Dear Cure Alzheimer’s Fund Supporters,
As I reflect on the research progress made in 2013, I not only am struck by how much the Cure Alzheimer’s Fund community has accomplished, but also how different our knowledge about Alzheimer’s and our progress toward successful treatment would be if there were no Cure Alzheimer’s Fund community. My research colleagues and I are deeply grateful for the support we have received that has enabled this work, which without Cure Alzheimer’s Fund would not have been possible. Now, let me share with you the highlights of what we have accomplished together.
Innate Immunity is Key
Thanks to the discovery of a host of new Alzheimer’s genes, we have learned that innate immunity and the genes that regulate it in the brain are the keys to understanding how the majority of neurons die from inflammation. Innate immunity is the process by which the body and brain are protected from infections owing to microbial pathogens like bacteria, viruses and yeast. Our seminal discovery of the association of Alzheimer’s disease with the CD33 gene in 2008 and, more recently, its relation to the Alzheimer’s-associated TREM2 gene (in 2012) has taught us an immense amount about how our brains defend against pathogens. This same process of defense also can be stimulated by rampant Alzheimer’s pathology in the brain—in the form of senile plaques and nerve cell tangles.
We now have found that the CD33 and TREM2 genes work together to regulate microglial cells and inflammation in the Alzheimer’s brain. Normally, microglial cells help to nourish nerve cells. But when they receive signals that the brain is under attack, e.g., by bacterial infection, they become soldierlike and try to kill the pathogens. Abundant Alzheimer’s pathology and nerve cell death also can trigger microglial cells to become soldiers shooting oxygen-based bullets called free radicals. While meant to protect the brain, the activated microglial cells inadvertently can kill nerve cells as part of “friendly fire” aimed at microbial pathogens. In this case, there are no microbial pathogens, just plaques, tangles and dying nerve cells that trick the brain into this neuroinflammatory state. This is arguably one of the biggest findings in the field in the last several years. In fact, Alzforum, the most authoritative online publication regarding Alzheimer’s research, listed our new genes in two of its just-released top five trends in Alzheimer’s for 2013. The Alzforum also listed our discovery of the late-onset AD mutations in the ADAM10 gene, which would not have been possible without Cure Alzheimer’s Fund support. Because of leverage from our early investment, we have federal grants to expand all of these programs.
Alzheimer’s Genome Project™ (AGP)
We now have discovered the very first new early-onset familial AD genes to be discovered since we and others first co-discovered the presenilin genes in 1995. This was largely attributable to our AGP Phase 2 results and a revolutionary new algorithm, developed in my lab, for finding structural DNA variants that segregate with disease in families. We were able to report 10 new AD genes with early-onset AD-linked mutations consisting of large insertions, deletions and rearrangements of the DNA in these genes.
Once again this year, TIME magazine listed the discovery of new AD genes in its top 10 medical breakthroughs. The piece generally referred to all new AD gene studies, not just a single paper, and specifically mentions “innate immune responses and inflammation,” which has been championed by us thanks to Cure Alzheimer’s Fund support!
Whole Genome Sequencing
We now have found many new mutations in APOE that may influence whether APOE4 leads to AD or not. We also have found 85,000 new mutations and DNA variants in and around the new AD genes that we and others have identified over the last several years. Of these, we have identified hundreds of new pathogenic mutations in virtually all of the new AD genes previously identified in the Alzheimer’s Genome Project™ and similar projects. We also now have begun a series of very exciting collaborations with world-renowned bioinformatics expert and new member of our Research Consortium Eric Schadt (Icahn School of Medicine at Mount Sinai), along with Win Hide (head of our bioinformatics subgroup; Harvard School of Public Health), to determine what these new genes and their mutations can tell us about a.) relevant biological and physiological pathways in AD that previously have not been implicated), and b.) what can these genes, when considered together as a group, tell us about currently approved drugs that may be useful for AD—those that never would have been considered until all of these genes were analyzed together in pathway- and systems-based analyses. As mentioned above, we are using the new gene mutations found with whole genome sequencing to make new neuronal and animal-based disease models and develop new therapies. So far, once again, innate immunity has emerged as a key event in Alzheimer’s pathology. As such, we are rapidly ramping up to develop therapies that will regulate brain neuroinflammation subsequent to the accumulation of Abeta, nerve cell tangles and nerve cell death in the brains of patients.
Gamma Secretase Modulators: Moving Toward Clinical Trials
Steve Wagner, Ph.D., Research Consortium member and professor at the University of California, San Diego, and I have developed drugs aimed at regulating the activity of an enzyme called gamma secretase, which is a critical contributor to Abeta production. This effort has been so successful the compounds we have developed have been adopted by the National Institutes of Health (NIH) as part of its fast-track, high-priority “Blueprint” program.We have some of the most promising gamma secretase modulators in the world, capable of lowering production of Abeta, safely, without adverse “off-target” effects. The NIH Steering Committee reviewed our drugs in November 2013 and gave us the thumbs up to continue and to aim at having a candidate go to the FDA for approval for clinical trials over the coming year. This is a huge achievement, especially for academic labs—all made possible by Cure Alzheimer’s funding.
Collaborative Work By Our Research Consortium and Scientific Advisory Board Members
If I had to point to one particular theme for 2013, it clearly would be “collaboration.” Our Research Consortium members have been working together with each other and their collaborators with increasing frequency and alacrity. We have exciting collaborations that have emerged by bringing together some of the greatest minds in the field for our Research Consortium (RC); they speak, email and meet on a regular basis and with increasing frequency. Dozens of high-impact papers have come out of these collaborations that otherwise would not have existed. For example, under the leadership of Sam Gandy at the Icahn School of Medicine at Mount Sinai, we have put together arguably the most powerful stem cell consortium in Alzheimer’s research. Exciting studies on our new Alzheimer’s genes are now in progress with Paul Greengard, Nobel Laureate at The Rockefeller University; Sam Sisodia, University of Chicago; John Hardy, Brain Research Trust; Allan Levey, Emory University; Roberto Malinow, University of California, San Diego; Gandy; Betza Zlokovic, University of Southern California; and Robert Vassar, Northwestern University, to name a few. Click here for a complete list of our Research Consortium and Scientific Advisory Board Members.
Cure Alzheimer’s Fund Stem Cell Consortium (CAFSCC)
The Cure Alzheimer’s Fund Stem Cell Consortium (CAFSCC) was founded in 2013 as a collaborative program involving laboratories at the Icahn School of Medicine at Mount Sinai (ISMMS), New York Stem Cell Foundation (NYSCF), Harvard Medical School (HMS), Massachusetts General Hospital (MGH); The Rockefeller University (RU); and Hadassah University (HU). The labs were chosen for their complementary skills and areas of focus, and these choices already have begun to yield dividends in terms of collaborative publications and collaborative grants elucidating the process of how Alzheimer’s disease begins and progresses.
The CAFSCC, within the space of one year, has developed highly productive collaborations wherein each lab employs its particular expertise to build one of the various technological way stations that mark the “bench-to-bedside” pathway, culminating in a trajectory that, within a short time, should yield information relevant to personalized pharmacogenomics recommendations in subjects with the most common deterministic cause of hereditary AD.
The Disease Model
The disease model of Alzheimer’s pathology is an outstanding example of the output of collaboration and progress of our Research Consortium. The model was produced by all of the members of the Research Consortium as a way to depict the current (2013) understanding of how Alzheimer’s starts and progresses through the brain, and indicates where the pathology is most vulnerable to intervention. The model shows essentially a vicious cycle of destruction of brain cells or neurons beginning with the overproduction of the protein Abeta, which stimulates the spreading of another protein called tau that “infects” other cells, causing inflammation in the brain. This inflammation stimulates the brain’s defenses to react in a way that creates more Abeta and tangles. We also have learned that while Alzheimer’s usually begins with the accumulation of Abeta, it also can start with either tangles or inflammation, e.g., subsequent to traumatic brain injury, as part of one vicious cycle. Each of these major transitions—creation of Abeta, creation and spreading of tau tangles and brain inflammation—offers clear opportunities for therapeutic intervention. It would have been impossible to get leading Alzheimer’s researchers to agree to such a depiction until very recently. But the work done by Cure Alzheimer’s Fund researchers and others has brought Alzheimer’s research to the point where most investigators agree on this broad outline. The details are many, complex and still unfolding, but this is strong indication of the accelerated pace toward the development of truly effective therapies to stop the disease before it starts, interrupt its development in the early stages and retard or perhaps even reverse its effects in those who already are symptomatic. Much work is left to be done, but the objectives and even some of the pathways to achieve the objectives now are much clearer.
The Science of Cure Alzheimer’s
These are just some of the highlights from 2013 alone. See the complete list of 2013 projects for an idea of the depth and scope of the research made possible by CAF, all of which is moving us more rapidly to our goal. The science of Cure Alzheimer’s Fund is now a powerful and well-oiled machine, moving so fast and efficiently that it is a challenge to keep up with the new discoveries, papers, grants and collaborations that are emerging in the CAF nexus. Emails concerning collaborations constantly are being sent among Research Consortium members and their team members. We are writing grants together. There is so much going on—the research we fund is exploding with results.
In closing, I can say these are the most exciting and productive days of my scientific career, largely thanks to Cure Alzheimer’s Fund. My goal, and that of my research colleagues, is to stop this disease. And as all of this tremendous collaboration and progress shows, we cannot do it without you.
Rudolph E. Tanzi, Ph.D.
Joseph P. and Rose F. Kennedy Professor of Neurology, Harvard Medical School
Vice Chair, Neurology
Director, Genetics and Aging Research Unit, Massachusetts General Hospital