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Meryl Comer:  Dr. Guarente, let’s move to the genetics of Alzheimer’s disease. 

Dr. Guarente:  Yes.  Some genes have been identified by virtue of studying families in which early onset of Alzheimer’s occurs and is inherited. So using regular standard genetic means scientists have identified a few genes that are important.  One is a gene called APP and that gene encodes a protein that gets cut up into bits. And one of those bits is the offending substance, the Abeta amyloid peptide that gives rise to plaques and gives rise to toxic species, oligomers, that figure in the disease.  Another gene that was identified through genetics is a protein called presenilin, which is the enzyme that cuts the APP protein into pieces that actually makes the last cut to liberate this offending A-beta peptide, so we can learn about the disease... And another locus that has been identified is APOE4, which is a risk factor for Alzheimer’s disease and is sort of less central in a molecular sense then are APP and the presenilin. So what the genetics tells us...  First of all, we can’t really do anything about our genes, so our genes are what they are, but genetics clues us in on what the players are that are important in a disease and what we do is we study those players and how they interact in the context of cells and organs, like the brain. And I think that it opens a door for us to develop strategies to tinker with these steps, but not with genes, but with drugs. And I think that drug development in this field there really is nothing right now for people with Alzheimer’s disease. And it’s really where there is an incredible demand, and a growing demand. And based on the biology that I just described really in a skeletal way of the relevant genes and the relevant pathways I think we have to hammer home to get to drugs and that is only going to come from experimentation and funding and a really intense effort because it’s not easy to develop drugs. And we’ve seen sort of a template for this with AIDS.  There was a tremendous emphasis put on getting drugs for AIDS, starting maybe 20, 25 years ago and it has led to drugs that don’t cure the disease, but treat it quite well. And I think that illustrates that once a society decides that they want to do something like this it can be done.

Meryl Comer:  Let’s put the genetic predisposition into perspective Dr. Gandy.  What percent?  If you say age is the greatest determinate of getting Alzheimer’s, what percentage of those are early onset or familial?

Dr. Gandy:  Well only about 3% of all of Alzheimer’s is early onset and completely familial, but APOE4 before increases the risk for Alzheimer’s and there are probably certainly more people with Alzheimer’s disease, partially because they have an APOE4 gene than with any other genetic risk factor. So it has been very challenging to understand exactly how APOE4 works and in fact that is an important clue for us to continue to follow because more people have APOE4 related Alzheimer’s disease than Alzheimer’s disease related to either APP or presenilin.

Dr. Guarente:  If I might just comment on that.  These other 90% of AD patients who don’t have a frank mutation in APP or the presenilin that is not to say that that pathway and those proteins, APP and A-beta are not critical in the disease.  I believe that very likely they are in all of Alzheimer’s cases, so by leveraging the genetics to get at these players and developing drugs I think we wouldn’t be just treating the 3%.  We potentially could treat everybody.

Dr. Gandy:  Yeah, but by the part of the power of these early onset genes is that the clinical manifestations and the pathology of the early onset genetic forms and the common later onset forms are indistinguishable except for the age at onset.  They look the same in your waiting room.  They look the same under the microscope, so Lenny is exactly right that this pathway points the way for all of Alzheimer’s disease.

Meryl Comer: Dr. Arancio, you wanted to make a point.

Dr. Arancio:  Yeah, my point is that I definitely agree with my friends here that interfering with this protein tau and A-beta could be beneficial in terms of therapy and to take advantage of that.  However, there is one thing that... an area that I think is underdeveloped in all our studies, which is what is behind that, what comes before that.  This is an area that when I see... which it’s my belief that there is... we need more attention because it’s totally a dark area because yes, in the 3% of cases there is for sure with a mutation these proteins are affected, but the remaining 97%, we should find out why.  It is not them directly.  It is something behind them that through them caused the damage and that is the area, a big area that could be very, very useful and I’d like to sort of find... to draw the attention on all of us that perhaps interfering with the protein that some of the protein that regulates the APP like Lenny just said for instance, also tau, we can interfere with physiological normal function of this factor and therefore we’re hoping to get rid of disease and we are causing other trouble and this could be the reason for failure of some of the drugs that even recently have failed.

Meryl Comer: Well let’s look at one of the other challenges and that is the area around finding biomarkers that will help in the early diagnostics and detection of this disease.

Dr. Gandy:  So biomarkers are sort of surrogates for the disease that can be measured perhaps before the clinical manifestations begin. And they primarily included things like blood tests, spinal fluid tests and brain scans. And we know now that we can visualize the buildup of amyloid in the brain long before any cognitive changes occur clinically.  About half of the people age 65 and older already have significant visualizable amyloid buildup in their brain yet they mostly aren’t demented. 

Dr. Troncoso:  I would like to add something, just one more point to the genetics.  It’s something that it’s very important to recognize that patients with Down Syndrome which have a definite genetic abnormality, all of them will have at least pathological Alzheimer’s diseases, if not necessarily a manifestation of dementia. And since they they have the APP gene is in chromosome 21 in the segment that is extra in patients with Down Syndrome, this also it supports the hypothesis that the APP and the amyloid is a triggering factor in the disease, but it’s also a very important genetic component.

 

Is Alzheimer’s Disease Gene...

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