Funding results, progress, innovation: Annual Report 2016

Message from the Co-Chairmen

Dear Friends,

We are pleased to report that in 2016, our cumulative committed research funding exceeded $50 million, and as of this writing, that number already has grown to $60 million. 

In 2016, we granted a record $13.5 million for 56 projects, an increase of 34 percent from 2015. The 2016 funding was provided by $15.6 million in donations from 15,000 donors, our 12th record fundraising year and an increase of 33 percent from 2015.

 

OUR LEADERSHIP ROLES

In last year’s chairman’s letter, Jeff Morby summarized five leadership roles that Cure Alzheimer’s Fund (CureAlz) has carried out within the field. We think these leadership roles make us unique among Alzheimer’s disease research groups, help explain our momentum, and are important to review with you.

 

First: Leadership in the Genetics of Alzheimer’s Disease. From the founding of CureAlz, we have emphasized the importance of genetics to Alzheimer’s research. Our goal has been to identify all risk genes, use those genes to identify disease mechanisms, and pursue potential therapies based on the knowledge gained from
AD genes. 

In 2005, there were only four known Alzheimer’s genes, representing about 30 percent of the genetic profile of the disease. Rudy Tanzi had co-discovered three of those four genes. Later, as head of our Alzheimer’s Genome Project™ (AGP), he discovered five new AD genes; the discovery was named one of the “Top 10 Medical Breakthroughs” in 2008 by TIME magazine. Since then, one of those five, CD33, has become the second-biggest drug target for Alzheimer’s in the biopharma industry (the first being the amyloid precursor protein discovered by Rudy in 1987). In 2013, we were the first research organization to use “whole genome sequencing” to sequence the entire DNA of more than 1,500 individuals from AD families, and this has led to the discovery of more than 100 new Alzheimer’s candidate genes.

We now have the most comprehensive Alzheimer’s genomics database in the world. It is being used to find the variants in the candidate genes that underlie biological risk for the disease, the results of which provide the underlying data for the Genes to Therapies™ (G2T) program. In that program we study how the newly identified Alzheimer’s gene variants cause AD and how we can design therapeutic leads to prevent them from doing so. 

More than two-thirds of the 5.4 million Americans living with Alzheimer’s are women. In 2016, CureAlz and the Rotary International Foundation co-funded a research project  to analyze databases of Alzheimer’s family genomes and, for the first time, identify gene variants that impact risk differently for women than for men. We already have found several new genes involved with inflammation in the brain that influence risk differently in females versus males, and expect to find additional differences in 2017.

 

Second: Leadership in the Creation of Advanced Research Tools. In order to study the new AD risk gene variants identified in the AGP, a large number of new mouse models of newly discovered AD genes are being created as part of G2T. Our scientists actively are using these mice “tools” to better understand different disease processes and test new therapies. In addition to the mouse models, the new Alzheimer’s genes and variants also are being studied using a unique new analytical tool developed by Rudy and Doo Yeon Kim in 2015, dubbed “Alzheimer’s in a Dish” (ADiD). The New York Times referred to it as “a giant step forward” for the field.

ADiD uses human stem cells to grow Alzheimer’s nerve cells and see them, which develop within an artificial mini-brain in a Petri dish gel that resembles the consistency of the brain. For the first time, this system is allowing both amyloid plaque and tau tangle pathology to be created and analyzed in a Petri dish. The system has been shared openly with the Alzheimer’s field and is potentially revolutionizing Alzheimer’s drug discovery; it now allows research studies to be carried out significantly faster and cheaper than with mice. Using this system and high-throughput screening of literally thousands of drugs, G2T has led to the discovery of nearly 50 known drugs and natural products that potentially reduce Alzheimer’s pathology. These drugs now are being analyzed for repurposing as Alzheimer’s drugs, with the expectation that some will become candidates for human trials. 

Our researchers continue to enhance the diagnostic capabilities of ADiD by adding inflammatory and blood-brain barrier genes to the ADiD mini-brain. Both inflammation and blood-brain deficiencies are major contributors to Alzheimer’s disease, and ADiD already is providing us with new insights. Furthermore, ADiD has proven to be a research tool of analysis for a number of different neurological diseases, such as Parkinson’s and ALS. Because of its analytical potential for the scientific community, in April 2017 CureAlz sponsored a highly successful symposium at the Alzheimer’s Disease/Parkinson’s Diseases Congress (ADPD) in Vienna, which updated more than 1,000 scientists on the latest advances in the ADiD model, and its use and results in drug screening.

 

Third: Leadership in the Development of Effective Forms of Scientific Collaboration. Our Research Consortium and Scientific Advisory Board members are some of the world’s most brilliant Alzheimer’s researchers. In 2016, we added three exceptional scientists to our Research Consortium: Ben Barres of Stanford University, Bart De Strooper of the UK Dementia Research Institute, and Nancy Ip of the Hong Kong University of Science and Technology. Apart from their capabilities, what truly distinguishes all of the scientists involved with our organization is their willingness to collaborate. All of them have developed in conjunction with CureAlz an atmosphere of trust and cooperation. All are willing to share their unpublished data and insights, and to participate in quarterly brainstorming sessions focused on attacking the disease in new and creative ways. Additionally, they are guided in their research decisions by the CureAlz Roadmap, a jointly shared overall research strategy, which is updated as new scientific insights are attained.

 

Fourth: Conceptual Leadership in the Field of Alzheimer’s Research. Our emphasis on genomics, translational drug discovery, the development of new tools and databases, and our collaborative approach to scientific exploration, has allowed CureAlz and its researchers to conceptualize a comprehensive model of Alzheimer’s disease that has led to a generally accepted scientific consensus about how Alzheimer’s disease originates and creates a vicious cycle of abeta peptide accumulation, tangle formation, nerve cell death and inflammation, leading to ever-accelerating nerve cell death. This model leads to three basic strategies for medical intervention (intervention points), around which we have organized our research: 1) early-phase intervention, inhibiting abeta peptide deposition and/or clearing it from the brain; 2) mid-phase intervention, preventing the formation and spreading of tau tangles; and 3) late-phase intervention, fighting inflammation and slowing down or stopping the disease process.  

In 2016, Rob Moir and Rudy Tanzi published a new paper on the “Anti-Microbial Hypothesis,” which The New York Times described as “provocative new research.” This revolutionary hypothesis about the underlying cause of Alzheimer’s disease shows that abeta, the peptide that forms plaque in the brain, is also a component of the brain’s innate immune system, the system that protects the brain from pathogens. Abeta traps and kills pathogens when they enter the brain, essential for the protection of the brain. However, too much of this activity, resulting from genetic or other defects, may cause the brain to overproduce, or fail to clear, abeta, thereby starting the vicious cycle of the disease. This radical new view has major implications for drug discovery. 

As new discoveries are made we adjust our research strategy (the Roadmap), which defines our priorities. Recently it has been found that the human gut microbiome has the capacity to influence how our genes code for a variety of Alzheimer’s-related phenomena, including brain inflammation. Accordingly, in 2016 we funded Sam Sisodia of the University of Chicago to investigate the link between the gut microbiome and Alzheimer’s disease; that investigation is continuing. Last year, Sam published an important paper showing that the gut microbiome controls plaque formation in AD mouse models. 

 

Fifth: Leadership in Foundation Management (Venture Philanthropy). Many of the CureAlz founders are former venture capitalists. The founders and directors have, over time, personally contributed more than $28 million to the foundation. The founders and directors pay all operating expenses of the foundation, so that 100 percent of any contribution from our generous donors goes directly into research. We want a cure or preventive measures identified as soon as possible, and we manage CureAlz with this goal. The management processes we have set up, which we call “venture philanthropy,” distinguish us as risk takers, fast decision makers and strategists. We proactively recruit the best researchers, fund them with no bureaucracy, challenge them for high-risk/high-reward projects and insist they collaborate. This venture philanthropy approach is one of the reasons for our significant momentum and successes, which have resulted in our being awarded—for the last five consecutive years—a four-star rating by Charity Navigator, including this last year under its new rating system a prestigious Perfect 100 Percent score, given to only 50 of 8,000 charities in the United States.

 

GOING FORWARD

While we are proud of these leadership roles we have achieved, we always are seeking to improve, and to make our research grants more impactful. To that end, during 2016 we conducted a detailed strategic review process, performed by a third-party strategy consultant. One of the recommendations adopted by the board from that process was to fund larger initiatives, involving multi-institutional consortia, to more deeply engage our leading researchers to holistically address strategic research themes. In that vein, we have formed our first consortium, CIRCUITS, a collaboration of nine research leaders from eight institutions, to use cutting-edge functional genomics, including epigenetic analysis and computational biostatistical tools, to model cellular pathways and gene interactions too complex to have been captured by past genetic analysis of protein production alone.  

The dataset of AD-relevant genes, variants, cell types and regulators produced will be made available to the entire field, providing a powerful new data-driven model to accelerate identification of potential points for therapeutic intervention. A second consortium focused on the APOE gene is in the process of being formed, as is a third, which is focused on the role of the brain’s immune response in Alzheimer’s disease. At the same time, we will continue to fund smaller “high-risk” and “proof-of-concept” grants, which have been such productive sources of our progress to date.

As we enter 2017, we acknowledge that Alzheimer’s disease increasingly has been in the news. On the positive side, awareness of AD in the public continues to increase, and research funding was a presidential campaign issue. On the negative side, several recent pharmaceutical-driven AD trials failed, and the initial 2017 U.S. budget proposal calls for cuts in National Institutes of Health research funding. All of this makes our focus on investigating the fundamental causes of Alzheimer’s disease even more important. We must have a comprehensive understanding of this disease to develop the successful therapies of the future. In the nearer term, we have two potential therapies entering clinical trials in 2017. One is a gamma secretase modulator, which has the potential of being a “statin” for AD. The second, Amylyx, is a medicine developed to protect neurons from cell damage, and is potentially useful for both ALS and AD.

All of the above would not have been possible without your generous support. We are forever grateful to each and every one of our donors, to our wonderful researchers—who are more excited with their progress than ever—and to our dedicated staff. We will not rest until a set of effective therapies rids this planet of this dreaded disease; with your help, we will succeed.

 

Very Best Wishes,

Jeffrey L. Morby
Henry F. McCance
Co-Chairmen and Co-Founders