1230 replies to this topic

[blood]

Here is the abstract. Unfortunately I don't have access to the full text.
 

An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

Yvette I. Sheline1,*, Tim West2, Kevin Yarasheski3, Robert Swarm4, Mateusz S. Jasielec5, Jonathan R. Fisher6, Whitney D. Ficker6, Ping Yan6, Chengjie Xiong5,7, Christine Frederiksen8, Monica V. Grzelak6, Robert Chott3, Randall J. Bateman6,7,9, John C. Morris6,7, Mark A. Mintun10, Jin-Moo Lee6,7,9 and John R. Cirrito6,7,9

Abstract

Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimers disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased Aβ in brain interstitial fluid in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of preexisting plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citaloprams effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.

Copyright © 2014, American Association for the Advancement of Science

According to this article, the dose used with healthy subjects was quite hefty (60 mg):
 

http://www.bioscienc...owth-78-percent

Anti-Depressant Reduces Alzheimers Plaque Growth by 78 Percent

The maximum effective dose of citalopram causing a reduction in brain Ab concentrations and plaques in mice (10 mg/kg) was comparable to a dose of citalopram (50 mg/day) often given to humans as an antidepressant, and similar to the dose used in this study: 60 mg.

There is a theoretical risk of cardiac arrhythmia & sudden death (no evidence this actually occurs) with doses above 40 mg/day:
 

Wikipedia - citalopram
http://en.wikipedia....wiki/Citalopram

In August 2011, the US Food and Drug Administration (FDA) announced that Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day.[34] Further clarification issued in March 2012 [35] restricted the maximum dose to 20 mg for subgroups of patients, including those older than 60 years and those taking an inhibitor of cytochrome P450 2 C19.7 This change, affecting the most widely prescribed antidepressant in the US, left clinicians unclear about appropriate next-step strategies because of the lack of data comparing citalopram with other antidepressants. In a cross-sectional study using electronic health records with almost 40,000 participants modest dose dependent QTc prolongation was confirmed. It was also true for escitalopram and amitriptyline[36] although the effect sizes were small and there is no epidemiological evidence for higher risk of cardiac arythmia.[37]

This earlier study (from 2011) find that elderly people who have spent some of the previous 5 years on an SSRI actually *do* have a lower brain amyloid burden (with time spent on SSRIs correlating negatively with amyloid burden):
 

http://www.pnas.org/...8/36/14968.full
 
Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

John R. Cirritoa,b,c,1,2, Brianne M. Disabatod, Jessica L. Restivoa, Deborah K. Vergesa, Whitney D. Goebela, Anshul Sathyana, Davinder Hayrehd, Gina D'Angelob,e, Tammie Benzingerb,f, Hyejin Yoona, Jungsu Kima,b,c, John C. Morrisa,b, Mark A. Mintunb,d,f,g, and Yvette I. Shelinea,b,c,d,f,1,2

Abstract

Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonin-dependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.

Another snippet from previously linked article:
 

Anti-Depressant Reduces Alzheimers Plaque Growth by 78 Percent

Anti-Depressant Reduces Alzheimers Plaque Growth by 78 Percent

In earlier work, Sheline and this study's senior author, University of Washington neurologist John Cirrito, showed SSRI exposure within the five years before amyloid PET scan was associated with lower amyloid binding as determined by PIB-PET imaging, according to the report. A recently discovered protective mutation in APP [amyloid precursor protein] (A673T) has approximately the same magnitude of Ab-lowering effect as the citalopram effect in the current study, strengthening the argument for SSRIs as a potential AD prevention strategy.

A potential problem, Steinman says: If plaque burden reflects severity of AD, and it's a big 'if, then a 78 percent reduction in plaque burden is impressive. But there are many with dementia without plaques at all.

Fillit agrees plaque could be a bystander. AD is complicated. There are all kinds of competing morbidities at work. But certainly, he said, depression is a key AD risk factor, one of many things that make SSRIs interesting candidates for study.

Furthermore, it may matter the above-mentioned JAMA study found citalopram may impede cognition after AD onsetwhile this study found it affected plaque before, he said. Cirrito, speaking by email, agreed. The data we have so far suggests that SSRIs prevent growth of plaques and reduce formation of new plaques, but does not shrink plaques. If SSRIs ever become a therapy, it would likely need to be very early in disease or before symptoms even start. I suspect this is likely true for most drugs currently being developed to target Ab as a therapy.

Edit: don't seem to be able to insert a functional link on this forum anymore. :/

Edited by blood, 24 May 2014 - 08:50 AM.

[Raptor87]

 

 

Too bad citalopram is a shitty drug, although it beats having alzheimers.

 

Shitty because it's an SSRI, and they're shitty as a class, or particularly shitty in comparison to other SSRIs?  What exactly is wrong with it?

 

 

Just generally the sideffects compared. It's often prescribed for panic attacks but from what I know. it doesn't work. Doctors usually prescribe Citalopram but when patients keep coming back they continue treatment with effexor instead.

[ceridwen]

It seems that there are a lot of drugs presently being tested in Alzheimer clinical trials that are of shitty  drugs that are becoming unpopular for what they were originally being sold for. Levitiracetram is one an epilepsy drug that has  become unpopular amongst epilepsy patients because of its sometimes deadly effects. The problem is it was certainly bringing back some of my memories. Other people say that it can cause memory loss. I don't know whetever to continue taking it now or not. Amazing what effect placebo effect can have? Perhaps all medicine is placebo effect? Should I go on taking Levitiracetam it was bringing my memory back? I was happy with Levitiracetam now I don't know what to think. V. disappointed. However if it can keep me hanging in there until there actually is a cure. It'll be worth it as far as I'm concerned. It felt like it was giving my memory a kick start where nothing else would.

Citalopram when tested worsened cognition but improved mood so I don't know why they are testing it for Alzheimers-. It sounds like a chemical cosh to make people docile and easier to deal with while worsening their memory. That's very bad. I'd hoped we were moving away from that sort of treatment.

[niner]

 

 

 

Too bad citalopram is a shitty drug, although it beats having alzheimers.

 

Shitty because it's an SSRI, and they're shitty as a class, or particularly shitty in comparison to other SSRIs?  What exactly is wrong with it?

 

Just generally the sideffects compared. It's often prescribed for panic attacks but from what I know. it doesn't work. Doctors usually prescribe Citalopram but when patients keep coming back they continue treatment with effexor instead.

 

Citalopram has the best side effect profile of all the SSRIs.  That's why doctors go to it first.  Not everyone reacts the same, though.  It won't be the best choice for everyone, Antidepressants are known for side effects.  Citalopram and the newer enatiomerically resolved version are the best of a bad lot.

Edited by niner, 25 May 2014 - 03:10 AM.

[ceridwen]

Citalopram worsens cognition

[blood]

Citalopram worsens cognition

The fact people with AD were found to perform less well on certain measures of cognitive function while on citalopram doesn't necessarily mean that the drug is worsening the underlying pathology (of their Alzheimer's). It's within the realm of possibility that it could make the early diagnosed AD patient slightly dumber (for want of a better word) as an acute effect, but still slow the disease progression in the long term.

Citalopram does appear to drastically lower amyloid production in people & in a mice model of Alzheimer's halts progression of the disease. That's why we're talking about it in relation to Alzheimer's.

Edited by blood, 25 May 2014 - 12:29 PM.

[niner]

Citalopram worsens cognition

Based on what evidence?

[mag1]

Lancet. 1991 Jun 1;337(8753):1304-8.

Intramuscular desferrioxamine in patients with Alzheimer's disease.

[Raptor87]

Does anyone here know exactly why such genes that lead to alzheimers may have survived? I mean there must be some sort of trait that comes with these genes due to natural selection? Or is it just some kind of error that wasn't weeded out due to short lifespans? 

[mag1]

Can anyone explain the phase 2 results of the AFFiRis drug AD04?

[mag1]

It was reported 4 days ago that a placebo stabilized 50% of early Alzheimer disease patients for 18 months ( p=0.0016). A dose effect was noted and there was reduced hippocampal 

shrinkage. The company considers this a true breakthrough in Alzheimer research and claims this is the first Alzheimer product that has ever demonstrated disease modification.

 

One possibility for the immuno-modulator used as placebo is Keyhole limpet hemocyanin (KLH) which has been widely used in medical research for decades (especially in cancer vaccines).

 

The fact that no one on this forum has responded to this stunning development must mean everyone is on vacation. 

 

When you return from the beach, I will be very interested in reading your comments.

[blood]

The fact that no one on this forum has responded to this stunning development must mean everyone is on vacation. 

 

When you return from the beach, I will be very interested in reading your comments.

 

Without knowing what the mysterious AD04 compound is, there's not much to comment on.

[niner]

 

The fact that no one on this forum has responded to this stunning development must mean everyone is on vacation. 

 

When you return from the beach, I will be very interested in reading your comments.

 

Without knowing what the mysterious AD04 compound is, there's not much to comment on.

 

The other agents in the AD0x series are therapeutic vaccines.  I don't understand mag1's post above saying that the result was from a placebo.

[André Cahuana]

This is actually of my interest since I've taken Citalopram for 1 month (2 years ago) due to some nervouness. But for some reasons  I have never  relied on Psiquiatrists so I improved my situtation on my own. Anyway, There isn't much info about the  relation between cognitive detriment and Citalopram, i've just read a few abstracts like this:

 

Effects of citalopram on cognitive performance in passive avoidance, elevated plus-maze and three-panel runway tasks in naïve rats.

 

Abstract

Recent studies have shown that learning and memory capacity is disturbed in depressive patients, and it is important to reveal the effects of antidepressant drugs on cognitive function in depressive patients with memory problems. Citalopram, a selective serotonin reuptake inhibitor (SSRI), is one of the most widely used drugs for the treatment of disorders related to serotonergic dysfunction like depression and anxiety. Contradictory findings exist regarding the effects of SSRIs on memory. The aim of this study is to investigate whether citalopram affects memory in various models of learning and memory tasks in rats. Citalopram (at 20 and 50 mg/kg) significantly shortened the retention latency in the passive avoidance test and prolonged the transfer latency on the second day at 10 and 50 mg/kg doses in the elevated plus-maze test. Citalopram also significantly increased the number of errors (at the 10 mg/kg dose) and prolonged the latency values compared to the control group in both reference and working memory trials in the three-panel runway test. Citalopram also impaired reference memory trials of animals at the 20 mg/kg dose. In conclusion, citalopram impaired cognitive performance in passive avoidance, elevated plus-maze and three-panel runway tasks in naive rats. These effects might be related to serotonergic and nitrergic mechanisms, which need to be investigated in further studies.

 

 

wanna know what you think about the disadvantages of Citalopram given to vulnerable people (to some extent) and other sort of side effects patients don't know.

 

Sorry for my  english.

Edited by André Cahuana, 01 July 2014 - 03:05 PM.

[Logic]

Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain.

The Novel multifunctional brain permeable iron, chelator M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In the present study, we demonstrate that systemic chronic administration of M30 resulted in up-regulation of hypoxia-inducible factor (HIF)-1? protein levels in various brain regions (e.g. cortex, striatum, and hippocampus) and spinal cord of adult mice. Real-time RT-PCR revealed that M30 differentially induced HIF-1?-dependent target genes, including vascular endothelial growth factor (VEGF), erythropoietin (EPO), enolase-1, transferrin receptor (TfR), heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and glucose transporter (GLUT)-1. In addition, mRNA expression levels of the growth factors, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) and three antioxidant enzymes (catalase, superoxide dismutase (SOD)-1, and glutathione peroxidase (GPx)) were up-regulated by M30 treatment in a brain-region-dependent manner. Signal transduction immunoblotting studies revealed that M30 induced a differential enhanced phosphorylation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), protein kinase B (PKB/Akt), and glycogen synthase kinase-3? (GSK-3?). Together, these results suggest that the multifunctional iron chelator M30 can up-regulate a number of neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain that might function as important therapeutic targets for the drug in the context of neurodegenerative disease therapy.


Neuroprotection by the multitarget iron chelator M30 on age-related alterations in mice.

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we report that a chronic systemic treatment of aged mice with M30 (1 and 5mg/kg; 4 times weekly for 6 months), had a significant positive impact on neuropsychiatry functions and cognitive age-related impairment. M30 significantly reduced cerebral iron accumulation as demonstrated by Perl's staining, accompanied by a marked decrease in cerebral ?-amyloid plaques. In addition, our results demonstrate that M30 caused a significant inhibition of both MAO-A and -B activities in the cerebellum of aged mice, compared with vehicle-treated aged control mice. In summary, the present study indicates that the novel MAO inhibitor/iron chelating drug, M30, acting against multiple brain targets could reverse age-associated memory impairment and provide a potential treatment against the progression of neurodegeneration in ageing.
 
From This thread:
http://www.longecity...f-catalase-sod/

There's talk of a group buy

[blood]

The other agents in the AD0x series are therapeutic vaccines.  I don't understand mag1's post above saying that the result was from a placebo.

The compound now being referred to as AD04 was one of the placebo arms in the Phase 2 clinical trial looking at AD02 in early-diagnosis Alzheimer's. AD02 was/is a vaccine (delivered via subcutaneous injection) comprising of 1) a synthetic peptide of six amino acids that mimics the N-terminus of A-beta and 2) an adjuvant. The placebo now referred to as AD04 consisted of an injection of the adjuvant only. Patients on the adjuvant alone seemed to get some protection against further cognitive decline; complicating things, the protective effect was absent when the adjuvant was given in combination with the peptide string (AD02 was more or less useless).

Affiris (the company concerned) hasn't said what the adjuvant that showed beneficial effects is. In the Phase 1 trial for AD02, the adjuvant used was aluminium hydroxide.

This article is worth a read:
 

In Surprise, Placebo, not Aβ Vaccine, Said to Slow Alzheimers

Outside experts were perplexed by the findings. Some pointed out that the company presented little actual data, such as sample sizes, standard errors, or dropout/completion numbers. "There is no reason why companies can't fully present their study design and protocol-specified outcomes in press conferences like this, so that outcomes can be fairly assessed, Lon Schneider, University of Southern California, Los Angeles, wrote to Alzforum in an email. Most commentators declined to speak on the record.

Other researchers noted that if AD04 is indeed a therapeutic, then the AD02 groups should have performed as well, if not better, because AD02 contained AD04 plus the Aβ-based antigen. Could it be that AD02 counters AD04s beneficial effects? Schmidt told Alzforum his group wondered the same thing but is unsure.

Some scientists suggested that the smaller patient numbers in the placebo groups versus the treatment groups could skew the results. Researchers commonly find that a significant number of AD patients do not progress during the time of trial observation, especially in early stages of the disease. In part because each trial features some non-progressors, the percent not progressing is not a commonly used way to show study results. It is more typical to show numeric decline on each outcome.

What about AD02 itself? This vaccine comprises a six-amino-acid affitope of Aβs N-terminus, meaning it mimics the primary amino acid structure of Aβ. According to AFFiRiS, the peptide fragment encourages B-cell recognition of Aβ while leaving the amyloid precursor protein alone and avoiding a pro-inflammatory T-cell response. Phase 1 data hinted that patients in the earliest stages of AD who took AD02 mounted a mild immune response and stopped declining on the Mini Mental State Examination (see Jun 2012 conference story). In the Phase 2 trial, patients on AD02 showed no statistically significant improvement over those in either placebo arm, though the safety monitoring board found all interventions to be safe and tolerable.

Patients from this study have been invited to participate in an open-label follow-up Phase 2 trial, though at the press conference, Schmidt said that the company was still deciding whether to continue that follow-up study. AFFiRiS plans to develop AD04 further, and perhaps AD02, but Schmidt said he and colleagues were still discussing how to move forward. In the future, the company would need to test AD04 against its own placebo and explore the optimum dose and injection frequency, he said

Edited by blood, 02 July 2014 - 06:29 AM.

[blood]

... Citalopram (at 20 and 50 mg/kg) significantly shortened the retention latency in the passive avoidance test and prolonged the transfer latency on the second day at 10 and 50 mg/kg doses in the elevated plus-maze test. Citalopram also significantly increased the number of errors (at the 10 mg/kg dose) and prolonged the latency values compared to the control group in both reference and working memory trials in the three-panel runway test. Citalopram also impaired reference memory trials of animals at the 20 mg/kg dose...

20-50 mg/kg citalopram (in rats) is a big dose. A human equivalent dose could be ~2-8 mg/kg (assuming an extrapolation based on body surface area is legitimate for this drug)... that would be 120-480 mg/day citalopram for a 60 kg person. Depressed people would never be given this much citalopram. The max. dose for depression is around 40 mg/day.

[mag1]

Thank you for commenting on the story!

AD04 might be a real breakthrough in AD research.

However, many in the AD community must still be baffled by AD04.

 

Strangely the AFFiRiS website has not updated the phase 2 study. AD02 is still being compared against placebo. http://www.affiris.c...impfstoffe.html

 

It is only elsewhere on their site that they claim AD04 (aka the placebo) as a breakthrough in Alzheimer's disease.

http://www.affiris.c...emeldungen.html

 

If the results with AD04 could be replicated, then this would be huge.

 

The phase 2 study was quite large, so the breakthrough result they are claiming probably could not have been caused by

small sub-group size (small sub-group analysis has resulted in several AD drugs not replicating {e.g. bapineuzumab} ).

One problem, though, could be that the early AD patients in the trial were simply non-decliners, so perhaps only a small number of patients on AD04 are driving the result.     

  

[ceridwen]

is it possible to get some?

[Logic]

Vince of Anti Aging Firewalls has a write-up on Trehalose that is worth reading:
http://www.anti-agin...-and-longevity/

"...Trehalose induces autophagy independently of mTOR pathway inhibition and has been shown in experimental models to help in neurodegenerative diseases. Trehalose can clear alpha-synuclein, polyglutamate, amyloid beta 40, amyloid beta 42, and tau proteins such as this seen in Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease..."

[Logic]

Inhibition of insulin amyloid formation by small stress molecules.

Amyloidogenic proteins undergo an alternative folding pathway under stressful conditions leading to formation of fibrils having cross beta-sheet structure, which is the hallmark of many neurodegenerative diseases. As a means of surviving against external stress, on the other hand, many microorganisms accumulate small stress molecules to prevent abnormal protein folding and to contribute to protein stability, which hints at the efficacy of the solutes against amyloid formation. The current work demonstrates the effectiveness of small stress molecules such as ectoine, betaine, trehalose, and citrulline on inhibition of insulin amyloid formation in vitro. The inhibitory effects were analyzed by thioflavin T-induced fluorescence, circular dichroism, and atomic force microscopy. This report suggests that naturally occurring small molecules may serve a function that is typically fulfilled by protein chaperones, and it provides a hint for designing inhibitors against amyloid formation associated with neurodegenerative disorders.

http://www.ncbi.nlm....2?dopt=Abstract

[Breestyle]

I looked back through the thread but couldn't find any mention of this article... 

 

Does anyone have any knowledge and/or additional information on this screening and when it might become available?

 

"In a first-of-its-kind study, researchers have developed a blood test for Alzheimer's disease that predicts with astonishing accuracy whether a healthy person will develop the disease."

 

I don't have the original published study - only the media report - http://www.cnn.com/2...ers-blood-test/

 

[corb]

Does anyone here know exactly why such genes that lead to alzheimers may have survived? I mean there must be some sort of trait that comes with these genes due to natural selection? Or is it just some kind of error that wasn't weeded out due to short lifespans? 

 

It's a defect which kills you long after you've had children, in fact it kills after you've become infertile. So unless we select against it artificially there really isn't any natural mechanism of evolution that can weed it out. Basically it's one of those things that we either kill it ourselves or it will follow us for as long as we exist as a species.

Of course I'm excluding the mutation which causes early onset AD, that should go away sooner rather than later. On an evolutionary scale of course.
 

[Nemo888]

Amyloid peptides are cleared before they become plaques in young healthy individuals. Amyloid precursors are essential and responsible for neuronal growth IIRC. They are situated in a very ancient part of our DNA. Once you get to newer cellular regulators like Gelsolin it is a different story. It seems some of the new upgrades do not play well with the older versions. It looks like a mix of things that turns amyloids into plaques. Mitochondrial dysfunction, inflammation and other forms of cellular dysregulation all work together to weaken homeostasis. My hope is that promoting health on a cellular level would alleviate symptoms for a few extra years.

 

Increase MG and decrease Ca in the diet and supplementing inositol are the easiest. HGH, TB4 and SS-31 have more reward at greater expense and risk.  Anyway, glad I have found this thread.

[mag1]

The main late onset AD risk factor mutation (APOE epsilon 4) is the ancestral genotype. During the last few hundred thousand years,this genotype has been selected against and now has a population frequency (in Western nations) of approximately 15%.

In a non-AD context, the epsilon 4 variant might have a survival benefit.    

 

Pre-implantation genetic technologies exist that are being used to stop the next generation from inheriting serious medical conditions (for example, early onset AD). However, humanity likely now has the most early onset AD of any time in human history. Several centuries ago someone with a PSEN1 mutation (E280A) migrated to Columbia. Columbia is probably an ideal environment for people with early onset AD to flourish. In most modern societies, the cognitive complexity and lifestyle choices would place considerable negative selective pressure on those with early onset AD mutations. The Columbia kindred is now the world's largest early onset AD cohort. This group is an important AD research resource: this group is guaranteed to develop AD within a narrow timeframe. A clinical trial is underway to prevent progression to AD in this group.

 

Another consideration regarding the selective pressures in AD is the complexity of the genetics of neuropsychiatric illness. For example, it is now believed that 10,000 mutations interact to confer risk for schizophrenia. With such complexity, it is hard to imagine that natural selection would be effective. (Global schizophrenia rates are similar across nations). AD also has interacting genotypes that are not likely to be selected against. For example, C282Y from the HFE gene and C2 from the TF gene when combined significantly increase the risk of AD, though they have minimal effect when inherited individually.

      

[John Schloendorn]

AD04 was one of the placebo arms in the Phase 2 clinical trial looking at AD02.

 

Haha.  I love how the disgusting spin-doctors are phrasing it "This success is owed to our strategy of clinical maturation..."  

 

I'm not sure there's much to explain there at this time.  Throw enough random stuff, and something's either gonna work, or at least you'll see some pretty weird random spikes in the data.

[Nemo888]

Comparison of three amyloid assembly inhibitors: the sugar scyllo-inositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01. http://www.ncbi.nlm....pubmed/22860214 The most promising one, CLR01

http://www.biomedcen...2050-6511/15/23

[Blankspace]

This new lithium compound (Li3PQQ) shows better efficacy at lower doses than traditional LiCl for attenuating symptoms of Alzheimer's disease:
 

Abstract:

Alzheimer's disease (AD) is a complicated, neurodegenerative disorder involving multifactorial pathogeneses and still lacks effective clinical treatment. Recent studies show that lithium exerts disease-modifying effects against AD. However, the intolerant side effects at conventional effective dosage limit the clinical use of lithium in treating AD. To explore a novel AD treatment strategy with microdose lithium, we designed and synthesized a new chemical, tri-lithium pyrroloquinoline quinone (Li3PQQ), to study the synergistic effects of low-dose lithium and pyrroloquinoline quinone, a native compound with powerful antioxidation and mitochondrial amelioration. The results showed that Li3PQQ at a relative low dose (6 and 12 mg/kg) exhibited more powerful effects in restoring the impairment of learning and memory, facilitating hippocampal long-term potentiation, and reducing cerebral amyloid deposition and phosphorylated tau level in APP/PS1 transgenic mice than that of lithium chloride at both low and high dose (5 and 100 mg/kg). We further found that Li3PQQ inhibited the activity of glycogen synthase kinase-3 and increased the activity of β-amyloid-binding alcohol dehydrogenase, which might underlie the beneficial effects of Li3PQQ on APP/PS1 transgenic mice. Our study demonstrated the efficacy of a novel AD therapeutic strategy targeting at multiple disease-causing mechanisms through the synergistic effects of microdose lithium and pyrroloquinoline quinone.

Full free text is available:
http://dx.doi.org/10...ing.2014.06.003

[Nemo888]

An oldy but a goody. Published 1976.

http://www.jimmunol..../1/156.abstract

 

Thymosin Restores T Cell Function and Reduces the Incidence of Amyloid Disease in Casein-Treated Mice¹

1. Morton A. Scheinberg,
2. Allan L. Goldstein and
3. Edgar S. Cathcart²

+ Author Affiliations

1. From the Arthritis and Connective Tissue Disease Section, Evans Department of Clinical Research, University Hospital and the Thorndike Memorial Laboratory and Division of Medicine, Boston City Hospital, Boston, Massachusetts 02118 and from the Division of Biochemistry, Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas

Abstract

Evidence is presented that T cell impairment appears to be specifically related to the pathogenesis of experimental amyloidosis. This conclusion is based on the finding that thymosin administration improves T cell function as measured by mitogen stimulation of spleen cell suspension and at the same time reduces the incidence and severity of amyloid disease in casein-treated mice.

 

Based on the Alzheimer's vaccines to activate T cells often reducing local proinflammatory markers one would wonder if T cell impairment was more causative than correlative in AD. If that proved to be true TB4 could slow the progression of the disease,....Based on forgotten data from 1976.

 

Edited by Nemo888, 31 July 2014 - 02:19 PM.

[GhostBuster]

Personally, I am almost convinced that Alzheimer's disease is caused by herpes simplex virus and possibly other pathogens also play role. If this is so, it means that a lot of alzheimer research is practically rubbish/idiotism that confuses effects with the cause (but luckily there is still good research). Immunosenescence is probably also related to AD as disease is progressively more common among old people. Ok, here were go (with the latest - more or less - research)...

 

 

How plausible is a link between HSV-1 infection and Alzheimer's disease?

 

...In the light of these considerations, why is HSV-1 a strong candidate in the pathogenesis of AD? HSV-1 primary infection usually occurs during childhood and involves initially the epithelial cells of the face mucosal membranes and secondarily the sensory nerve terminals. From these sites, the virus invades the nervous system where it can remain in a latent condition in the sensory ganglia. Secondary HSV-1 reactivation is relatively frequent, resulting in cold sores, a harmless nuisance, in about 25% of infected individuals, and much more seldomly in serious neurological complications including encephalitis [7]. From an epidemiological standpoint, many neurological chronic pathologies are suspected to be triggered by viral persistence. Thus, not only herpesviruses, but many other DNA and RNA viruses (e.g., measles, HIV, varicella zoster virus, JCV) are known to be associated with severe pathologies of the nervous system (e.g., subacute sclerosing panencephalitis, HIV-associated dementia, progressive multifocal leukoencephalopathy). All these diseases can develop decades after the primary infection. Molecular evidences show that HSV-1 infection of neuronal and glial cells results in an increase of the intracellular levels of β amyloid (Aβ), a decrease of the amyloid precursor protein and the phosphorylation of Tau protein, the main component of neurofibrillary tangles [8–11]: these are the same cellular events associated with the development of AD. Recent results have also demonstrated that the interaction between amyloid precursor protein and the HSV-1 capsid proteins [12] is essential to allow the migration of new viral particles inside infected cells. Moreover, HSV-1 can modulate the host autophagy, inhibiting the homeostatic process involved in turnover/elimination of cytoplasmatic components, damaged organelles and protein aggregates [13]; this mechanism was recently suggested to contribute to deposition of amyloid plaques within the brain. Finally, neuropathology of human HSV-1 acute encephalitis and studies on animal models showed that HSV-1 infection preferentially targets the same brain regions that are altered in AD: the frontal and temporal cortices as well as the hippocampus

http://informahealth...210.2014.887442

 

 

HSV-1 and Alzheimer's disease: more than a hypothesis.

 

http://www.ncbi.nlm....pubmed/24847267

 

 

Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature.

 

BACKGROUND:

Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology?

DISCUSSION:

Both ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology.

MECHANISM:

Infection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of 'immunosterol' 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease.

SUMMARY:

We postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology.

 

http://www.ncbi.nlm....pubmed/24656052

 

 

Alzheimer's disease plaques and tangles: cemeteries of a pyrrhic victory of the immune defence network against herpes simplex infection at the expense of complement and inflammation-mediated neuronal destruction.

 

Plaques and tangles are highly and significantly enriched in herpes simplex (HSV-1) binding proteins (by 11 and 15 fold respectively (P<4.47466E-39) and 132/341 (39%) of the known HSV-1 binding partners or associates are present in these structures. The classes involved include the majority (63-100%) of the known HSV-1 host protein carriers and receptors, 85-91% of the viral associated proteins involved in endocytosis, intracellular transport and exocytosis and 71% of the host proteins associated with the HSV-1 virion. The viral associated proteins found in plaques or tangles trace out a complete itinerary of the virus from entry to exocytosis and the virus also binds to plaque or tangle components involved in apoptosis, DNA transcription, translation initiation, protein chaperoning, the ubiquitin/proteasome system and the immune network. Along this route, the virus deletes mitochondrial DNA, as seen in Alzheimer's disease, sequesters the neuroprotective peptide, ADNP, and interferes with key proteins related to amyloid precursor protein processing and signalling as well as beta-amyloid processing, microtubule stability and tau phosphorylation, the core pathologies of Alzheimer's disease. Amyloid-containing plaques or neurofibrillary tangles also contain a large number of complement, acute phase and immune-related proteins, and the presence of these pathogen defence related classes along with HSV-1 binding proteins suggests that amyloid plaques and tangles represent cemeteries for a battle between the virus and the host's defence network. The presence of the complement membrane attack complex in Alzheimer's disease neurones suggests that complement mediated neuronal lysis may be a consequence of this struggle. HSV-1 infection is known to increase beta-amyloid deposition and tau phosphorylation and also results in cortical and hippocampal neuronal loss, cerebral shrinkage and memory deficits in mice. This survey supports the contention that herpes simplex viral infection contributes to Alzheimer's disease, in genetically predisposed individuals. Genetic conditioning effects are likely to be important, as all of the major risk promoting genes in Alzheimer's disease (apolipoprotein E, clusterin, complement receptor 1 and the phosphatidylinositol binding clathrin assembly protein PICALM), and many lesser susceptibility genes, are related to the herpes simplex life cycle. 33 susceptibility genes are related to the immune system. Vaccination or antiviral agents and immune suppressants should therefore perhaps be considered as viable therapeutic options, prior to, or in the early stages of Alzheimer's disease.

 

http://www.ncbi.nlm....pubmed/21167244

 

 

Reactivated herpes simplex infection increases the risk of Alzheimer's disease.

Abstract

BACKGROUND:

Previous studies have suggested a link between herpes simplex virus (HSV) type 1 and the development of Alzheimer's disease (AD).

METHODS:

The present analysis included 3432 persons (53.9% women, mean age at inclusion 62.7 ± 14.4 years) with a mean follow-up time of 11.3 years. The number of incident AD cases was 245. Serum samples were analyzed for anti-HSV antibodies (immunoglobulin (Ig)G and IgM) by enzyme-linked immunosorbent assays.

RESULTS:

The presence of anti-HSV IgG antibodies was not associated with an increased risk for AD, controlled for age and sex (hazard ratio, HR, 0.993, P = .979). However, the presence of anti-HSV IgM at baseline was associated with an increased risk of developing AD (HR 1.959, P = .012).

CONCLUSION:

Positivity for anti-HSV IgM, a sign of reactivated infection, was found to almost double the risk for AD, whereas the presence of anti-HSV IgG antibodies did not affect the risk.

 

http://www.ncbi.nlm....pubmed/25043910

 

 

Oxidative stress enhances neurodegeneration markers induced by herpes simplex virus type 1 infection in human neuroblastoma cells.

 

Mounting evidence suggests that Herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer's disease (AD). Previous work from our laboratory has shown HSV-1 infection to induce the most important pathological hallmarks of AD brains. Oxidative damage is one of the earliest events of AD and is thought to play a crucial role in the onset and development of the disease. Indeed, many studies show the biomarkers of oxidative stress to be elevated in AD brains. In the present work the combined effects of HSV-1 infection and oxidative stress on Aβ levels and autophagy (neurodegeneration markers characteristic of AD) were investigated. Oxidative stress significantly potentiated the accumulation of intracellular Aβ mediated by HSV-1 infection, and further inhibited its secretion to the extracellular medium. It also triggered the accumulation of autophagic compartments without increasing the degradation of long-lived proteins, and enhanced the inhibition of the autophagic flux induced by HSV-1. These effects of oxidative stress were not due to enhanced virus replication. Together, these results suggest that HSV-1 infection and oxidative damage interact to promote the neurodegeneration events seen in AD.

 

http://www.ncbi.nlm....pubmed/24124518

 

 

Intracerebral propagation of Alzheimer's disease: strengthening evidence of a herpes simplex virus etiology

 

http://www.ncbi.nlm....pubmed/23159044

 

 

Emerging roles of pathogens in Alzheimer disease.

 

http://www.ncbi.nlm....pubmed/21933454

Edited by GhostBuster, 28 November 2014 - 12:02 PM.