(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?