Zilkha Symposium on AD

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RichardS
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Zilkha Symposium on AD

Postby RichardS » Sat Apr 16, 2016 3:51 pm

Notes on the 3rd Annual Zilkha Symposium on Alzheimer Disease & Related Disorders: Bench to Bedside and Beyond
(4/15/2016, University of Southern California, )


Yesterday, I spent the day at the Zilkha Neurgenetic Institute at USC. I wanted to share what I learned and some impressions.

Overall, the speakers were addressing mostly basic research without direct clinical application. It was heavy on molecular biology which meant, to this neuropsychologist, that I struggled to keep up during most talks. Two talks were entirely over my head. That noted I would like to share some things presented that may be of interest plus my impressions. It is also a way for me to digest and archive my day at the meeting, so some information below may be of marginal interest to many.

There was essentially neither discussion of diet or other lifestyle interventions nor anything about supplements. This was an effort to disseminate basic mechanisms of Alzheimer’s disease and related pathology and, to a lesser extent, addressing biomarkers.

My favorite talk (not coincidentally the only one I completely understood start to finish) was by Jeffrey Cummings who spoke on “Clinical Trials: Translating Basic Science to Clinical Care.” I had heard him speak during my psych internship and post-doc years, always articulate and interesting. He now has over 650 peer-reviewed papers!

Dr. Cummings highlighted a paper of his that I later found out has been downloaded 35,000 times: “Alzheimer’s disease drug-development pipeline: few candidates, frequent failures” Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4095696/ Most striking in his review of AD drug trials from 2002-2012 was “A very high attrition rate was found, with an overall success rate during the 2002 to 2012 period of 0.4% (99.6% failure).” (emphasis mine). Somehow he managed to spin this into optimism that we learn from each trial so that the field advances. I had a hard time sharing this impression.

He made a powerful argument that drug developers need to spend more time in Phase 2 trials to learn more about mechanism before moving on to Phase 3 efficacy trials. That said, he lamented that there are only 24 agents at Phase 1 trials for AD, highlighting the expected attrition rates at Phases 2 and 3.

Reliable biomarkers were a recurrent theme as was “precision medicine” where treatments identify the right biological targets, drugs, disease model, right patients (think genetic predisposition), and the right trial based on all of these. He was encouraged by inflammation targets but said the trials were not far along. He made a strong argument for needing to start intervening earlier with prevention strategies and focused on the lack of consensus on how to measure success when testing subjects who were enrolled as asymptomatic or with only subjective complaints. Some of the early biomarkers discussed were spinal Abeta42 and tau, amyloid-based PET scanning, and certain advanced MRI measures which I forgot to make note of.

Because the Q&A session for Dr. Cummings was cut short, I managed to catch him as he was running out the door to ask some questions about apoe both as a biomarker and for E4-specific therapies. He keeps close tabs on current clinical trials and could not think of any that specifically addressed E4’s. We did not get to discussing apoe as a biomarker. When I asked about what clinicians could do for E4’s, his first thought was the positive findings on exercise saying E4’s may find it especially helpful citing a former mentor of mine from 25 years ago (Steven Rao) http://www.ncbi.nlm.nih.gov/pubmed/26265157.

Based on what Cummings said, I would say we cannot look to the pharmaceutical world for much help for quite some time and less so for drug treatments targeting E4 carriers.


Dr. David M. Hotzman (Washington Univ) “Different Therapeutic Approaches to Targeting apoE” was the other talk I think would be of greatest interest to our community. From his presentation summary talking about mouse work
“…Our lab and others have shown that lowering apoE levels, at least for apoE3 and apoE4 results in significantly less Abet deposition and associated pathology. We have taken 3 different approaches to target apoE that will be discussed. Lowering apoE with anti-sense oligonucleotides (ASOs), over expressing the LDL receptor, and binding to apoE present in plaques with anti-apoE antibodies…”

From my notes:
• APOE controls Abeta aggregation and clearance. APOE4 status slows clearance
• Hypothesis-APOE shifts when Abeta deposition starts (E4’s maybe 10 years earlier than non-E4’s)
• Treatment option-disrupt APOE/Abeta interaction but the question is whether we would want to increase APOE or decrease it
• Use anti-sense oligonucleotides (ASO) to alter APOE expression (very early mouse work)
• Modifying LDLR receptors affects APOE and Abeta. Over-expression of LDLR decreases Abeta deposition in mice (Neuron, 2009)
• Immunotherapy-APOE binds to all amyloids found in the brain, may influence tau-opathies independent of Abeta


I hope to work through more of my notes, but in the mean time, I'm attaching a scan of the program and my likely illegible notes. Let me know if there are particular talks for which I have notes I could translate for you.

Questions? Comments? Rude remarks?
You do not have the required permissions to view the files attached to this post.

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Re: Zilkha Symposium on AD

Postby hill dweller » Sat Apr 16, 2016 4:02 pm

Many thanks.

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Re: Zilkha Symposium on AD

Postby Stavia » Sat Apr 16, 2016 5:20 pm

Richard thanks so much for sharing. I read the scanned document but its way above my pay grade.
Pity Holtzmann didn't mention sleep, I see it in his CV.
Take away message for me is that it's still so many unknowns biochemically.

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Re: Zilkha Symposium on AD

Postby RichardS » Sat Apr 16, 2016 11:33 pm

Regarding Holtzman, AD, and sleep, check out his paper from last year...full text http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351409/.

Disturbances in the sleep–wake cycle and circadian rhythms are common symptoms of Alzheimer Disease (AD), and they have generally been considered as late consequences of the neurodegenerative processes. Recent evidence demonstrates that sleep–wake and circadian disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Furthermore, the sleep–wake cycle appears to regulate levels of the pathogenic amyloid-beta peptide in the brain, and manipulating sleep can influence AD-related pathology in mouse models via multiple mechanisms. Finally, the circadian clock system, which controls the sleep–wake cycle and other diurnal oscillations in mice and humans, may also have a role in the neurodegenerative process. In this review, we examine the current literature related to the mechanisms by which sleep and circadian rhythms might impact AD pathogenesis, and we discuss potential therapeutic strategies targeting these systems for the prevention of AD.

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Re: Zilkha Symposium on AD

Postby Stavia » Sun Apr 17, 2016 3:22 am

Cool! Thanks so much Richard. I'm fascinated by circadian rhythm.

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Re: Zilkha Symposium on AD

Postby Julie G » Sun Apr 17, 2016 10:38 am

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

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Re: Zilkha Symposium on AD

Postby RichardS » Sun Apr 17, 2016 5:20 pm

Julie,

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.

I'm just that much more convinced that the very unsexy approach of lifestyle optimization is our best chance for prevention.

In a later post, I want to focus more on the vascular perspective. I've long assumed the main idea is that having clogged vascular in the brain is just another hazard to overall risk for dementia, but there was research that more directly linked neurovasculature health with the pathology of AD.

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Re: Zilkha Symposium on AD

Postby KatieS » Sun Apr 17, 2016 5:40 pm

Thanks you Richard for diligently posting on this symposium. Holtzman's article on sleep & AD was particularly interesting, noting a sleep study of the effects specially on E4s:
http://archneur.jamanetwork.com/article ... id=1757018
It appears to me that the risk is about halved with good sleep consolidation tracked actigraphically (those wrist motion detectors). My 4-month Fitbit sleep tracker is consistently in the high 90%, so this is encouraging.

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Re: Zilkha Symposium on AD

Postby RichardS » Wed Apr 20, 2016 3:58 pm

As I mentioned earlier:
I've long assumed the main idea is that having clogged vascular in the brain is just another hazard to overall risk for dementia, but there was research that more directly linked neurovasculature health with the pathology of AD.


The presentation by Dr. Iadecola on "Neurovascular Dysregulation in Mouse Tauopathy Models" got me thinking in new directions. His work on the interaction of the cells and substances that influence vascular response in the brain struck me. We know that tau proteins become more messed up as AD progresses. The parts that I have been missing are that (1) amyloid beta induces oxidative stress [ETA which then harms the vasculature], and separately (2) tau is directly involved in vasodilation (which, in turn, affects blood flow) through NMDA receptor activity (of which Namenda, an AD drug, is an antagonist). It is not simply that compromised blood flow as seen in cardiovascular disease or diabetes makes AD worse, although I have not doubt it does. It seems the ability of the brain to regulate cerebrovascular blood pressure in the optimal range is diminished. The brain likes to manage a relatively narrow range of blood flow from what we think of as the normal range of blood pressure. Tauopathy seems to make it so that this self-regulating mechanism of cerebral blood flow is less and less effective.

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.
Last edited by RichardS on Wed Apr 20, 2016 9:13 pm, edited 1 time in total.

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Re: Zilkha Symposium on AD

Postby KatieS » Wed Apr 20, 2016 7:49 pm

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.


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