug development is too slow please give their solution and please cure all known illnesses within the next 2 years? Given the FDA's unwillingness to take any risks, the army of lawyers that sue everyone who sells any new drug or medical device, and the greed of everyone throughout the process, I don't know how any drugs make it through the process now.

If we found a solution to AZ in the next 10 years I would be astounded, but that does not mean we should not keep trying, as it will eventually be figured out, but it may take trying many ideas before it does. I would like it to be figured out soon, as AZ runs in the family, and I am not getting younger each year.

As for metabolism, Avandia was going into AZ trials when the overzealous people completely screwed that up, and it looked as good as anything else I have seen. Yes it had side effects, like every other drugs, but they were not worse than most any other drug, and it showed real potential.

The sad part is that a Pihkal type approach where many scientists test their own ideas on themselves might be faster than the current process of doing trials, which is going to take 5-10 years per compound, and only a few are tested per year, mostly on young, healthy people, which is not very helpful.

Permalink to Comment

19. Harrison on April 10, 2014 10:10 AM writes...

@12, The AD field spent years chasing AB plaques. In the end those drugs might be the equivalent of a drug that removes chicken pox scabs.

@18, Unless you have some inside information, Rosiglitazone failed it's Phase II trial. The original signal was observed in a sub-population based on apoE genotype and which was not subsequently replicated. Don't worry, though, because Pioglitazone is going into an MCI trial run by the same people despite it's less-than-stellar brain penetration. Another metabolic target, HSD-1 also failed in a Phase II AD study, and the jury is still out on Inhalable Insulin.

Permalink to Comment

20. Lane Simonian on April 10, 2014 11:10 AM writes...

#14 Mediterranean diet, epidemiology, and Alzheimer's disease.

Neurology. 2007 Sep 11;69(11):1084-93.
Mediterranean diet and Alzheimer disease mortality.
Scarmeas N1, Luchsinger JA, Mayeux R, Stern Y.

Abstract
BACKGROUND:
We previously reported that the Mediterranean diet (MeDi) is related to lower risk for Alzheimer disease (AD). Whether MeDi is associated with subsequent AD course and outcomes has not been investigated.

OBJECTIVES:
To examine the association between MeDi and mortality in patients with AD.

METHODS:
A total of 192 community-based individuals in New York who were diagnosed with AD were prospectively followed every 1.5 years. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of mortality in Cox models that were adjusted for period of recruitment, age, gender, ethnicity, education, APOE genotype, caloric intake, smoking, and body mass index.

RESULTS:
Eighty-five patients with AD (44%) died during the course of 4.4 (+/-3.6, 0.2 to 13.6) years of follow-up. In unadjusted models, higher adherence to MeDi was associated with lower mortality risk (for each additional MeDi point hazard ratio 0.79; 95% CI 0.69 to 0.91; p = 0.001). This result remained significant after controlling for all covariates (0.76; 0.65 to 0.89; p = 0.001). In adjusted models, as compared with AD patients at the lowest MeDi adherence tertile, those at the middle tertile had lower mortality risk (0.65; 0.38 to 1.09; 1.33 years' longer survival), whereas subjects at the highest tertile had an even lower risk (0.27; 0.10 to 0.69; 3.91 years' longer survival; p for trend = 0.003).

CONCLUSION:
Adherence to the Mediterranean diet (MeDi) may affect not only risk for Alzheimer disease (AD) but also subsequent disease course: Higher adherence to the MeDi is associated with lower mortality in AD. The gradual reduction in mortality risk for higher MeDi adherence tertiles suggests a possible dose-response effect.

#11 Alzheimer's disease has been called but is not a type 3 diabetes. High levels of glucose (pre-dabetic or diabetic) lead to high levels of myo-inositol in the brain. High blood pressure due to high sodium levels and Down syndrome lead to high levels of myo-inositol in the brain. All are risk factors for Alzheimer's disease. Myo-inositol leads to peroxynitrites and amyloid. Elements/compounds such as lithium and scyllo-inositol limit myo-inositol formation. Ferulic acid binds to myo-inositol. The latter is the safest compound to limit the effects of myo-inositol.


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.

Reducing concentration

Lead researcher Professor Declan Murphy said: "We have shown in this study that adults with Down's syndrome have a significantly higher concentration of myo-inositol in the hippocampal region of their brains, and this increase is associated with a reduced cognitive ability.

"We are now carrying out more studies to see if we can reduce the concentration of myo-inositol in the brains of people with Down's.

"We hope that if we can do this, it will be a new way of treating this devastating disorder."


Alzheimer's disease is not insulin resistance in the brain (although peroxynitrites contribute to insulin resistance), it is likely the result of the disruption of glucose transport and metabolism caused by peroxynitrites (or its lipid peroxidation product HNE).

Impairment of Glucose and Glutamate Transport and Induction of Mitochondrial Oxidative Stress and Dysfunction in Synaptosomes by Amyloid β-Peptide: Role of the Lipid Peroxidation Product 4-Hydroxynonenal


#1, #12 Beta-secretase activation is likely caused by peroxynitrite and hydrogen peroxide oxidation of cysteine and occurs primarily within lipid rafts (which explains the recent study linking particular lipid markers with Alzheimer's disease).

Mol Neurodegener. 2011 Mar 3;6:17.
Differential regulation of BACE1 expression by oxidative and nitrosative signals.
Kwak YD1, Wang R, Li JJ, Zhang YW, Xu H, Liao FF.

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.

Work upstream of beta-secretase and early on you have a chance to stop the progression of Alzheimer's disease. By contrast, inhibiting beta-secretase itself likely does no good. Hopefully, the drug companies trying to develop beta-secretase inhibitors are working upstream of BACE1.

Gamma secretase is controlled by intracellular calcium levels and makes little difference in the progression of Alzheimer's disease. It leads to amyloid oligomers and plaques and may increase levels of peroxynitrites but is not required for Alzheimer's disease. It is possible to have Alzheimer's disease only with the c-terminal fragment of the amyloid precursor protein which is caused in part by the peroxynitrite activation of BACE1.

J Neurochem. 2001 Jul;78(1):109-20.
C-terminal fragment of amyloid precursor protein induces astrocytosis.
Bach JH1, 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 [order mixed up, but otherwise perfect anaylsis].

Efforts to treat Alzheimer's disease by reducing levels of amyloid plaques, oligomers (see recent PRANA Pbt2 study), or gamma secretases should be dead. Efforts to treat Alzheimer's disease by inhibiting beta secretase will likely not succeed unless they are working upstream of BACE1.

Plant compounds such as ferulic acid limit the damage done by myo-inositol, inhibit the production of peroxynitrites, scavenge peroxynitrites, and reverse part of their damage. They have been highly successful in reducing neuropsychiatric problems in people with Alzheimer's disease and other forms of dementia. Combine ferulic acid with more bioavailable peroxynitrite scavengers such as eugenol in various essential oils or vanillic acid and syringic acid in heat-processed ginseng and you can partially reverse cognitive decline in Alzheimer's disease. The studies showing this are small, but the results don't lie and they make perfect sense once the biochemistry behind Alzheimer's disease is understood.

Permalink to Comment

21. anon on April 10, 2014 12:14 PM writes...

One of the biggest hurdles I see in treating AD is detecting it early enough and being able to distinguish it readily from other types of dementia. While analogues such as florbeptir appear promising, their predictive potential for AD has yet to be determined and there are other issues that remain to be resolved. Even establishing florbetapir is going to take many more years and I am not terribly optimistic.
Secondly, intervening with a disease modifying drug is going to require long-term clinical trials. Given the state of funding for AD and/or pharma being willing to attempt such a trial given its cost, I really don't see anything happening.

Permalink to Comment

22. Anonymous on April 10, 2014 12:46 PM writes...

@20

Myo-inositol is biosynthesis is a branch off of primary glycolytic metabolism. MIPS, which is highly regulated and likely impaired in diseases such as AD, cancer, or diabetes, transforms glucose-6-phosphate into 1D-myo-inositol-3-p. Also, many, many, if not all of the effectors that utilize inositol derived messengers are modified by O-GlcNAc, which is also a product of metabolic states. AD is almost always accomanied by lower rates of glucose metabolism. O-GlcNAc modification of almost all intracellular proteins is going to be perturbed. On top of that, many of the precursors used for protein glycosylation, which is absolutely critical for correct protein folding, are derived also from pathways that branch from glycolysis. Is it surprising then that unfolded proteins are a problem in a disease like AD, when you have depressed glucose/glycolytic metabolism. Glucose receptors themselves are glycosylates--glycans can affect their transport, half life, and even total amount of GLUT transporters on the surface. Primary glucose metabolism cross talks with an insane amount of signaling cascades, DNA events, and protein functions.


Part of the problem as well is the fact that many of the scientists that are at companies and in positions of power are not trained or don't even know about the most up to date cell biology. Systems problems need systems approaches, such as attacking altered metabolic states.

Permalink to Comment

23. Harrison on April 10, 2014 2:24 PM writes...

@20: Scyllo-inositol failed to improve core AD symptoms in a 78-week Phase 2 study:

A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease.
Salloway S, Sperling R, Keren R, Porsteinsson AP, van Dyck CH, Tariot PN, Gilman S, Arnold D, Abushakra S, Hernandez C, Crans G, Liang E, Quinn G, Bairu M, Pastrak A, Cedarbaum JM; ELND005-AD201 Investigators. Neurology. 2011 Sep 27;77(13):1253-62. doi: 10.1212/WNL.0b013e3182309fa5. Epub 2011 Sep 14. PMID:21917766[PubMed - indexed for MEDLINE]

However, in a subsequent post-hoc analysis it did appear to decrease agitation and aggression (AAIC, 2013).

Permalink to Comment

24. Lane Simonian on April 10, 2014 2:41 PM writes...

# 22 Oxidation and nitration may be one of several factors affecting glucose metabolism and transport. Other factors may indeed also be involved in Alzheimer's disease.

High glucose levels in the brain is one of the factors that likely leads to increased myo-inositol levels in the brain during Mild Cognitive Impairment and early Alzheimer's disease. The oxidation and nitration of tyrosine receptor kinases and g protein-coupled receptors later often limits the production of inositol 1,4,5 triphosphate via phospholipase C beta and gamma and the recycling of myo-inositol. However, several factors can independently activate g proteins and thus phospholipase C beta including aluminium fluoride, sodium fluoride, and perhaps stress. In people with Alzheimer's disease who continue to have high levels of myo-inositol, various neuropsychiatric problems are present.


Elan’s Gene Kinney recounted how falling myoinositol levels were discovered when company researchers used NMR to confirm scyllo-inositol had made its way into the brain. The researchers noticed that, as brain scyllo-inositol rose, its myo-isoform fell. Going back to animal models, they found that the myo isoform dropped by as much as 70 percent when the animals imbibed drinking water laced with scyllo-inositol. Why is this important? Previously, researchers had reported elevated brain myoinositol in patients with AD, Down's syndrome, and bipolar disorder, said Kinney (see Miller et al., 1993). More recently, a group in Japan correlated elevated brain myoinositol with behavioral and psychological problems in AD patients. Lithium, which has been used for many years to treat neuropsychiatric disorders, may work in part by reducing myoinositol. In fact, a 30 percent reduction of myoinositol is predictive of lithium efficacy, said Kinney. By reducing myoinositol, could scyllo-inositol treat neuropsychiatric symptoms in AD patients?

Given the poor safety profile of these compounds, ferulic acid may be a beneficial alternative.

Preparation of a (+/-)-1,6-di-O-feruloyl-myo-inositol derivative: an efficient method for introduction of ferulic acid to 1,6-vicinal hydroxyl groups of myo-inositol.


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 T1, Hayashida H, Murata M, Takamatsu J.

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.

Effects of ferulic acid and Angelica archangelica extract (Feruguard) in patients with Alzheimer's disease
Kiyoshi Kanaya

Background: Feruguard is a health food supplement composed of ferulic acid extracted from rice bran and garden angelica obtained from Angelica archangelica. In recent years, Feruguard has been reported to be effective against the core symptoms and behavioral and psychological symptoms of dementia (BPSD) of Alzheimer disease (AD) and dementia with Lewy bodies (DLB). We conducted a prospective study to verify the efficacy of this supplement with respect to the BPSD, the results of which are reported here. Methods: The subjects consisted of 24 patients who had been definitively diagnosed with AD or DLB. Based on an observation period of 4 months, a crossover study was conducted in which 12 patients were assigned to group A and 12 patients were assigned to group B. Each patient in group A took two packets of Feruguard daily for the first two months. The patients in group B took the same for the latter two months. The assessment methods consisted of NPI-D scores combining neuropsychiatric inventory (NPI), which is an evaluation scale for BPSD, with an evaluation of distress of the caregiver, MMSE and ADAS as tests of cognitive functions, and GDS15 as a depression scale. These parameters were measured before and after taking Feruguard followed by an examination of their changes. Moreover, SPECT imaging were also performed, and a comparative study of changes in cerebral blood flow before and after administration was conducted using SPM8. Results: In the 12 patients of group A at completion of testing, mean NPI score was observed to have decreased significantly (P = 0.003) from 18.08 before administration to 10.58 after administration. In addition, distress scores also decreased significantly (P = 0.000) from 12.17 to 7.50, thus demonstrating the ameliorative effects of Feru-Guard on BPSD. There were no significant differences observed for MMSE, ADAS or GDS15 scores before and after administration. In the comparison of changes in cerebral blood flow, significant increases were observed in the right occipital lobe, and left cerebellar hemisphere as compared with before administration. Conclusions: This study verified the usefulness of Feruguard for BPSD. We intend to conduct additional studies on larger numbers of subjects in the future.

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25. Lane Simonian on April 10, 2014 3:01 PM writes...

@23. The results for scyllo-inositol make sense. The main pathway to peroxynitrite formation after the early stages of Alzheimer's disease is via the peroxynitrite-mediated nitration of NMDA receptors. However, in people with continued high levels of myo-inositol there is the extra production of peroxynitrites which increases noradrenaline/norepinephrine release via NMDA receptors.

Increased noradrenergic activity has been associated with anxiety and aggression. Postmortem studies have shown that Alzheimer's disease patients exhibiting psychotic behaviors and agitation have higher levels of norepinephrine than AD patients without psychotic symptoms.

Scyllo-inositol should help to relieve to a degree neuropyschiatric problems in Alzheimer's disease.

Ferulic acid is a more difficult character. It may limit the damaging effects of myo-inositol. It also inhibits the beta-secretase, excitoxicity, and scavenges peroxynitrites, yet in no study does it improve cognition in addition to behavior in various forms of dementia. But when combined with other peroxynitrite scavengers that may be less lipophobic, it improves both cognition and behavior.

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 KS1, Tanaka T, Cho EJ, Yokozawa T.

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.

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26. bank on April 10, 2014 6:59 PM writes...

Frankly, when I see Lane Simonians comments it reminds me only of how little we know about AD, and how easy it is for second-rate science to lead people astray.

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27. Lane Simonian on April 10, 2014 8:34 PM writes...

Tell the scientists who conducted the studies that they are second-rate. I am sure that they would like to know.

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28. bank on April 11, 2014 1:29 AM writes...

Lane,

The following article is worth reading "between the lines" when it comes to AD research; indeed many AD studies in mice are worthless; more than 300 treatments have modified AD pathology in mice and none translate to humans.

"Too much good news’ – are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer’s disease?"
http://www.ncbi.nlm.nih.gov/pubmed/?term=20542579

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29. Lane Simonian on April 11, 2014 9:32 AM writes...

I am trying to avoid the mouse models of Alzheimer's disease these days. I used to heavily cite them, but I know they have limitations.

To excerpt from the quote in post 8: "Excellent results have been obtained with peroxynitrite scavengers with reversals in Alzheimer's disease in human clinical trials being repeatedly demonstrated." I am not sure if I would have used the word repeatedly as we are talking about a handful of very small studies. But with the partial exception of curcumin so far (and there are ongoing trials using more bioavailable forms of curcumin), the best peroxynitrite scavengers (methoxyphenols such as eugenol, ferulic acid, vanillic acid, and syringic acid) have partially reversed Alzheimer's disease in people between the early and severe stages of the disease. Most of the gains were seen between one month and 24 weeks, but in one extended study with ginseng no further decline was seen for two years.

I know many people are either intellectually or financially invested in the amyloid or tau hypotheses of Alzheimer's disease, but they are both downstream effects of peroxynitrite production and removing amyloid or de-phosphorylated/de-nitrating tau does little to hinder the progression of the disease. The idea of a single cause (or almost a single cause) for Alzheimer's disease that can be combated with specific antioxidants from natural products may sound preposterous, but so far it is the only thing that has worked. Now if someone wants to get creative and develop better synthetic versions of peroxynitrite scavengers to treat Alzheimer's disease, I would bow to their genius as my only "genius" lies in stringing hundreds of studies together to try to tell the story of this disease. That is all that I am able to do, but in the hands of someone much more capable maybe that is enough.

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30. bank on April 11, 2014 11:16 AM writes...

Lane,

Most small clinical trials are not worth the effort. The group sizes are too small for any conclusions derived to be meaningful, whatever the claims of the authors. A quick online search yields many sites that allow one to perform a "power calculation"; this statistical test lets one know how large group sizes should be for an expected improvement in the measured parameters. You can do this for the numbers provided in the various manuscripts. Small clinical trials almost always fail this test, and are said to be "underpowered".

There may be ways to perform meta-analyses of several clinical trials and thereby pool the data. However different trials are almost never conducted in a standardized fashion, making this a difficult objective to achieve.

In summary, not only have mice been shown to represent a next-to-useless method of testing drugs for AD, the vast majority of small clinical trials are also useless.

Indeed, as you suggest, the scientists involved should be castigated for wasting everyone's time and money, and for foregoing alternate opportunities.

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31. Lane Simonian on April 11, 2014 11:51 AM writes...

Bank,

You are, of course, fundamentally correct. But until something fails in a larger clinical trial you cannot determine if it is ineffective. My problem is that certain things such as bapineuzumab have already failed in large-scale stage 3 clinical trials and yet are being repackaged and repurposed for yet further studies. Rather than re-testing the things that have failed; re-test the things that have succeeded.

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32. bank on April 11, 2014 6:43 PM writes...

Lane,

Those things that have "succeeded" in smaller trials cannot be said to have succeeded if the trials were underpowered. It's similar to tossing a randomly selected coin four times, having it land heads all four times and then declaring that it a double-headed coin. The likelihood of that conclusion being true for a random coin is vanishingly small.

As to bapineuzumab, I would have to agree with you, unfortunately. I think the further trials on bapineuzumab are a very cynical move that is essentially gambling on an "accidental" favorable outcome. For example if the probability of a "false positive" outcome in the new trials is 5%, then it is worth investing X dollars in the trial, since with a false positive outcome the subsequent revenues will be very fine indeed, even if the drug truly has no effect.

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33. Anonymous on April 12, 2014 6:29 AM writes...

Interesting Bank (Hi Lane!)

Methylene Blue was the same, right? Looked like a miracle cure in a single-centre study in Russia: Bombed in PhaseIII. Bapi (Or maybe ur talking about solanezumab? - same difference!) Also looked OK-ish in phaseII. The only 'positive' results in PhaseIII for both were in post-hoc subgroup analyses, which are pretty much statistical dead-ends.

Lane: Listen to Bank. MCI/early AD is notoriously sensitive to trials and meticulous controls are required to weed out false positives. Pets, social interaction, music...all these things can 'cure' AD at early stages. Look for the term 'open label' in a clinical study. If it contains these words (As one of ur references in this thread does), disregard the data as noise.

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34. Lane Simonian on April 12, 2014 10:48 AM writes...

I am listening and largely agreeing, but not entirely on board. Pets, social interaction, music, art, exercise, etc. change mood states through changing biochemistry. This effect is mainly palliative but can be an important adjunct to other treatments.

Here is a long list of reasons why trials on Alzheimer's disease and Alzheimer's medicines have failed (or will likely fail).

Treats a symptom (and in most cases an early symptom) of the disease but not the cause(acetylcholinesterase inhibitors).

Ineffectively inhibits a step in the process of the disease (Namenda--NMDA receptor antagonists).

Lowers levels of amyloid plaque which contributes little to nothing to the disease (solanezumab).

Lowers levels of amyloid oligomers which only slightly slows down the progression of the disease (bapinezumab and Pbt2).

Attacks a cause of the disease but not effectively (rosmarinic acid--A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).

Attacks only one element of the disease (drugs targeted against hyperphosporylated tau).

Some of the clinical trials I cite were rigorously conducted and some were not. All were directed at people somewhere after early Alzheimer's disease and before the severe stages of the disease. Some used a placebo and were double-blinded. They each used the same category of compound (methoxyphenols) and they produced similar results regarding cognition and behavior and the difference in results can largely be explained by how well the substance reached the brain.

Then you fit the results in with the larger picture.

The risk factors for Alzheimer's disease all correlate with peroxynitrite formation.

The specific pathways and biomarkers linked to Alzheimer's disease (high levels of myo-inositol, high levels of phospholipase C activity, p38 MAPK activity, lipid rafts, NMDA receptor activation) all lead to the production of peroxynitrites.

Measures that may inhibit Alzheimer's disease (polyphenols and DHA) limit the formation of peroxynitrites.

Directly or indirectly peroxynitrites can be linked to every feature of Alzheimer's disease.

The best peroxynitrite scavengers have improved memory and behavior in a series of small-scale clinical trials and in at least in one case the results held after two years.

Now all of this may be by chance, but there are multiple lines of evidence suggesting that it is not.

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35. bank on April 12, 2014 7:53 PM writes...

Lane,

I really admire your dedication!

I think the most straight-forward way to tackle AD is to consider first those things that are unambiguously known to *cause* it.

Two genes are known to have a causative effect in AD, presenilin and APP. These genes are causative because if you have one of several mutations in either you *will* get AD.

A third gene may also be causative, depending on one's perspective, and that is APOE. People who have the APOE2 form of the gene almost never get AD, and those who have the APOE4 form almost always get AD. Most people have another form APOE3, and they get AD at a frequency of around 5% over their lifetime (these statements refer to homozygotes).

Genome-wide studies have suggested the involvement of another 10 or so genes, but their involvement is not yet as clear-cut as that of presenilin, APP or APOE.

If your ideas surrounding peroxynitrites were correct, then there might be a biological connection between peroxynitrites and either presenilin, APP or APOE. That is to say that peroxynitrites might modify either the inputs to, or the outputs from, the biological function(s) of one of these three genes.

If you could come up with a convincing argument connecting peroxynitrites to APP, presenilin or APOE you would have the beginnings of a proposal that might receive wider attention.

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36. Lane Simonian on April 13, 2014 1:27 AM writes...

I continue to work on this evidence. The APOE4 gene increases lipid rafts and the peroxynitrite stimulated beta secretase cut of the amyloid precursor protein takes place in lipid rafts.

TNFα potentiates protein-tyrosine nitration through activation of eNOS and NADPH oxidase localized in caveolae of bovine aortic
endothelial cells

Baohua Yang, Victor Rizzo. Cardiovascular Research Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA,
19140

A major source of ROS in endothelial cells is the NADPH oxidase enzyme complex. The selective distributions of any enzyme within the cell have
important implications in regulating enzyme effectiveness through facilitating access to local substrates and/or product targets. Since lipid rafts and caveolae provide a spatially preferable environment for a variety of enzyme systems, we sought to determine if NADPH oxidase is present and functional in this plasma membrane compartment in endothelial cells. We found that NADPH oxidase subunits were preassembled and the enzyme
functional in membrane rafts/caveolae. In addition, TNFα induced: a) recruitment of p47phox regulatory subunit, b) interaction with the p22phox subunit and c) enhanced ROS production within rafts/caveolae domains. TNFα also induced phosphorylation and activation of eNOS [should be iNOS in brain at least] present in plasma membrane raft/caveolae compartments. The dual activation of superoxide and nitric oxide generating systems within the same membrane compartment provided a spatially favorable environment for formation of peroxynitrite as evidence by detection of nitration of tyrosine containing proteins localized to rafts/caveolae. Perturbation of lipid raft/caveolae structural integrity with cholesterol sequestering compounds caused the relocalization of eNOS and NADPH oxidase subunits from the lipid rafts and inhibited TNF.α-induced peroxynitrite formation. Together, these data provide the first evidence that lipid rafts/caveolae play a role in regulating NADPH oxidase and subsequent ROS generation in endothelial cells.

APOE4 and presenilin gene mutations also inhibit the activation of the phosphatidylinositol 3 kinase--a kinase which inhibits peroxynitrite formation in the brain.

APOE4-VLDL inhibits the HDL-activated phosphatidylinositol 3-kinase/Akt Pathway via the phosphoinositol phosphatase SHIP2.


J Neurosci. 2008 Jan 9;28(2):483-90. doi: 10.1523/JNEUROSCI.4067-07.2008.
Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling.
Baki L1, Neve RL, Shao Z, Shioi J, Georgakopoulos A, Robakis NK.

Abstract
The role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1-/-) embryonic mouse brains. Here we show that in PS1-/- cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylation-inactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1-/- neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1-/- neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to gamma-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. 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.

Cell Death Differ. 2006 Sep;13(9):1506-14. Epub 2006 Jan 20.
Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells.
Shacka JJ1, Sahawneh MA, Gonzalez JD, Ye YZ, D'Alessandro TL, Estévez AG.

Abstract
The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death.

Good scientifically based questions and approach. My overarching point is that there are specific reasons why peroxynitrite scavengers have produced positive results in small-scale human clinical trials for patients with Alzheimer's disease.

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37. Pharma Heretic on April 13, 2014 11:05 AM writes...

It's hard to formulate, and compliance historically sucks, but maybe it's time to focus on prevention and back off on the search for panaceas until we better understand mechanisms?

The price is right, and it's proven to work, though the time course of treatment will probably need to be decades. I hate to say it, but the Baby Boomers are screwed as far as AD goes.

Sleep, diet, exercise, smokelessness, meditation or other forms of stress relief...and lastly, picking one's parents well. ApoE genetic testing of embryos may be a reasonable place to start.


Permalink to Comment

38. Lane Simonian on April 13, 2014 11:15 AM writes...

This one I have been looking for for a long time: what is exactly the role of the Swedish mutation of the amyloid precursor protein in Alzheimer's disease. This study although it is for stroke shows a connection between this mutation and p38 MAPK.

Inhibiting p38 MAPK attenuates cerebral ischemic injury in APP/SWE transgenic mice

The Swedish mutant amyloid precursor protein mutation exacerbates ischemic brain injury, and this could be alleviated by inhibiting p38 mitogen-activated protein kinase activity, according to a study in the Neural Regeneration Research Journal (Vol. 7, No. 14, 2012). Liangyu Zou and colleagues induced cerebral ischemia using photothrombosis 1 hour after intraperitoneal injection of the p38 mitogen-activated protein kinase inhibitor SB239063 into Swedish mutant amyloid precursor protein transgenic and non-transgenic mice.

The researchers found that the number of surviving neurons in the penumbra was significantly reduced in Swedish mutant amyloid precursor protein transgenic mice compared with non-transgenic controls 7 days after cerebral ischemia, but the activity of p38 mitogen-activated protein kinases was significantly elevated compared with the non-ischemic hemisphere in the Swedish mutant amyloid precursor protein transgenic mice. Meanwhile, SB239063 prevented the above-mentioned changes.

The mutation may work upstream of p38 MAPK or it may increase lipid rafts or it may increase the activity of p38 MAPK itself but whatever the case, it is acting upstream of beta secretase.

P38 MAPK is a key player in Alzheimer's disease. Its activation by phospholipase C and protein kinase C is the likely trigger for Alzheimer's disease.

Neurochem Int. 2008 May;52(6):1188-97. doi: 10.1016/j.neuint.2007.12.009. Epub 2007 Dec 27.
Activation of p38 MAPK induced peroxynitrite generation in LPS plus IFN-gamma-stimulated rat primary astrocytes via activation of iNOS and NADPH oxidase.


The subsequent peroxynitrite-mediated nitration of NMDA receptors perpetuates the production of p38 MAPK and peroxynitrites.

Biochem Biophys Res Commun. 2009 Jun 26;384(2):221-5. doi: 10.1016/j.bbrc.2009.04.091. Epub 2009 Apr 23.
Peroxynitrite-induced p38 MAPK pro-apoptotic signaling in enterocytes.
Guner YS1, Ochoa CJ, Wang J, Zhang X, Steinhauser S, Stephenson L, Grishin A, Upperman JS.

Abstract
Enterocyte apoptosis in necrotizing enterocolitis is partly due to the elaboration of toxic intermediates of nitric oxide (NO), such as peroxynitrite (PN). Because p38 mitogen-activated protein kinase (MAPK) and serine-threonine kinase (AKT) are well-characterized pro- and anti-apoptotic mediators, respectively, we hypothesized that PN could induce enterocyte apoptosis via activation of p38 and deactivation of AKT.

This last one attributes p38 activation and peroxynitrite formation to the c-terminal fragment of the amyloid precursor protein, but it is mainly the other way around.

J Neurochem. 2001 Jul;78(1):109-20.
C-terminal fragment of amyloid precursor protein induces astrocytosis.
Bach JH1, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS.

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.

So here are the links: APOE4 increases peroxynitrite activity through increasing lipid rafts. Presenilin gene mutations increase peroxynitrite formation by cutting off the phoshatidylinositol 3-kinase/Akt pathway. The Swedish mutation of the amyloid precursor protein increases peroxynitrite formation by increasing p38 MAPK activity.

The links are there; enough of them at least such that the path toward treating this disease becomes considerably less muddled.

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39. aa3 on April 15, 2014 2:12 AM writes...

It seems like an area where basic science still has further to go. Other players in the ecosystem of biology like universities, government funded research, charitable research, have to gradually explore the disease and use logic step by arduous step to learn its nature.

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40. Proteus on April 15, 2014 9:34 PM writes...

@35: "...consider first those things that are unambiguously known to *cause* it. Two genes are known to have a causative effect in AD, presenilin and APP. These genes are causative because if you have one of several mutations in either you *will* get AD."

I agree with your overall message about pursuing targets, but my leisure reading and non-expert understanding of the field left me with a jumbled Venn diagram based on:
-- app, ps mutations drive something like 1% of AD cases
--folks can have plaques without having Alzheimer's
--the reverse logic is impossible since AD is defined by plaques, but there is plenty of dementia types with out therm

These may be incorrect assumptions,so please correct. I have no strong conclusion other than that cancer is more of a syndrome/phenomenon than a single disease. AD may be the similar.
May we live and be coherent long enough to learn the answer.
--

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41. Lane Simonian on April 16, 2014 12:58 PM writes...

While waiting for Bank to respond (and I hope that Bank will respond or anonymous or anyone who supports the amyloid hypothesis for Alzheimer's disease), let me say that you have hit upon some key points. The fact that folks can have plaques without having Alzheimer's should in itself make people question whether plaques are the sole cause of Alzheimer's disease. Indeed the insistence by many in the field that plaques are the cause of Alzheimer's disease has impeded progress against this disease for more than a decade.

The reverse logic is not impossible since Alzheimer's disease has only been defined by plaques by those who support the amyloid hypothesis of Alzheimer's disease. Here are two pieces of evidence that people without plaques can have Alzheimer's disease.

Alzheimer’s Disease Without Amyloid Plaques

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. The report challenges the notion that amyloid deposits outside of the cells are necessary for neuron death in Alzheimer’s disease.

Their results also indicate that by reducing the amount of APP within neurons it may be possible to rescue them.

J Neurochem. 2001 Jul;78(1):109-20.
C-terminal fragment of amyloid precursor protein induces astrocytosis.
Bach JH1, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS.

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.


But it is not the amyloid precursor protein that is toxic, it is what causes the formation of the amyloid precursor protein--peroxynitrite--that is toxic. Lower levels of this neurotoxin and reverse part of its damage (oxidation, nitration, mitochondrial dysfunction, glucose scarcity, restricted blood flow in the brain, inhibited synthesis and release of critical neurotransmitters, hyperphosphorylation and nitration of tau proteins, calcium influx, and inhibition of neurogenesis)and you can effectively treat the disease.

Most scientists claim to be objective, analytical, and have flexible minds, but for Alzheimer's disease most are stuck on the set paradigm and no amount of evidence is sufficient for them to shift from this paradigm. And thus we drift from one failed trial to another while millions of people are denied the possibility of a better life with the disease.

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42. Lane Simonian on April 26, 2014 10:03 AM writes...

Here is the direct link between the Swedish mutation of the amyloid precursor protein and peroxynitrites.

There is a significant flux of the neurotoxic oxysterol 27-hydroxycholesterol (27OHC) from the circulation across the blood-brain barrier. Because there is a correlation between 27OHC and cholesterol in the circulation and lipoprotein-bound cholesterol does not pass the blood-brain barrier, we have suggested that 27OHC may mediate the effects of hypercholesterolemia on the brain. We previously demonstrated a modest accumulation of 27OHC in brains of patients with sporadic Alzheimer's disease (AD), consistent with a role of 27OHC as a primary pathogenetic factor. We show here that there is a 4-fold accumulation of 27OHC in different regions of the cortexes of patients carrying the Swedish amyloid precursor protein (APPswe) 670/671 mutation.

This mutation increases the activation of Nuclear factor kappa B and thus the production of inducible nitric oxide and peroxynitrites. The formation of peroxynitrites in turn increases the production of the amyloid precursor protein, but it is oxidative stress and not amyloid that is the driving factor behind Alzheimer's disease.


Results:27-OHC dose-dependently increased Aβ peptide production, increased levels of ER stress specific markers caspase 12 and gadd153 (also called CHOP), reduced mitochondrial membrane potential, triggered Ca2+ dyshomeostasis, increased levels of the nuclear factor κB (NFκB) and heme-oxygenase 1 (HO-1), two proteins activated by oxidative stress. Additionally, 27-OHC caused glutathione depletion, ROS generation, inflammation and apoptotic-mediated cell death.

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No Scripps/USC
Studies Show? Not So Fast.
Outsourced Assays, Now a Cause For Wonder?
An Alzheimer's Blood Test? Not So Fast.