On behalf of the Cure Alzheimer’s Fund Research Consortium, it is my pleasure to share with you some of our key research findings in 2012. Last year was a stellar one for Cure Alzheimer’s Fund and arguably unprecedented in terms of the quality and quantity of research progress made. It seems like every new year brings us a treasure trove of valuable findings thanks to your support, but this year was particularly special. Below, I summarize some of the highlights of the achievements in Alzheimer’s research made possible by Cure Alzheimer’s Fund in 2012.
1. Alzheimer’s Genome Project™
The goal of the Alzheimer’s Genome Project is to elucidate all of the genetic factors that influence risk for Alzheimer’s disease. We then use this information to guide the development of novel therapies while also being able to more reliably predict lifetime risk for Alzheimer’s. The completion of Phase I of the Alzheimer’s Genome Project (AGP) in 2008 informed us as to “where,” in the human genome, there lie stretches of DNA that influence risk for Alzheimer’s disease (either positively or negatively). The study describing several new Alzheimer’s risk genes was named a Top Ten Medical Breakthrough of 2008 by TIME magazine. In Phase I, we focused only on the DNA in our genome that makes up the actual genes. But genes make up only 4 percent of our genome, and as you will see later in this letter, we now have found it necessary to tackle the other 96 percent of the DNA in the genome, since it recently was shown to regulate the activity of our genes.
Beginning in 2009, we embarked on Phase II of the AGP, functional studies asking how the new Alzheimer’s genes identified in Phase I of the AGP impact risk for Alzheimer’s. For example, we asked how novel Alzheimer’s genes impact beta-amyloid (plaque) deposition in both cell-based and disease animal models. Three Alzheimer’s genes that we have focused on using Alzheimer’s disease transgenic mouse models are CD33, ATXN1 and ADAM10. All of these were found to increase the accumulation of beta-amyloid in the brain owing to specific mutations and/or lack of activity. Phase II also has targeted certain Alzheimer’s disease candidate genes for “DNA sequencing,” with the goal of identifying DNA variants that alter the function of the genes, directly affecting one’s risk for Alzheimer’s.
To understand the concept of “DNA sequencing,” we need to first review some basic genetic concepts. Approximately 35,000 genes provide the blueprints for the roughly 350,000 proteins made in the human body. Genes are chemically made of deoxyribose nucleic acid (DNA), first described by Jim Watson and Francis Crick in the late 1950s. The structure of DNA resembles a double helix consisting of chemicals called nucleotides (bases). The bases are named by letters: A (red), T (green), C (blue) and G (yellow). A on one strand always binds to T on the other, and C always to G. These are called “base pairs.” The human genome consists of 3 billion of these base pairs of DNA. This sequential determination of the base pairs is called “sequencing” of the DNA.
On average, the DNA in two different individuals contains about 3 million variations in the DNA sequence. Some variants have no effect on disease, while others may increase risk or cause the disease, and still others may protect against disease. When a DNA variant directly impacts one’s risk for disease, it is called a “functional DNA variant.” In Phase II of the AGP, we have been sequencing the DNA of the specific genes shown in Phase I to be associated with Alzheimer’s risk, with the goal of identifying functional DNA variants responsible for risk. Identifying these functional variants is essential for accelerating our understanding of “how” a particular Alzheimer’s-associated gene directly increases or decreases risk for Alzheimer’s disease at the biological level. This is critical information needed for translating the genetic information into ideas for novel therapies and to someday carry out reliable genetic testing for one’s lifetime risk for Alzheimer’s, so that early prevention measures can be taken once effective disease-modifying drugs are available.
Surprisingly, as we sequenced the DNA of the new Alzheimer’s genes found in Phase I of the AGP, we found very few obvious functional DNA variants that could explain how the genes influence risk. As an exception, we found rare risk-enhancing mutations in the gene ADAM10 and protective mutations in the gene CD33 (see more below). But for most of the genes that had been confirmed by us (and others) to be bona fide novel Alzheimer’s disease genes, we could not find the functional variants to explain how they influenced risk for Alzheimer’s!
At this point, we decided it would be necessary to sequence all of the DNA in our genome—not just the 4 percent of the DNA of the genes themselves, but also the other 96 percent, so-called “junk” DNA, to get the full story of how our genome influences risk for Alzheimer’s disease. Meanwhile, the eagerly awaited and groundbreaking “ENCODE” project results were published in late 2012, validating the new direction we already had decided on—once again, we were ahead of the curve! ENCODE showed that, indeed, most of the action when it comes to inherited disease risk resides in “junk” DNA (more formally known as “intergenic” DNA) and not necessarily in the DNA of the genes! This intergenic DNA appears to affect the gene activity across long distances in the genome.
We’ve now formally launched Phase III of the AGP, known as “Whole Genome Sequencing,” in which we will sequence the entire genomes of the subjects in our Alzheimer’s families to search for functional DNA variants influencing risk for Alzheimer’s. It is the largest project of its type focusing on families. It’s also amazingly cost-effective: While it cost billions of dollars to obtain the first whole genome sequence of a human being at the turn of the century, we now can do so for $2,000 per human genome. Most importantly, Whole Genome Sequencing ensures we will not miss the bulk of functional DNA variants that most likely reside in the intergenic DNA between the genes. (See page 6, “What is Whole Genome Sequencing (WGS)?”)
So very exciting days lie ahead for the AGP. Whole Genome Sequencing is the final stop, the “Holy Grail,” in this journey to elucidate the entire genetic profile of Alzheimer’s disease risk in terms of both susceptibility and protection. We look most forward to analyzing the new data in 2013! Meanwhile, in other aspects of the AGP, we are submitting a series of research reports describing the other groundbreaking discoveries made in Phase I and II of the AGP. These include papers presenting (1)The analyses of the ADAM10 mutations in animal models of Alzheimer’s disease; (2) Elucidation of 100 or so genes (or stretches of junk DNA) found to influence risk for Alzheimer’s disease based on our genomewide association studies (GWAS); and (3) Large structural aberrations in the human genome (copy number variants), including large deletions, duplications and rearrangement of DNA that we found to directly cause Alzheimer’s disease in subsets of our Alzheimer’s families. While these results are all very exciting, the best is yet to come with Whole Genome Sequencing. And we are ready!
2. CD33: Novel Alzheimer’s Disease Gene
One of the new Alzheimer’s disease genes we reported in our 2008 AGP study that was named a top breakthrough by TIME magazine is called “CD33.” At the time, all that was known about CD33 was that this gene was involved in the brain’s innate immune system. This finding helped inspire parallel studies demonstrating a role for the amyloid beta protein (Abeta) as an anti-microbial peptide, fighting infection in the brain. (See 5. Understanding Alzheimer’s Pathology, page 8.) In line with the Cure Alzheimer’s Fund Roadmap, we reached out to investigators who had been studying CD33, (but not as part of Alzheimer’s research), and attained their valuable advice and expertise on how to investigate this gene’s potential role in Alzheimer’s pathology. After four years of intensive study, culminating this past year, we found a functional variant in the CD33 gene that protects against Alzheimer’s disease. Based on what we have learned from this functional variant in CD33, we already have begun the process of translating these findings into a novel Alzheimer’s disease therapeutic program. We think a CD33-targeted drug could be a potential blockbuster for Alzheimer’s disease by preventing nerve cell death caused by inflammation in the brain as part of Alzheimer’s pathology.
3. Gamma-Secretase Modulators (GSM)
Several years ago, Cure Alzheimer’s Fund provided the initial seed funding to develop a novel class of drug (GSM) that would hopefully lower beta-amyloid levels safely, avoiding the adverse side effects of so-called gamma-secretase inhibitors (GSI). The funding was provided to Dr. Steve Wagner at the University of California, San Diego (UCSD) and the studies were carried out collaboratively with my laboratory, which had the initial drugs synthesized and tested.
As a result of that seed funding, we generated ample positive data, enabling Dr. Wagner to obtain a highly prestigious NIH Neurotherapeutics Blueprint grant to develop the GSMs and advance them toward clinical trials in Alzheimer’s disease patients. This drug program is directed by an NIH Lead Development Team (LDT), on which Dr. Wagner and I serve. The LDT oversees the development of the drug with a host of NIH-supported consultants, who have a strong background in pharmaceutical drug development. The NIH provides funds for the drugs to be tested for toxicity, brain penetration, half-life, etc., all of which are needed to advance them to human clinical trials. To date, the NIH has provided millions of dollars to develop these drugs, a tremendous amount of leverage on the initial investment of Cure Alzheimer’s Fund! After synthesizing and testing hundreds of drugs in this class, we recently have identified a subseries of the GSMs with very high potency and a safety profile that predicts we could have a clinical candidate nominated for human trials over the next year or so.
We envision using such a drug to both treat acute Alzheimer’s and to protect against it—much like statins like Lipitor are now used to protect against heart disease. Our hope is to obtain NIH funding to test the best GSM in this class in Phase I and II clinical trials at Massachusetts General Hospital (MGH) and the University of California, San Diego (UCSD). If the trials are successful, a large pharmaceutical partner would be courted for larger Phase III clinical trials. In the meantime, in order to pave the way for FDA approval of Phase I trials, we also will need data regarding the precise molecular mechanism action by which these GSMs safely and effectively lower Abeta production. For this purpose, Cure Alzheimer’s Fund continues to support such studies in the laboratory of Dr. Steve Wagner at UCSD, in close collaboration with our laboratory at MGH.
4. Other Alzheimer’s Disease TherapiesOver the past year, Cure Alzheimer’s Fund has supported a number of exciting projects testing a variety of promising therapies aimed at halting or reversing disease progress. There was much excitement about a drug called bexarotene based on a study from the Cleveland Clinic in an Alzheimer’s mouse model. Members of our Research Consortium, including Drs. David Holtzman (Washington University, St. Louis), Sam Sisodia (University of Chicago) and Robert Vassar (Northwestern University), in collaboration with my laboratory, have attempted to replicate those studies. So far, our studies do not strongly support a role for bexarotene in treating Alzheimer’s. However, our investigation is ongoing. An important role for the Cure Alzheimer’s Fund Research Consortium is to provide critical information such as this to the AD research community so that time, effort and funding are targeted only toward the most promising research endeavors.
Cure Alzheimer’s Fund also has continued to support the development of cholesterol-targeted drugs for Alzheimer’s in the laboratory of Dr. Dora Kovacs at MGH. Dr. Kovacs has been developing drugs known as “ACAT inhibitors,” which have been shown to dramatically reduce Abeta levels in Alzheimer’s animal models. Dr. Kovacs is now testing novel ACAT inhibitors being designed and synthesized with Cure Alzheimer’s Fund support. Dr. Philip Haydon (Tufts University; UDP analogs) and Dr. Gal Bitan (University of California, Los Angeles; “molecular tweezers”) also are developing compounds aimed at lowering Abeta accumulation in the brain. The UDP analogs (Haydon) are intended to promote clearance of beta-amyloid in the brain via microglial cells, while the “molecular tweezers” (Bitan) are targeted at preventing the aggregation of the Abeta protein into deposits of beta-amyloid in the brain.
Cure Alzheimer’s Fund has continued to fund projects aimed at preventing tangle formation. Beta-amyloid deposits in the brain must induce tangle formation inside nerve cells to drive their dysfunction and death. Working with Research Consortium member Dr. Charles Glabe (University of California, Irvine), Dr. George Bloom (University of Virginia) discovered specific forms of aggregated Abeta (oligomers) that induce the formation of tangles. Over the last five years, it has become increasingly clear that tangles, made up of an aggregated form of the protein called “Tau,” can “spread” from dying, tangle-ridden nerve cells to healthy ones, leading to serial nerve cell death in the brains of Alzheimer’s patients. Thus, Cure Alzheimer’s Fund also has been funding the development of therapies targeted at stopping the formation and spread of tangles as part of research being carried out in the laboratories of Drs. Dennis Selkoe and Dominic Walsh at Harvard Medical School, and Dr. Virginia Lee at the University of Pennsylvania.
5. Understanding Alzheimer’s Pathology
Cure Alzheimer’s Fund also continues to support state-of-the art research aimed at furthering our understanding of the pathological process in Alzheimer’s disease. Several years ago Dr. Robert Moir (MGH) was supported by Cure Alzheimer’s Fund to follow up his groundbreaking studies showing Abeta may help protect the brain from infection in its capacity as an anti-microbial peptide. More recently, Dr. Moir has been investigating (1) How Abeta neutralizes bacterial/fungal infections; and (2) Whether other amyloids, e.g., in diabetes and Parkinson’s disease, carry out similar roles. These studies are testing the basic premise that diseases characterized by amyloids of various types may be initiated by certain microbial pathogens, which trigger the formation of amyloids as anti-microbial peptides. In 2012, Dr. Moir showed that Abeta counters bacterial and fungal (yeast) infections by forming a cage (nano-net) that traps the pathogen and suffocates it from obtaining nutrients. He also definitively showed that the amyloid of the pancreas in diabetes, amylin, is a potent anti-microbial peptide. The anti-microbial capabilities of both Alzheimer’s-related beta-amyloid and diabetes-related amylin were shown in cell-based experiments and in Drosophila (fruit fly) disease models. Potentially protective roles of beta-amyloid also are being investigated in mice with brain infections, e.g., meningitis.
In collaboration with Scientific Advisory Board member Dr. Paul Greengard (Nobel Laureate, The Rockefeller University), we have shown that some of the key genes active in vulnerable vs. resistant nerve cell populations of the brain in Alzheimer’s disease patients exhibit strong association with risk for Alzheimer’s disease in the genomic studies of our AGP. These genes are being studied further in collaboration with Dr. Greengard’s laboratory. In other studies addressing vulnerable vs. resistant brain regions in Alzheimer’s disease, Dr. Lee Goldstein (Boston University) has carried out state-of-the-art imaging studies in Alzheimer’s disease mouse models to determine the role of reactive metals such as copper and iron in driving Alzheimer’s disease pathology. In yet other studies of vulnerable vs. resistant nerve cell populations of the brain in Alzheimer’s disease, Dr. Sam Sisodia has been collaborating with our group to determine exactly which nerve cell and glial cell populations of the brain contribute to neurodegenerative processes in Alzheimer’s disease.
In studies aimed at investigating the propagation of Alzheimer’s disease pathology in the brain, Dr. Giuseppina Tesco (Tufts University) and Dr. Zhongcong Xie (MGH) have been funded by Cure Alzheimer’s Fund to explore how traumatic brain injury and surgical wound-induced brain inflammation contribute to Alzheimer’s pathology, respectively. Drs. Doo Yeon Kim (MGH), Sehoon Choi (MGH) and Marc Tessier-Lavigne (The Rockefeller University) were supported to study how the generation of new nerve cells in the brain (neurogenesis) and injection of neural stem cells into the brain can slow down or prevent Alzheimer’s pathology. Skin cells also are being used to create neural stem cells from genetically defined Alzheimer’s disease patients. These are injected in the brains of mice to study the properties of these Alzheimer’s disease patient-derived “neurons” in a natural environment in the brain.
Research Consortium member Dr. Bob Vassar has been funded to collaborate with Dr. Gopal Thinakaran (University of Chicago) to study the mechanism of Abeta production in synapses, focusing on the enzyme BACE1, which serves as the beta-secretase needed for the first step in Abeta generation. This study is centered on how beta-secretase is controlled by the EHD genes, which also have been shown to be associated with AD in the AGP. Finally, Cure Alzheimer’s Fund has supported follow-up studies of two other novel AD candidate genes discovered in the AGP. Dr. Betza Zlokovic (University of Southern California) is studying how the novel AD gene PICALM affects the clearance of Abeta out of the brain into the blood, while Dr. Cindy Lemere (Harvard Medical School) is studying how the novel AD gene CR1 governs the onset of inflammation in Alzheimer’s brain pathology. Both genes, PICALM and CR1, represent excellent drug targets for the treatment and prevention of Alzheimer’s disease.
In conclusion, 2012 truly has been a banner year for research efforts supported by Cure Alzheimer’s Fund, ranging from gene discovery to translation research fostering our understanding of Alzheimer’s disease pathology to novel drug development. On behalf of the Research Consortium and all scientists being supported by Cure Alzheimer’s Fund, we thank you for your very generous and continuous support of this cutting-edge research aimed at ending this devastating disease in our lifetimes.
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
MassGeneral Institute for Neurodegenerative Disease
Massachusetts General Hospital