From our 2011 Annual Report.
On behalf of the Board of Directors and the Research Consortium, we want to thank all the donors, researchers and academic institutional partners supporting Cure Alzheimer’s Fund research for your help in making 2011 such a successful science year. Guided by leading scientists in the field, Cure Alzheimer’s Fund-supported research continues to make breakthrough progress toward our goal of eradicating Alzheimer’s disease.
Research supported by Cure Alzheimer’s Fund has helped reshape the current view of the pathological processes underlying Alzheimer’s disease. Not long ago, it was thought that beta-amyloid plaques in the brain, made up of the protein called “Abeta,” were the main causes of the disease. Though beta-amyloid continues to be an important factor in the Alzheimer’s picture, we now have progressed to a more sophisticated understanding of Alzheimer’s pathology—one that will allow us to develop much more effective therapies and early interventions.
A quick summary of this current and more sophisticated view is as follows:
- We now know genetic mutations and “insults” to the brain (e.g., undetected mini-strokes, head bangs, chemical toxins and other harmful impacts) cause excessive amounts of Abeta to accumulate in the brain.
- While a good deal of Abeta is found in the toxic, beta- amyloid, senile plaques, most of the Abeta floats around nerve cells in toxic clumps known as “oligomers.” In excess, these clumps of Abeta somehow trigger the clumping of another protein, Tau, which produces toxic tangles inside the nerve cells of the brain.
- The toxic tangles then can spread to other brain cells, causing more tangles. In this process, the tangle-bearing nerve cells ultimately die. The combination of both dead nerve cells and beta-amyloid plaques triggers inflammation in the brain.
- Inflammation then becomes a major “insult” to the brain and causes even more Abeta production, tangle formation and nerve cell death.
- A vicious cycle ensues.
The Alzheimer’s Genome Project (AGP) and Novel Animal Models
The flagship project of the Cure Alzheimer’s Fund is the AGP, begun in 2007 and carried out in Dr. Tanzi’s laboratory at Massachusetts General Hospital. It also includes the AlzGene database maintained by Dr. Lars Bertram at the Max Planck Institute in Berlin. The AGP has successfully completed Phase I, resulting in the identification of more than 100 new candidate genes affecting susceptibility for Alzheimer’s disease. We now are actively engaged in sharing this information in public databases, including those maintained by the National Institutes of Health and the Cure Alzheimer’s Fund-supported database AlzGene.org. The identification of these genes has implicated several new biological pathways and systems in the Alzheimer’s disease process that previously were not known to be involved.
In the second phase of the AGP, we have been analyzing the DNA of the many new Alzheimer’s gene candidates to pinpoint the human gene variants that directly influence one’s susceptibility for the disease. Introduction of these human gene variants into mice already is accelerating the creation of new animal models for the disease and new drug screening programs. In fact, over the past year, we have created four new animal models for Alzheimer’s based on discoveries made in the AGP. The generation of these new animal models is paving the way for the development of new therapies aimed at more effectively preventing and treating Alzheimer’s from novel angles. The ultimate goal of the AGP is to use the dozens of validated Alzheimer’s genes to predict one’s risk for the disease, and then treat to prevent the disease from striking before symptoms appear.
Novel Therapeutics for Alzheimer’s Disease
Currently available therapies only treat the symptoms of Alzheimer’s but do not stop the disease from progressing. They generally provide modest and only temporary benefit from the ravages of this terrible disease. To effectively treat and prevent this disease, we will need therapies that directly slow down, stop or reverse the disease process. This means we must first fully understand how the disease progresses and then develop therapies that intervene. Cure Alzheimer’s Fund has been supporting numerous drug programs from bench to bedside. Over the past year, Cure Alzheimer’s Fund has made significant progress in novel drug discovery for Alzheimer’s.
Some examples are listed below.Adding to this picture is the very new discovery made by our researchers that Abeta, the peptide that begins this whole process, may be part of the brain’s innate immune system, and as such, attacks and attempts to eliminate toxic bacteria, fungus and viruses that enter the brain as we age. In fact, Cure Alzheimer’s Fund is actively funding research into the possibility the initial accumulation of excess Abeta in the brain may be triggered by the brain’s own immune system trying to fight a chronic infection of various origins.
Cure Alzheimer’s Fund has played a major role in the development and confirmation of each piece of the above- described emerging understanding of the process of generation of Alzheimer’s pathology. 2011 has been a particularly important year. Genetic studies conducted as a consequence of our Alzheimer’s Genome ProjectTM have taught us, in particular, that this whole process is triggered when, over one’s lifetime, too much Abeta accumulates in the brain. This is usually due to poor clearance of Abeta in the form of plaques and clump-like oligomers. This then leads to the tangles, nerve cell death and inflammation as part of a vicious cycle. Once enough nerve cells and their connections, called synapses, are lost, cognitive impairment and, ultimately, dementia, is the result, causing Alzheimer’s disease.
Since the inception of the Cure Alzheimer’s Fund, nearly $15 million dollars has been distributed to more than 50 projects in 24 of the top Alzheimer’s research laboratories in the world. As a result, more than 100 research publications in top-tier scientific journals have acknowledged Cure Alzheimer’s Fund for support. It is safe to say our understanding of the causes of Alzheimer’s disease and how to more effectively treat this devastating disease have been profoundly impacted by Cure Alzheimer’s Fund-supported research efforts, with 2011 hitting new highs.
A summary of these achievements is provided below.
Cure Alzheimer’s Fund supported the groundbreaking work of Dr. Gary Landreth and colleagues at Case Western Reserve University, who showed in a mouse model for Alzheimer’s that the FDA-approved lymphoma drug bexarotene was able to stop the accumulation of beta- amyloid (made up of Abeta and more particularly, its most toxic form, Abeta42) in the brain and, to some extent, reverse beta-amyloid-induced pathology and cognitive deficits. The researchers found bexarotene could rapidly clear beta- amyloid deposits in the mice, and that this process dependedon the Alzheimer’s risk gene known as APOE. While the results in the mice were nothing short of remarkable, the leap from mouse to man does not guarantee success in humans. However, as a result of this landmark study, bexarotene is now beginning to undergo testing in human clinical trials for efficacy and safety for the potential treatment and prevention of Alzheimer’s disease. Cure Alzheimer’s Fund has supported Dr. Landreth and his collaborator, Dr. David Holtzman of Washington University, St. Louis, to explore the effects of bexarotene on Alzheimer’s pathology, and also plans to help support pivotal clinical trials.
Gamma Secretase Modulators
Preventing the accumulation of toxic Abeta in the brain is currently the goal of thousands of academic and pharmaceutical laboratories attempting to discover effective new drugs for Alzheimer’s disease. One approach involves trying to curb the production of Abeta by inhibiting the enzyme called gamma secretase, which is required for the production of the toxic material. Previous attempts to do this used drugs called “gamma secretase inhibitors.” However, in a recent clinical trial by Lilly, these drugs caused major side effects, including skin cancer.
Dr. Steve Wagner, University of California, San Diego, in collaboration with Dr. Tanzi’s laboratory, has been supported by the Cure Alzheimer’s Fund since 2009 to develop safer versions of these drugs, which we call “gamma secretase modulators.” We were able to avoid what is thought to cause the toxic side effects of the original drugs and made new drugs that slow down the production of Abeta in the brain.
As a major validation of the promise of these new drugs made possible by Cure Alzheimer’s Fund, Dr. Wagner recently was awarded a multimillion-dollar National Institutes of Health “Blueprint” Neurotherapeutics grant for the fast-track development of these drugs. Drs. Wagner and Tanzi serve on the lead development team for the five-year NIH project, which brings together 15 agencies that will help shepherd these new drug candidates into human clinical trials by 2014.
Cure Alzheimer’s Fund also has been engaged in supporting a number of promising new therapies for Alzheimer’s in 2011. In the pathological cascade of Alzheimer’s, toxic clumps of Abeta drive the formation of tangles, which choke the inside of nerve cells in Alzheimer’s patients’ brain. Dr. Charles Glabe, University of California, Irvine, and Dr. George Bloom, University of Virginia, received Cure Alzheimer’s Fund funding to discover exactly which forms of Abeta cause tangles to form in nerve cells.
Over the past several years, tangles were shown to “spread” from one nerve cell to another, causing serial nerve cell death in the brains of Alzheimer’s patients. In addition to curbing beta-amyloid deposition, we also will need therapies for stopping the formation and spread of tangles. In pursuit of better understanding of how this works, Cure Alzheimer’s Fund has been funding Dr. Dennis Selkoe and Dr. Dominic Walsh, Harvard Medical School, in 2011 as well as Dr. Virginia Lee (University of Pennsylvania) in 2010 to devise therapies that can prevent Abeta from triggering tangles and prevent the spread of tangles from dying nerve cells to healthy ones.
Cholesterol-Targeted Drugs and Other New Alzheimer’s Therapeutics
Several other new Alzheimer’s therapies are being developed by other investigators with Cure Alzheimer’s Fund money. For example, some cholesterol-lowering drugs carry the potential to lower Abeta levels and are being developed as new therapeutics for Alzheimer’s in the laboratory of Dr. Dora Kovacs, Massachusetts General Hospital (MGH). Dr. Kovacs has been funded by Cure Alzheimer’s Fund to develop drugs known as “ACAT inhibitors,” which she has shown dramatically reduce Abeta levels in Alzheimer’s animal models. Other 2011 Cure Alzheimer’s Fund-supported projects aimed at drugs that can lower Abeta levels in the brain include compound being developed by Dr. Phillip Haydon, Tufts University (UDP analogs), Dr. Nicholas Seeds, University of New Mexico (neuroserpin inhibitors), and Dr. Gal Bitan, UCLA, (molecular tweezers).
Understanding Alzheimer’s Disease Pathology
In addition to the very exciting work that has been supported by Cure Alzheimer’s Fund in genetics and drug discovery, we also are supporting critical research aimed at further understanding the pathological process in Alzheimer’s disease. In a revolutionary study, Dr. Robert Moir (MGH) was supported by Cure Alzheimer’s Fund to uncover the normal role of Abeta, showing it may protect the brain from microbial infections. He now is being funded to investigate whether amyloids in other diseases such as diabetes and Parkinson’s disease carry out similar roles. These studies carry profound implications for the causes of these diseases and especially whether infections by certain microbial pathogens may initially trigger the formation of beta-amyloid as well as other amyloids, such as amylin in the pancreas of diabetes patients. Dr. Moir’s studies also call for much more careful consideration as we develop therapiesto lower Abeta levels, in view of the small protein’s potential “normal” role in the brain.
In other studies, Dr. Paul Greengard, Rockefeller University, Nobel Laureate, is studying why only certain sets of nerve cells die in the brains of Alzheimer’s patients, while others are spared. Similarly, Dr. Lee Goldstein, Boston University, is performing state-of-the-art mapping of metal (zinc and copper) distributions in the brain to investigate their contribution to disease pathology. Dr. Sam Sisodia, University of Chicago, was funded to search for factors in the brain that drive the generation and toxicity of Abeta. Dr. Doo Yeon Kim and Dr. Sehoon Choi (MGH) are being supported to explore how the propagation of new nerve cells in the brain and delivery of neural stem cells (made from skin cells) into the brain can ameliorate Alzheimer’s pathology. And finally, Dr. Giuseppina Tesco, Tufts University, and Dr. Zhongcong Xie (MGH) were funded in 2011 to explore how traumatic brain injury and surgery-induced brain inflammation contribute to risk for Alzheimer’s pathology, respectively.
In summary, 2011 has been a tremendously successful and busy year for Cure Alzheimer’s Fund. The groundbreaking work described above would not have been possible without thegenerous support of more than 4,000 supporters, including the founding families and board members who provide both financial and personal support on so many levels. While there is still a great deal of work to be done before we achieve our overarching goal of eradicating Alzheimer’s disease through early prediction-early prevention, huge strides were made in 2011 toward this end.
On behalf of the Cure Alzheimer’s Fund, we thank you all for your devotion, perseverance and passion in supporting the research necessary to end this devastating disease in our lifetimes.
Jeffrey L. Morby
Chairman and Co-Founder Cure Alzheimer’s Fund
Rudolph E. Tanzi, Ph.D.
Chair, Cure Alzheimer’s Fund Research Consortium Joseph P. and Rose F. Kennedy Professor of Neurology, Harvard Medical School Director, Genetics and Aging Research Unit, Massachusetts General Hospital