At a recent meeting of our Research Consortium, made up of some of the world’s most brilliant scientists in the field of Alzheimer’s research, there was virtually unanimous agreement among the participants that CAF has been one of the principal leaders in the field and is unique among the research groups grappling with the disease.
The above described perception has motivated me to share with you what I believe are five important leadership roles CAF has carried out within the field:
First: Leadership in the Genetics of Alzheimer’s Disease
Twelve years ago, when we first established the foundation, there were only 4 known Alzheimer’s genes, representing about 30% of the causes of the problem. We knew that we had to find and understand the many other undiscovered genes in order to make headway against the disease. Consequently, in 2006 we performed the first genomic scan of the disease and made a truly breakthrough discovery at the time—we discovered 5 new genes, a discovery which was dubbed one of the “Top 10 medical breakthroughs in 2008” by TIME Magazine. Subsequently we were the first in 2011 to perform another genomic scan using the newest technology at the time. After that, in 2013, we were the first organization in the world to use new state-of-the-art technology “whole genome sequencing” to sequence the entire DNA of a database of more than 1,500 individuals from families afflicted by Alzheimer’s disease.
Today we have one of the largest databases in the world of the genomics of Alzheimer’s disease, having discovered more than 50 new Alzheimer’s genes containing over 350 genetic variants associated with risk for the disease. As Rudy Tanzi will describe, this database has allowed us to undertake the Genes to Therapies™ (G2T) program, in which we have launched a major effort to understand 20 of the most significant Alzheimer’s genes—how they interact individually and collectively to cause AD—and how we can stop them from doing so.
Second: Leadership in the Creation of Advanced Research Tools
Of course, the genomic database combined with the genomic analytics is our major research tool. But, also importantly, Rudy, Doo Yeon Kim, and their team have developed a breakthrough technology, called “Alzheimer’s in a Dish” (ADD), which allows scientists for the first time to grow a neuron in a 3-dimensional environment, a mini-brain, in order to see how the neuron develops its pathology and how it reacts to potential medications. The analytical tool is so powerful that it can be used for analysis of a variety of other neurological diseases. Its importance was underlined both by a full-page article in The New York Times as well as a special blog post by Francis Collins, director of the NIH.
ADD is also leading CAF to develop additional tools. One of these represents an extension of the mini-brain concept to include visualization of the formation and spreading of Tau, the actions of microglia, and the operation of the blood-brain barrier.
Another is the creation of rapid throughput analysis processes, using ADD, to ascertain whether or not existing drugs currently on the market can be repurposed to be used as preventatives for Alzheimer’s disease. We have already analyzed approximately 1,200 drugs and have identified dozens of high-potential prospects for consideration in future trials.
Finally, an important analytical tool for most of biological science is what is called a “transgenic mouse,” which is a mouse grown with human DNA, which causes such mice to neurologically respond to stimuli as a human brain would do with the same set of genes. Such mice, with Alzheimer’s DNA, can be used to test potential drugs for use against Alzheimer’s disease. As mentioned earlier, in 2004, there were only 4 known AD genes. These same genes, incorporated into the brains of transgenic mice, have been for more than 10 years the “mice standard” against which potential drugs have been tested. However, we now know that there are far more AD genes than 4. Therefore, many more transgenic mice beyond those of the 4 genes are required if we are to have the proper vehicles for testing drugs. So, as part of the G2T project, we are now developing new transgenic mice with the information provided by our genomic database. Importantly, as we develop such mice, we make them available to both our researchers and the whole scientific community – a major contribution to science.
Third: Leadership in the Development of Effective Forms of Scientific Collaboration
It is hard to imagine a more talented group of scientists than the list of our Research Consortium and SAB collaborators. This last year we have added another group of exceptional scientists, as Rudy will describe below. But apart from capabilities, what truly distinguishes these groupings of scientists is their willingness, in fact eagerness, to collaborate. Over time, all of them have developed with us an atmosphere of trust and cooperation and are willing to share their unpublished insights and participate in quarterly brainstorming sessions focused on attacking the disease in new and creative ways. Additionally, they are guided in their research decisions by CAF’s Roadmap, a jointly shared strategy, which is changed as new scientific insights are attained.
Fourth: Conceptual Leadership in the Attainment of New Scientific Insights
I believe that it is safe to say that we have been a conceptual leader in the field of Alzheimer’s research. Our emphasis on genomics, the development of new tools, and our collaborative approach to scientific exploration, as described above, are some examples. But there are others. One of these is the conceptualization of a comprehensive model of Alzheimer’s disease. This model has allowed us to identify what we call “intervention points” to use in potentially combatting the disease as it spreads. Each one of these intervention points represents a stage of development of the disease, which stage, if stopped, will arrest the progression of the disease. We have organized our research around those intervention points and the G2T project, and this year have committed to fund 44 different research projects totaling $10 million.
Of significant importance to the understanding of Alzheimer’s disease is our new conceptualization of what is called the “Anti-Microbial Protection Hypothesis.” Rob Moir and Rudy Tanzi of Mass General have been working for 5 years to validate this concept, and their paper providing strong evidence for the hypothesis in various experimental models was published in Science Translational Medicine in May 2016. This revolutionary hypothesis has the potential to fundamentally alter the current paradigm regarding how Alzheimer’s pathology is triggered in the brain. They have shown that Abeta is a component of the brain’s innate immune system, which is protective of the brain. Abeta traps pathogens in plaques when they enter the brain and kills them, which is a good thing and essential for the protection of the brain. However, too much of this activity, or genetic defects, may cause the brain to overproduce Abeta or fail to clear Abeta, thereby leaving too much Abeta in the brain. This results in “tangles” which kill neuronal cells from within, ultimately leading to Alzheimer’s disease. This radical, new view has major implications for drug discovery.
As new discoveries are made in the field, we adjust our priorities. One example of that is the human “microbiome” and what is called “epigenetics.” Based on solid scientific evidence, we now know that our human microbiome (made up of bacteria and other microbes in our gut and elsewhere within our body) has the capacity to influence how our genes code for proteins, with major implications for the disease. The gut microbiome also regulates brain inflammation, a key pathological feature of Alzheimer’s disease. We have already undertaken two new research projects with leaders in that field.
Fifth: Leadership in Foundation Management (Venture Philanthropy)
Many of the founders of this organization are former venture capitalists. The founders and directors have, over time, personally contributed $23.8 million to the foundation. These monies are used to pay the operating expenses of the foundation so that any contributions received from third parties go 100% into research. Given our backgrounds and financial contributions to the organization, we don’t want to waste money or waste time. We want a cure or preventative as soon as possible, and we manage the institution with this aim. We call the way we manage “Venture Philanthropy.” And the management processes we have set up have distinguished us as risk takers, fast decision makers, and strategists. These processes represent one of the reasons for our success (and one of the reasons we have been given a four star rating by Charity Navigator for the fifth consecutive time).
Cures in the Pipeline
Potential cures/preventatives have been long in coming, but we now have two in the pipeline. One of these, a gamma secretase modulator, is the equivalent of a statin for AD. It is, in essence, a preventative for Abeta accumulation in the brain in much the same way a statin is a preventative for the over-accumulation of cholesterol in the arteries. The second, Amylyx, is a medicine developed to protect neurons from cell damage which might occur as a result of over-concentration of Amyloid in the brain and brain inflammation. We expect Amylyx to go to human trials in 2016 and the gamma secretase modulator in early 2017. We also have preliminarily identified numerous existing medications which could possibly be repurposed for Alzheimer’s disease and, of course, have underway a great number of scientific studies, any one of which could identify a promising new drug at any time.
Many, Many Thanks
All of the above would not have been possible without your support and the support of the more than 23,000 contributors to our organization. In 2015 we raised $11.7 million, our 11th record fundraising year. Thanks to all of you very much for your significant generosity. A thank you, also, to our wonderful researchers and staff, all of whom continue to be inspired by our quest to rid this planet of the dread disease and as a result produce inspirational results, which continue to amaze.
Very Best Wishes,
Jeffrey L. Morby
Chairman and Co-Founder