Ignored work of Dr. Allen Roses at Duke?

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Russ
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Ignored work of Dr. Allen Roses at Duke?

Postby Russ » Mon May 04, 2015 12:43 pm

Stumbled across a very interesting article in my lunchtime reading today from Science Friday about long-term Alzheimer's researcher Dr. Allen Roses at Duke University...

http://sciencefriday.com/blogs/04/23/2015/against-the-grain-an-alternative-view-of-alzheimer-s.html?series=36

Throughout his career, Duke University neurology professor Allen Roses has challenged what for decades has been the prevailing orthodoxy in Alzheimer’s research: namely, the “amyloid hypothesis,” which suggests that a protein called beta-amyloid clogs up the brain, killing neurons and causing the dementia associated with Alzheimer’s disease. But “beta-amyloid is the result [of Alzheimer’s], rather than a cause,” he says.

For more than 20 years, Roses, 72, has pursued a hunch that dementia in Alzheimer’s patients stems from an inability in the brain to metabolize energy sources, such as glucose and oxygen. The trigger, he argues, is variations in two genes—ApoE and TOMM40—which ultimately inhibit mitochondria from supplying energy to neurons, causing them to die. A growing body of published literature supports his theory, Roses says, but by and large, he “has been totally ignored” by the field.


Not recalling the name at all, indeed I find only 3 hits to 'roses' in our forum all of which refer to the flower, not this work. Per the article, his work is very APOE4 specific and also TOMM40. An important section from the article...

After decades of plugging away at the Alzheimer’s puzzle, Roses’ overarching explanation for what causes the late-onset form of the disease concerns the effect that gene variants, such as ApoE4, have on mitochondria—the “engines” that use oxygen and glucose to supply cells with energy.

Mitochondria are critical for the normal functioning of neurons, which need energy to communicate with each other. But unlike other cells in the body, neurons can’t reproduce. Consequently, when mitochondrial motors slow down—as they do with age—they deprive neurons of vital fuel. As energy-starved neurons die with nothing to replace them, the brain’s cognitive functions also deteriorate.

Necessary to normal mitochondrial function is a gene called TOMM40. In 2009, Roses’ team reported that different lengths of a genetic variation in TOMM40, in concert with variations in the ApoE gene—located next door on the same chromosome—interrupt mitochondrial function within neurons. In studies performed to date, Roses’ team has shown that by testing patients for variations in TOMM40 and ApoE, they can identify those who have degraded mitochondrial function and are therefore at the highest risk of losing memory and thinking skills due to Alzheimer’s before age 80.

The involvement of TOMM40 can also help explain the presence of beta-amyloid in late-onset Alzheimer’s patients, according to Roses. The gene makes a protein that shuttles aggregates of other proteins into the mitochondria—and one of those proteins is the precursor to beta-amyloid. “The amyloid plaque is not pure,” says Roses.


He also has a major randomized controlled trial underway for both a prediction algorithm and intervention via a drug called pioglitazone...

But the biggest test of Roses’ algorithm is a 5,800-subject, five-year, double-blind, randomized, placebo-controlled trial currently underway through a collaboration between his startup Zinfandel Pharmaceuticals and Japanese drug firm Takeda Pharmaceutical. If the study shows that the algorithm does what it’s designed to do, the findings could give the field what it desperately lacks: a way to predict if a person is at risk for developing cognitive problems from late-onset Alzheimer’s disease.

For participants deemed at high risk by the algorithm, the investigators are also testing whether a very low dose of a drug called pioglitazone can delay the onset of memory- and thinking-impairments. If a drug were available today that staves off dementia by five years, it would reduce the cost of patient care by $50 billion by 2020, the Alzheimer’s Association estimates. Rodent and human studies have already shown that low-dose pioglitazone improved mitochondrial function and enabled them to better metabolize energy sources.

“At a point in time when people are about to suffer from mitochondrial inadequacy in their brain, the aim of the study [with Takeda] is to double the number of mitochondria and increase their ability to metabolize glucose and oxygen," Roses says.


Anyone here looked into Dr. Roses' work or this angle before?
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Re: Ignored work of Dr. Allen Roses at Duke?

Postby asiagillett » Mon May 04, 2015 2:11 pm

Came across this on YouTube. Haven't gotten gone through much of it yet.

https://www.youtube.com/watch?v=-WcvIcbtiEw

Looks like a very promising trial.

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Re: Ignored work of Dr. Allen Roses at Duke?

Postby Gilgamesh » Mon May 04, 2015 4:39 pm

Russ, fantastic, thanks! PubMeders, look here:

http://www.ncbi.nlm.nih.gov/pubmed/?term=Roses+AD%5BAuthor%5D

More for my infinite reading list.... But I think I'm going to bump this one up.

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Re: Ignored work of Dr. Allen Roses at Duke?

Postby Julie G » Mon May 04, 2015 5:00 pm

Thanks Russ, Asia & G- lots to pour through!

I've just skimmed a bit, but this looks like further corroboration that for our genotype, especially when combined with TOMM40 (ME :shock: !!!,) it's all about the mitochondria. Addressing this EARLY may be key.

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Re: Ignored work of Dr. Allen Roses at Duke?

Postby alysson » Mon May 04, 2015 6:58 pm

I haven't had time to read beyond this page, but does anyone know what the risk allele is for TOMM40?

I suspect that mitochondrial dysfunction is my biggest obstacle right know.
ApoE 4/4

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Re: Ignored work of Dr. Allen Roses at Duke?

Postby J11 » Mon May 04, 2015 7:59 pm

Well, I think I deserve some credit for my input on this.

For example, I have posted several times about the methylene blue trial (Phase 3 trial in AD should end in November of this year!).
See below for MB's Mitochondrial effect.

BMC Cancer. 2015 May 1;15(1):335. [Epub ahead of print]
Transient elevation of glycolysis confers radio-resistance by facilitating DNA repair in cells.

There is also my Dec 12 2014 post on the thread "Choosing the genetic future for your children". The figure included with my post is quite startling. It shows that the TOMM40 523 genotype appears to be highly relevant in determining age of onset of those with e34 and e33. For an e33 knowing one's 523 genotype would seem to be very helpful. My suggestion to rename our forum 523 LL did not gain much traction.

523 is rs10524523. We just missed out on this one with our exome scan.

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Re: Ignored work of Dr. Allen Roses at Duke?

Postby SarahAnne » Tue May 05, 2015 12:16 am

I read about Dr. Roses study with Takeda Pharma about a year ago. As a result, I started my mom on a tiny dose of Actos/Pioglitazone. The dosage in his study with Takeda Pharma is only 0.8mg (way below the standard 15-45mg pills). I urged my mom's doctor to prescribe a tiny dose of Actos and, fortunately, her fasting insulin levels were sufficient to justify it. So now my mom (in early/mid AD) is on Actos, but only a very tiny dose.

I have wanted to ask this group how they feel about implementing pharmaceuticals in this way (with the assistance/approval of an MD of course) with drugs like Metformin or Actos or Rosiglitazone, etc. It is a very loaded question. But it's one that, I believe, we should be able to directly address. For example, the supplement vendor Life Extension Foundation (lef.org) has reported publicly for years that Metformin is potentially helpful in a host of major illnesses from cancer to AD. They refer to it as a drug that "virtually everyone should ask their doctor about." And, they suggest that it goes hand in hand with a calorie restriction regimen and is recommended for those with poor glycemic control. I am not in the medical field and am not suggesting pharmaceuticals. Rather, with so many knowledgable and scientifically trained contributors on this website I would genuinely appreciate educated opinions, and/or references to published research in this area.

Many thanks...

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Re: Ignored work of Dr. Allen Roses at Duke?

Postby SarahAnne » Tue May 05, 2015 12:38 am

By the way, I should say that I met with Dr. Roses last year. He could not and did not suggest going vigilante on taking Pioglitazone. I did that fully on my own. His analysis of TOMM40 is much more detailed than whether one has a particular SNP. I have a bunch of variants on Tomm40. He's looking at impossibly small spaces between genes in that region, if I understand things correctly (which I may not!). We just have to stay tuned. But the difficult part is that his current Pioglitazone study will take five years. I gather that the very low dosage of 0.8mg in the 5-yr study is based on how much seemed to be required to benefit the mice/rats in those models/studies.

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Re: Ignored work of Dr. Allen Roses at Duke?

Postby Gilgamesh » Tue May 05, 2015 6:45 am

J11, my friend! You deserve credit for a lot! I was thinking specifically of Roses's work, which I hadn't seen mentioned specifically before. But about TOMM40, yes, we've seen that before, from you and others.

Allyson, it's always good to know what the relevant SNP is, look it up on SNPedia, and know how to adjust one's risk, but, as SarahAnne points out (and J11 and others have pointed out previously), this is a tricky one. There are all kinds of variants and mutations in the gene that are being correlated with dementia. Often it's a case not of a particular variant of a SNP, but of variations in the length of the DNA strand (if II understand corr'ly, which I may not -- another non-fully-followed bookmark...).

GB

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Re: Ignored work of Dr. Allen Roses at Duke?

Postby Russ » Tue May 05, 2015 7:44 am

SarahAnne wrote: I have wanted to ask this group how they feel about implementing pharmaceuticals in this way (with the assistance/approval of an MD of course) with drugs like Metformin or Actos or Rosiglitazone, etc. It is a very loaded question. But it's one that, I believe, we should be able to directly address. For example, the supplement vendor Life Extension Foundation (lef.org) has reported publicly for years that Metformin is potentially helpful in a host of major illnesses from cancer to AD. They refer to it as a drug that "virtually everyone should ask their doctor about." And, they suggest that it goes hand in hand with a calorie restriction regimen and is recommended for those with poor glycemic control. I am not in the medical field and am not suggesting pharmaceuticals. Rather, with so many knowledgable and scientifically trained contributors on this website I would genuinely appreciate educated opinions, and/or references to published research in this area.

Well my opinion is that whereas I agree such selective drugs can go hand-in-hand with diet and lifestyle interventions, my bias is to look at evidence associated with the former (drugs) for clues on how to adjust the latter (diet/lifestyle)... the latter being more likely to address causes rather than symptoms (and cheaper and longer-lasting). But where time matters, and there just aren't any clues yet, then it can be very sensible to go for the drug earlier.

Still, personally, having been down the road of statin side effects, I would be much more cautious to dig deeper into underlying mechanisms of the drug to consider the side effects before actually pulling the trigger. Point interventions in a complex system seem likely prone to have tricky side-effects. In the end, informed, balanced and enlightened systemic thinking certainly can lead to a place involving both drugs and diet/lifestyle for optimal health. Sounds to me like that's exactly what you're doing...
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