Zilkha Symposium on AD

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
Harrison
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Re: Zilkha Symposium on AD

Postby Harrison » Wed Apr 20, 2016 8:10 pm

RichardS wrote:I, too, was baffled when I thought I heard Holtzman say we are unsure whether increasing or decreasing apoe would be therapeutic. I may have to chalk that one up to misunderstanding him. As Stavia said, a lot of it was above my pay grade and many of the speakers talked at a pace that left me behind. Still, I think it was encouraging that apoe levels were mentioned in the context of possible therapies.


Holtzman very much believes that decreasing apoE levels is the way to go for treating Alzheimer's, but there are others who believe just as strongly that increasing apoE levels is the way to go. Many pharma companies pursed LXR agonists, which increase apoE levels, but they never got past Phase I due to toxicity. If he was being even handed, it's quite possible that Holtzman could have said he was unsure about increasing or decreasing levels.

I'm surprised Jeff Cummings didn't say anything about his bexorotene trial when you asked him about apoE related therapies. Of course that trial looks like it didn't really work, but it was not very well powered to begin with.

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Re: Zilkha Symposium on AD

Postby Harrison » Wed Apr 20, 2016 8:15 pm

Juliegee wrote:No rude comments! On the contrary, I greatly appreciate you making the effort on our behalf. I agree that it's terribly disappointing to see the little progress mainstream medicine is making on our behalf primarily by focusing so narrowly on abeta.

I’m struck, once again, by the supposed unknowns re. ApoE loss of function vs. gain of function. It’s worth noting that Hotzman’s work seems to directly contradict the conclusion that Rasmussen reached regarding ApoE levels. Hmmm; a couple dozen genetically engineered mice vs over 75,000 humans?

Plasma levels of apolipoprotein E and risk of dementia in the general population.
http://www.ncbi.nlm.nih.gov/pubmed/25469919


An important distinction here is that Holtzman is probably talking about decreasing brain apoE levels, which would probably mean you would end up with higher plasma apoE levels. Maybe the study by Rasmussen is reflecting increased apoE in the brain and less in the plasma?

What complicates this is that it is generally considered that the brain makes all its own apoE and the the plasma apoE all comes from the liver, and the two pools do not mix. But maybe that breaks down in Alzheimer's disease with the leaky blood brain barrier?

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Re: Zilkha Symposium on AD

Postby RichardS » Wed Apr 20, 2016 9:04 pm

Harrison wrote:What complicates this is that it is generally considered that the brain makes all its own apoE and the the plasma apoE all comes from the liver, and the two pools do not mix. But maybe that breaks down in Alzheimer's disease with the leaky blood brain barrier?


Harrison -- Very good point. In my day job, I'm working on a gene expression project where we are keenly interested in biomarkers for depression, bipolar and schizophrenia. There are a number of biomarkers my group has pursued than ended up showing over expression in the human brain but under expression in peripheral blood or vice versa.

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Re: Zilkha Symposium on AD

Postby RichardS » Wed Apr 20, 2016 9:10 pm

Harrison wrote:I'm surprised Jeff Cummings didn't say anything about his bexorotene trial when you asked him about apoE related therapies. Of course that trial looks like it didn't really work, but it was not very well powered to begin with.


I vaguely remember him mentioning bexorotene during his talk but not afterwards when I was speaking with him directly. Based on the tenor of his talk, he may very well have discounted it, if as you say, "it didn't really work." He seemingly knows just about everyone doing AD clinical drug trials, so I trust his assessment.

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Re: Zilkha Symposium on AD

Postby RichardS » Wed Apr 20, 2016 9:43 pm

KatieS wrote:Richard, interesting mechanism of cerebral blood flow's relationship with tau and amyloid, would concussions, which do alter the ability to control the cerebral blood pressure, factor in how ultimately CTE/dementia occur? I hope the NFL's funded studies will reap more insights.


My dear wife, the pediatric neurologist, tells me that after the initial swelling from a concussion has gone, there is often ongoing blood pressure instability due to the effect of the inflammatory substances increasing reactivity of the smooth muscles that make up blood vessels. This is why after a concussion, many people will get their symptoms again with exercise or other physical maneuvers that increase cerebral blood flow and blood pressure. Concussed athletes are supposed to not engage in contact sports until there are no issues with headache or pulsations on exertion. You need to have an honest assessment from the patient, so athletes wanting to get back in the game are not ideal patients in this respect. Wild swings of blood pressure in the skull are seen during and after acute recovery.

I think it is fair to say the long term problems concussions lead to in the brain are a result of some or all of multiple factors including breakdown of blood brain barrier, accumulated scar tissue including microscopic tears, damage to the long nerve tracks that connect distant parts of the brain, compromised ability to remove waste products, and hormonal dysregulation from the pituitary and hypothalamus at the base of the skull which are particularly at risk from concussive forces. We can only hope the NFL does the good work needed to understand how CTE develops and what to do to prevent it. It is a sad mess they have created.

I'm glad that I and none of my kids participated in high contact sports.

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Re: Zilkha Symposium on AD

Postby Julie G » Thu Apr 21, 2016 7:10 am

An important distinction here is that Holtzman is probably talking about decreasing brain apoE levels, which would probably mean you would end up with higher plasma apoE levels. Maybe the study by Rasmussen is reflecting increased apoE in the brain and less in the plasma?

Rasmussen actually uses plasma apoE levels and finds a significant association with low levels leading to risk of dementia. His data set is comprised of over 75,000 people. This seems like not only a potentially important clinical biomarker, but also an opportunity for an intervention if we can determine what raises apoE levels.
Plasma levels of apolipoprotein E and risk of dementia in the general population.
http://www.ncbi.nlm.nih.gov/pubmed/25469919

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Re: Zilkha Symposium on AD

Postby Harrison » Thu Apr 21, 2016 10:05 am

Juliegee wrote:
An important distinction here is that Holtzman is probably talking about decreasing brain apoE levels, which would probably mean you would end up with higher plasma apoE levels. Maybe the study by Rasmussen is reflecting increased apoE in the brain and less in the plasma?

Rasmussen actually uses plasma apoE levels and finds a significant association with low levels leading to risk of dementia. His data set is comprised of over 75,000 people. This seems like not only a potentially important clinical biomarker, but also an opportunity for an intervention if we can determine what raises apoE levels.
Plasma levels of apolipoprotein E and risk of dementia in the general population.
http://www.ncbi.nlm.nih.gov/pubmed/25469919

Sorry Julie, I don't think I stated that very well. What I should have said is that Rasmussen observes lower levels of plasma associated with AD. Usually the blood brain barrier keeps the two pools of apoE separate, but with blood brain barrier leakiness observed in Alzheimer's, maybe the ApoE is concentrating in the brain (which Rasmussen didn't measure). This increased brain ApoE is what Holtzman thinks is pathological. Holtzman would like to decrease brain apoE by increasing uptake through the LDL receptor. Maybe that would push the apoE back to the periphery and you would see an increase in plasma ApoE with an effective treatment. I hope that makes more sense.

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Re: Zilkha Symposium on AD

Postby Silverlining » Thu Apr 21, 2016 2:30 pm

RichardS wrote:

Of course, this is a line of research about basic mechanisms. WARNING: my speculation follows...
I suspect that those with accumulating tau problems are more susceptible to messed up cerebral blood flow regulation. While this would logically happen in the case of cardiovascular disease, it may also be a result of low blood pressure, hypertension (separate from risk of stroke), sleep apnea (where repeated temporary drops in blood pressure happen), orthostatic hypotension (suddenly low blood pressure when moving from recumbent to standing), use of vasoactive substances, substances that affect one or more NMDA receptors adversely, etc. However, on the NMDA receptor idea, Namenda is an NMDA receptor antagonist which is thought to combat potential excitatory toxicity in AD, not a simple tie in with the vascular issue I've discussed.

A simplistic interpretation is that, in addition to keeping the pipes clean (not accumulating plaques or hardening the arteries) across the lifetime, try to keep blood pressure in a healthy range and for those already feeling the effects of AD, a fairly narrow range when not exercising. That said, what represents a healthy range can change as a result of age and vascular status. Don't assume low as possible is always better. Talk to a doctor who is smart about this stuff.


I feel so freakin doomed some days (today being one). I have low blood pressure and postural hypotension or orthostatic hypotension, whatever you want to call it. I see a cardiologist annually, but take no meds. I eat a lot of salt and focus on fluid intake. Anything else one can do to raise their blood pressure? There is midodrine that raises BP, but from what I understand it can cause extreme hypertension while supine and is dispensed cautiously. I've already experienced a retinal vasospasm due to who knows what, but the retina specialist also said she sees narrowing of the retinal vessels...sigh. What type of doctor is "smart" about this stuff?

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Re: Zilkha Symposium on AD

Postby RichardS » Thu Apr 21, 2016 6:11 pm

Silverlining wrote:I feel so freakin doomed some days (today being one). I have low blood pressure and postural hypotension or orthostatic hypotension, whatever you want to call it. I see a cardiologist annually, but take no meds. I eat a lot of salt and focus on fluid intake. Anything else one can do to raise their blood pressure? There is midodrine that raises BP, but from what I understand it can cause extreme hypertension while supine and is dispensed cautiously. I've already experienced a retinal vasospasm due to who knows what, but the retina specialist also said she sees narrowing of the retinal vessels...sigh. What type of doctor is "smart" about this stuff?


Silverlining - sorry to hear of your BP troubles. Keep in mind two things from what I said, (1) this is total speculation on my part as much of this stuff goes over my head and (2) if there is an effect on cerebral blood pressure auto-regulation and it is related to a tauopathy, then I suspect it mainly shows up once AD symptoms appear given the graph of timelines I saw at the conference that cover amyloid, tau, and other biomarkers.

Honestly, I don't know what doctors are good at this stuff. I commented about this because my wife had seen strokes or lesser vascular events when ER docs freaked out about someone with chronic hypertension showing up and assumed the BP had to be dropped immediately. She told me that people with chronically high BP are more at risk for troubles when their BP is suddenly dropped leaving the brain under-perfused and at risk for hypoxic brain damage. I really did not mean to freak anybody out. I'm just speculating about possible vascular mechanisms in people who have AD symptoms, not just having an apoE4 gene, and certainly did not mean any of my comments to sound like medical advice.

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Re: Zilkha Symposium on AD

Postby J11 » Thu Apr 21, 2016 6:34 pm

I think it is going to be very interesting to watch these forums with clinical AD leaders to see when they might just give way to the
CRISPR / gene editing revolution. There has been so many decades of this near 0.0% success rate in AD and so many other diseases.

What happens when the research community simply gives up and says "Let's not even bother to understand all this convoluted biochemistry! Let's simply gene edit our way to cures."? CRISPR could be this fantastic black box. It would not be necessary to understand any of the background chemistry of any of the diseases. All you would ever need to do is gene edit the problem away: problem solved. This is almost
certain to work once the CRISPR technology is perfected because we know that the genotype that is being engineered is "normal" and is by definition safe.


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