We have at last achieved an integrated understanding of the causes of Alzheimer’s disease and have created a scientific infrastructure and processes that are allowing us to understand and address most, if not all, of Alzheimer’s multifaceted causes. As a result, we have entered into a highly productive stage of our research, in which we now are in a position to define with some precision “intervention points” at which we can target specific potential scientific interventions focused on different causes of the disease.
Dr. Tanzi has remarked to me he is as excited about this facet of our evolution as he was more than 15 years ago when he co-discovered the first three Alzheimer’s genes. In his commentary, which follows, Rudy will provide you with a discussion of the state-of-the-art projects he oversees as chairman of our Research Consortium. But below, let me provide you with an overview from my perspective.
In terms of immediacy, our first potential cure/preventive will shortly be on its way to human trials—a statin-type drug for Alzheimer’s disease.
A gamma secretase modulator (GSM) is a therapy for modulating (e.g., safely reducing) the production of Abeta in the brain. We have been funding the development of such a preventive for some time, and the National Institutes of Health (NIH) now has become so enthused it is “fast tracking” the project and pouring millions of its own money into refining the product in preparation for human trials this year. The GSM is a drug that would be taken by mouth, with the dosage dependent on Abeta concentrations in the brain—in much the same way that statin dosage is determined by cholesterol levels.
We have developed the first “Alzheimer’s Model,” which defines the principal causal dimensions of the disease and allows us to identify “intervention points” to which research is directed.
As the reader will note from our disease model, Alzheimer’s disease pathology arises in different stages in the life of an individual, usually beginning early with the excessive creation of Abeta proteins in the brain, the impact of which does not show up until later in life. If one can moderate that process, it is likely that Alzheimer’s pathology will not develop. Therefore, one early-stage intervention strategy is to be able to moderate that process, and that is the purpose of the GSM described above (as well as other projects under way).
However, as Alzheimer’s progresses, there are a variety of intervention points at which research projects can be aimed to avoid the evolution of Alzheimer’s pathologies at those stages. As described in the body of this report, our research is focused on a number of these intervention points. The research interventions are designed (among other things) to develop means to:
a. prevent the accumulation of Abeta by lowering production or enhancing clearance;
b. prevent Abeta from damaging brain cells and synapses;
c. prevent the generation of tau tangles by Abeta or other factors;
d. prevent the spread of tau tangles within the brain;
e. prevent inflammation within the brain; and
f. speed or accelerate the clearance from the brain of Abeta and other toxic substances.
Our Scientific Infrastructure
One of the reasons we think we are at a new stage of evolution is that we now have a complete scientific infrastructure, which will allow us to greatly accelerate our progress. Some of the elements of that infrastructure are:
Databases of the genetics and biology of Alzheimer’s disease
The accumulated information includes results from the first genome-wide association screen for Alzheimer’s disease genes started in 2005, and the first Whole Genome Sequencing (WGS) of Alzheimer’s disease families, begun in 2012. In addition, our AlzGene database, updated continually, available free of charge to all scientists and containing systematic information on all Alzheimer’s-related genetic research from all over the world, now is being completely overhauled to include whole genome sequencing information as well.
This collection of databases, particularly that of the WGS, has permitted us in an extremely short time to identify nearly 1,000 new genetic mutations in more than 50 different AD genes. Perhaps most importantly, Dr. Tanzi and his team have been able to identify the conceptual linchpin (key causal agent) that creates the environment enabling other causal agents to become “bad actors” in the proliferation of Alzheimer’s pathology. As Dr. Tanzi will explain, that linchpin is the brain’s innate immune system.
A Powerful Stem Cell Consortium
Under the leadership of Dr. Sam Gandy of the Icahn School of Medicine at Mount Sinai, we have been able to put together one of the most powerful groups of stem cell institutions in the world. The Cure Alzheimer’s Fund Stem Cell Consortium focuses on a variety of opportunities for creating stem cells from normal tissue, using those cells for gaining insights into the nature of neurogenesis in the brain, developing new scientific applications of such knowledge, and using stem cells created from Alzheimer’s patients to analyze the pathology of Alzheimer’s disease and potentially to heal cell damage in the brains of Alzheimer’s patients.
Totally new advanced research tools
To take full advantage of the new technologies described above, it has been necessary to create new research tools. A few of these tools are as follows:
a. Alzheimer’s in a dish: Unbelievably, the stem cell researchers in Dr. Tanzi’s lab have been able to create an amazing new technology: “AD in a dish.” The dish in this instance is a miniature container of nerve cells produced from human stems cells with Alzheimer’s mutations that produce the pathology of the disease: senile plaques, Abeta oligomers and tau tangles. It is the first true recapitulation of Alzheimer’s disease brain pathology in a Petri dish, in which researchers now can better understand the disease process and rapidly test new potential drugs, etc. It is a tremendous research tool, since these “mini-brains” can be created quickly for a variety of tests—much cheaper and faster than using transgenic mice for testing. Furthermore, the system can be customized to one’s own personal genetics, as each new drug is tested to get an idea of whether a specific drug will work in that individual.
b. Proprietary algorithms to be used to analyze and manipulate the “big data” generated as a result of the WGS project: As a result of a $4 million grant from the National Institute of Mental Health, our researchers have been able to develop truly advanced mathematical and statistical tools for analyzing the data contained in the WGS database. This essentially is a highly advanced type of bioinformatic analysis system, which has to be used when analyzing quadrillions of bytes of genomic information (petabytes) in a biological context. With these tools it is possible to analyze DNA sequences down to a single base or base pair (of which there are 6 billion in the human genome) and to view sequences of bases and see the relationships between different segments or repeat segments. These algorithms are allowing us to identify countless genetic variants never before discovered and understand how they affect human physiology.
c. Screening currently available drugs against our database of Alzheimer’s genes: There currently are thousands of existing and approved drugs used for a great variety of human illness. Some of these could have application to Alzheimer’s disease and may offer the possibility of protection against the disease. If such drugs were found and tested, this could advance the pace to a cure dramatically, since FDA testing and approval processes would be rapid, and the drugs could be brought to market quickly. As Rudy will explain, we now are in the process of creating another large database in which approved drugs are matched against our AD gene database to identify those drugs that possibly may have some impact on the Alzheimer’s genes.
Thanks and Congratulations
Finally, this letter would not be complete without thanks and congratulations from our founders and directors, our staff and our scientists.
We received resounding support from all of our old and new friends this year. More than 2,500 new families chose to support us this year, bringing our funding to record levels (and as usual, the founding families and directors paid all operating costs so that third-party donations could go 100 percent into research).
The funds you provide through your generosity, in addition to supporting research, also are leveraged by others. CAF is an innovator and risk taker. Once we demonstrate “proof of concept,” others are happy to join with us to fully exploit whatever innovation we have originated, either in the form of direct funding or co-funding of joint projects. So your funds go a long way, as shown here.
The innovations just described would not be possible without the brilliance of our researchers. A hearty thanks goes out to all of them for their outstanding work this year. And particular, thanks and “welcome” go to our new members of the Research Consortium and Scientific Advisory Board:
Richard Huganir, Ph.D.;
William Mobley, M.D., Ph.D.;
Eric Schadt, Ph.D.; and
Marc Tessier-Lavigne, Ph.D.
Finally, our congratulations go to Thomas Sϋdhof, M.D., a member of our Scientific Advisory Board, who was honored in 2013 with the award of the Nobel Prize in Physiology or Medicine. Congratulations, Tom.
Nine years since the founding of Cure Alzheimer’s Fund have passed quickly. All of you have made CAF what it is. I personally thank you for all of your support over the years.
Jeffrey L. Morby
Chairman and Co-Founder