Annual Report 2012

Message from the Chairman


Introducing a New Era in the Field of Alzheimer’s Research

Dear Friends,

On behalf of the Board of Directors and the Research Consortium, I want to thank all the donors, researchers and academic institutional partners supporting Cure Alzheimer’s Fund research for your help in making 2012 such a successful science and fundraising year. We welcomed new board member Robert F. Greenhill and quickly benefited from his guidance and wisdom, and we thank outgoing founding board member John S. Lazo, Ph.D., for his years of scientific oversight and service on the board. To the newest members of our community, I welcome you.

2012 was a fantastic year for us in three respects: 

  1. We are entering into a new era in Alzheimer’s research as a result of our $5.4 million commitment to Massachusetts General Hospital to fund the first and largest Whole Genome Sequencing Project for Alzheimer’s disease. 
  2. In 2012 we carried out a vast array of impactful research projects, all of which are moving us closer and closer to our goal of finding a preventative or cure for Alzheimer’s disease.
  3. The quality and scope of our research now is being recognized by an ever-larger group of supporters. This year we increased the number of our supporters by more than 1,300, to a total of 6,900. And we increased our funding receipt to $6.7 million, an increase of 53 percent over last year’s total of $4.34 million. As always, the founders/directors pay all of the operating costs of the foundation so that 100 percent of donor funds go into research. 

Largest and Most Advanced Alzheimer’s Database in the World
As many of you know, we have led the way in genomic analysis of Alzheimer’s genes, in all cases using the newest technologies available. With the results in hand from Phases I and II of the Alzheimer’s Genome Project™, we, through our funding of Whole Genome Sequencing at Mass General (AGP III), will have one of the largest and most comprehensive databases of Alzheimer’s genes in the world. AGP III is important for three reasons:
It greatly speeds up the process of understanding the “mechanism of action” of the genes we are studying.

  • The AGP III will allow us to sequence the entire 3 billion base pairs of the human genome, something that never was possible to do. Prior to the AGP III, we only could look at select genes, one at a time, which misses most of the genome and is not very cost effective. Whole Genome Sequencing will greatly speed up our ability to understand the Alzheimer’s genes and develop potential cures for forms of Alzheimer’s disease caused by various gene defects.
  • The AGP III also will facilitate our further understanding of Alzheimer’s genes. With AGP III we will be able for the first time to understand the contribution of what is called “junk DNA” to disease processes. The “junk DNA” is formally called “intergenic” DNA, since it resides in between the genes. While genes represent only 2 to 3 percent of the DNA in the human genome, 97 percent of human DNA is “intergenic.” The recent release of data from the ENCODE Project (described later by Dr. Tanzi) now is allowing the scientific community to begin understanding the functions of the “intergenic” DNA in health and disease, including Alzheimer’s disease. Thus, with the initiation of AGP III, we now are in a position to take the final genetic step in our understanding of Alzheimer’s genes. As Dr. Tanzi will tell you, for many of the Alzheimer’s genes, we have discovered it was impossible to identify the mechanisms of actions that caused the deleterious effects of specific Alzheimer’s genes. The ENCODE Project revealed that intergenic DNA has an important regulatory function vis-à-vis genes. Therefore, with the new Whole Genome Sequencing methodologies and bioinformatic analyses, we will have a powerful vehicle for truly understanding the basic causes of the malfunctions of the various Alzheimer’s genes we have discovered in the AGP.
  • Finally, because intergenic DNA does perform regulatory functions, one can potentially eliminate certain functions within intergenic DNA and emphasize others, etc., in order to regulate or impact the underlying genes. Therefore the AGP III will lead us to further potential therapies for Alzheimer’s disease. 

Breakthrough Research Projects—Attacking AD from a Variety of Perspectives
Alzheimer’s is thought to be caused or influenced by three related phenomena: excessive accumulation of beta-amyloid in the brain; neurofibrillary tangles made of the protein, Tau, which damage and kill neurons and spread rapidly through the brain; and finally, inflammation, which is induced by beta-amyloid and neurodegeneration associated with tangle formation. In the detailed descriptions that follow, you will read about a variety of exciting approaches we are taking to deal with these three problems. These approaches include:

  • reducing the production of beta-amyloid;
  • creating a mechanism that “crunches up” beta-amyloid and removes it from the brain;
  • creating mechanisms that improve the clearance of beta-amyloid from the brain;
  • stopping the formation of tangles; 
  • preventing the spread of tangles throughout the brain; and
  • protecting the brain from excessive inflammation.
  • There are a great many potential ways of dealing with the above problems, as you will see from reading the individual reports that follow. 

An Extremely Important Insight into a Fundamental Cause of Many Neurological Diseases
In the process of trying to understand the function of abeta amyloid in the brain, Rob Moir of Massachusetts General Hospital, supported by us, performed research that led to an extremely important insight, namely, that beta-amyloid is actually a component of our innate immune system and performs important protective functions within the brain. So, beta-amyloid is good, and only bad when in excess, e.g., due to genetic mutations or lifestyle choices that cause too much beta-amyloid to remain in the brain. Excess beta-amyloid triggers tangle formation and nerve cell death followed by inflammation and more nerve cell death. These findings suggest that in new drug development programs, we must take into account that we do not want to wipe out beta-amyloid in the brain!

Perhaps equally interestingly is the fact that within the etiology of other neurological diseases, such as Parkinson’s and diabetes, there are “amyloid equivalents” that perform the same protective functions as beta-amyloid. But these substances (such as Lewy bodies made of alpha-synuclein in the case of Parkinson’s and amylin (pancreas) in the case of diabetes) also are involved in a major way in the causes of those diseases. We actually have done some research on Parkinson’s and diabetes and have found the amyloid substances of both to be protective at normal levels of concentrations and harmful at higher levels—quite similar to that which occurs with Alzheimer’s. Consequently, we think we may have discovered at least one universal cause of these neurological diseases (and perhaps others as well). Obviously, this insight again could result in a mantra for drug development—modulate, not wipe out.

Scientific Impact of Our Work
In the Our Research Influence section that begins on page 27, we have summarized the number of scientific papers we have financed that have appeared in major scientific journals. The list is extremely long and impressive in terms of the impact, quality and depth of the work. As an indication of the scientific impact of our work, we have identified within the literature more than 4,000 references made by other researchers to our work. We think this is a record relative to other research groups.

Sharing Information With Others:
We continue to maintain the Alzgene database on the Internet, which is freely available to scientists who would like to interrogate that database. The database contains up-to-date information on all research projects undertaken anywhere in the world on Alzheimer’s disease. Since its inception in 2006, there have been about 150,000 hits on the Alzgene website, which is an indication of the impact our research is having on the scientific community.

Leveraging Our Efforts: The Multiplier Effect of Our Funding
One of our strategies at the very outset of the formation of Cure Alzheimer’s Fund was to attempt to leverage our own resources with the resources of others. The basic idea is that if we can do that, we will have greater chances of finding a cure as quickly as possible. Over the last eight years we have been able to generate more than $23 million in additional funding for Alzheimer’s-related efforts as a consequence of our involvement. This number incorporates co-funding projects with others, as well as research projects initially funded by us and taken over by others either as co-funders or absolute funders. One example is the gamma-secretase project that will be discussed in the pages to follow. In that particular instance, we carried out all the basic research for the gamma-secretase modulator, but the results were so spectacular the National Institutes of Health (NIH) basically worked with us to significantly increase the funding of the project by putting millions of dollars into it and by committing substantial scientific resources to it. We continue to work on the mechanisms of action related to the project, but NIH is now providing the bulk of the funding. 

To Conclude, a Great Year
We at the Cure Alzheimer’s Fund have had a wonderful year both in terms of our science and our funding. Now, with the Whole Genome Sequencing project under way, we are moving the science of Alzheimer’s into a totally new technological arena, one that should result in the acceleration of our quest to find a cure.

Thank you very much for your generous support. 

Best wishes,

Jeff L. Morby
Chairman and Co-Founder
Cure Alzheimer’s Fund