Jeff Morby: The Answers Are Being Revealed

Posted: Nov. 21, 2013

Several weeks ago, the Cure Alzheimer’s Fund (CAF) Executive Committee and staff met with the members of our Research Consortium in Chicago. The purpose of the meeting was to review the progress of the different researchers and to brainstorm with them, as we do every year, about what modifications we should make to our roadmap to take advantage of our findings to date and to determine research targets for the coming year – always with the objective of accelerating our progress in finding a cure/preventative for Alzheimer’s.

This year the meeting with the researchers was different from past meetings, because we believe we have reached an important inflection point:

First, as a result of our research to date, we believe we now have a very comprehensive understanding of the causes of Alzheimer’s disease. We and our researchers have jointly agreed upon a standardized model of the many causes of Alzheimer’s disease stemming from our research, and we have linked those causes to specific genes. This is a tremendous breakthrough because it gives us a clear pathway with which to focus our research – the genes and the causes have now been linked!

Second, we now have acquired the complete dataset with which we can determine with precision where within the entire human genome occur “functional variants.” These are variations in the DNA of any gene of interest which alter protein functions as compared to the functions of normal proteins. We are specifically searching for functional variants in the genetic subset of the 100+ Alzheimer’s genes that now have been discovered and which would be predicted to directly impact risk for disease.

The new genomic dataset has been created by us as a result of two achievements:

  1. The completion of our $5.4 million Alzheimer’s Disease Whole Genome Sequencing Project (WGSP) of 1,500 Alzheimer’s families, combined with
  2. the development of state-of-the-art algorithms and software (the biometrics) to permit us to efficiently analyze the “big data” generated by the WGSP. The WGSP was financed entirely by Cure Alzheimer’s Fund, and the biometrics project was supported both by Cure Alzheimer’s Fund and a $4 million grant to Dr. Tanzi from the National Institute of Mental Health. We are the first research group to generate a comprehensive familial Alzheimer’s disease database capable of linking gene defects directly with brain malfunction for virtually any gene of interest. We believe this is currently the most comprehensive database of Alzheimer’s genetics in the world.

Third, we have three key potential cures in advance states of development. One, the Gamma Secretase Modulator (GSM) project, which we funded initially and now are continuing to fund and refine with the NIH (which is contributing millions of dollars to the project), should be moving into human trials over the coming year. Two other drug development projects, one revolving around the Alzheimer’s gene known as CD33 and the other involving ACAT inhibitors (which inhibit the production of amyloid), are also well underway. The CD33 gene, which we were the first to identify 5 years ago in our first whole genome scan, is extremely powerful in terms of impact, and we have been working to understand its “mechanisms of action” (that is, understand how it works) – this we now have accomplished! The CD33 genetic variant is protective against Alzheimer’s and has provided valuable clues for identifying therapies that would mimic that mode of protection.

Fourth, we are planning a large number of new research projects to be directed by a wide variety of outstanding scientists aimed at understanding and finding cures for every one of the new Alzheimer’s genes shown in the attached chart, with the APOE gene and tau tangles as top priority targets. Our progress on all of these efforts is being greatly accelerated by our ability, using our new tools and datasets to identify the precise variations in our DNA that explain how our new Alzheimer’s genes impact risk for disease.

So what is the “inflection point” I mentioned above? It is the point at which we are finally in a position to believe that we have all the information we now need to find a cure. That information is in the form of a comprehensive model of AD pathology; an advanced database and algorithms to pinpoint variants with precision and link them to their deleterious manifestations; a rich prior history of experimentation (over 100 research papers in the best publications), which provides us with the background to intelligently interpret data identified with our new tools; and a world-class group of AD researchers, totally knowledgeable and committed to working in a collaborative way to rid this planet of Alzheimer’s disease.

But it will cost money to take full advantage of our unique and privileged position in understanding the link between Alzheimer’s genetics and brain pathology, now provided to us by our highly successful whole genome sequencing efforts. The founding families and directors both contribute to research funding as well as pay all of the operating costs of the foundation so that all charitable contributions go 100% into research. We continue to make that commitment - putting our money and efforts “where our mouths are.” We and our researchers are very excited about the promise offered by this new stage of our development, and we hope you are too. If you have already made your annual appeal contribution, I thank you. If you have not yet, please help us in this quest.

Best wishes,

Jeff Morby
Chairman, Cure Alzheimer’s Fund