Q&A from July 22, 2010 Webinar

Posted July 30, 2010

Thank you again to the attendees of our webinar. Below are the questions we received from participants with answers from Dr. Rudy Tanzi, as well as links to additional information. We have also posted the slides of the presentation here. If you would like to download the PowerPoint file, e-mail Katie Cutler at [email protected].

1.We know the disease process of Alzheimer’s starts long before the actual pathology and symptoms develop. With the growing knowledge of genes involved, wouldn’t it be better to try the novel approaches in select individuals long before (say in their 50’s) instead of those that have established Alzheimer’s? It is disappointing (both to the researchers and the wider Alz community) to hear every time a study results are published, they come up with unsatisfactory results- Dimebon, Rember, Immunisation trials to name a few.

Yes, our goal is to use the genes to predict AD before it strikes and prevent the disease presymptomatically. I agree that it is not constructive to only focus on failed clinical trials of drugs that were not very good to begin with. Let’s focus on the next wave of therapies that have learned from these failures!

Note from Cure Alzheimer’s Fund: Check out more info on this in “Why the Drugs Don’t Work” and in “Sharing Data is Good But We Need to Better Understand Causes of the Disease”

I also wonder if other dementias – vascular/multi-infarct, mixed and frontotemporal dementias will respond to the treatments being developed for Alzheimer’s as the general consensus now appears to be mitochondrial dysfunction and neurotoxicity!

The frontal lobe dementias are based on tangle formation and tau protein abnormalities. So, drugs targeting abeta will most likely not be very helpful. This is why we also need anti-tangle drug programs.

2.What is the difference between genetic predisposition to Alzheimer’s disease and familial predisposition to Alzheimer’s?

The bottom line is that in familial early onset cases involving mutations in APP, presenilin 1 or presenilin 2, it is not so much predisposition as it is “causation”. Any one of the ~200 mutations in these three genes guarantee Alzheimer’s when inherited, usually before the patient turns 60 years old. In contrast, in late-onset AD (>60), the APOE4 gene variant increases susceptibility for AD usually between 60 and 80 (~3-fold if one parent transmits it, ~10-fold if both parents transmit it). So, this would be considered a gene variant that predisposes to AD but does not cause the disease with certainty the way the early-onset familial AD gene mutations do. Of course, you can also have familial late-onset AD and here we have found rare mutations in the ADAM10 gene that have strong effects on risk for getting the disease at about 72 years-old. In our Alzheimer’s Genome Project, we have found 200 new AD gene candidates. We are currently scouring these genes to find the defects and determine whether they are causative like the early-onset familial AD gene mutations, or predisposing like the APOE 4 variant.

3.Given (as you have found) that beta amyloid has an antibiotic role in the brain, the “Alzheimer’s vaccine” seemed to be the perfect Trojan Horse–wiping out beta amyloid and leaving the brain vulnerable to the agents that b-a were fighting off in the first place. You claim PBT2 takes this role of beta amyloid into account, leaving the fighting capacity of beta amyloid while removing the toxic “leftovers” of the fight. Is research also concerned about reducing the foreign cause of aggression in the brain–the agents that beta amyloid is designed to fight off? Is there perhaps an overabundance of these damaging bodies in Alzheimer’s cases?

Yes, we are looking into what types of brain insults trigger the innate immune system to produce excess abeta. These insults could range from neurovascular insults, e.g. strokes or traumatic brain injury, to infections.  With regard to the latter, we are focusing on Chlamydia pneumoniae and candida albicans, given our and other’s findings.

Note from Cure Alzheimer’s Fund: For more info check out “Abeta May Have Beneficial Function as Part of the Innate Immune System

4.You said Dimebon was a failure without giving specifics of why it was a failure. From web articles, it’s clear it was a failure because it did not improve memory. You also mentioned that another drug showed success (I think it was Bapi) in that it improved higher reasoning. There are plenty anecdotal accounts that Dimebon improved attention, social engagement and wit–functions that are regulated by the frontal cortex–the same area that affects higher reasoning. Why is one considered a success while the other is considered a failure for doing the same thing?

The official clinical trail results for both Dimebon and Bapi were negative in regard to cognitive improvement, which was the major primary endpoint measured for both drugs. However, in the case of Bapi, post-hoc stratification of APOE4-positive versus APOE4-negative patients showed that the latter group had some benefit. So, in the ongoing Bapi trial, I believe they included the APOE4 stratification as a primary endpoint and there could again be a positive result. The major caveat is that in the first trial and beginning of the current trial, APOE4-positive patients also suffered from more adverse side effects, including vasogenic edema (inflammation) of the brain and in some cases cerebal micro-hemorrhage. So the dose of Bapi in the ongoing trial had to be lowered for the APOE4-positive patients. We will have to wait and see if Bapi still has benefits for Cognition. Let’s hope so.

Note from Cure Alzheimer’s Fund: For more info check out “The Success Stories of Tomorrow” and “Why Don’t the Drugs Work”

From Twitter:

1.@CureAlzheimers How are Alzheimer’s and Chronic Traumatic Encephalopathy different?

They are entirely different. However, any brain trauma can theoretically increase downstream risk for AD. I don’t know of any data specifically linking chronic traumatic encephalopathy to AD.

2.@CureAlzheimers Opinions on the action on the alpha-7 nAch receptor in Alzheimer’s?

These drugs have strong potential for cognitive enhancement, perhaps even beyond that of current drugs on the market and maybe even working well in concert with each other. However, they would most likely just be treating the symptoms rather than the actual disease. We would certainly welcome their appearance!

Thank you again for attending our webinar! To stay up-to-date on our work, follow us on twitter at twitter.com/curealzheimers or like us on facebook at facebook.com/curealzheimers