Posted August 20, 2009
Prepared by:
Rudolph E. Tanzi, Ph.D.
Chairperson, 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
Department of Neurology
Massachusetts General Hospital
114 16th Street
Charletown, MA 02129
[email protected]
Timothy W. Armour
President and CEO
Cure Alzheimer’s Fund
34 Washington Street Suite 300
Wellesly Hills, MA 02481
[email protected]
The overarching goal of a national AD research strategy is to reach a cure most efficiently by accelerating studies aimed at identifying and characterizing all of the genes that influence susceptibility to AD, placing highest priority on those that will most readily lead to effective therapeutics for the treatment and prevention of AD.
Over the next decade, the influx of roughly 50 billion dollars into AD research should allow us by 2020 to identify all of the genes involved in AD susceptibility, and to arrive at a cure based largely on prevention.
Alzheimer’s disease (AD), the most common form of dementia in the elderly, was first described roughly 100 years ago by Dr. Alois Alzheimer. AD is a progressive and fatal neurodegenerative disease that impairs memory and cognition. There are more than five million AD patients in the U.S., and the number of new cases will grow by more than 10% per year.
Almost half of people aged 85 and older have the disease. AD will become a certain epidemic as the baby boomers enter the age range in which Alzheimer’s is most prevalent.
In 2004, 25% of the combined Medicare and Medicaid expenses (about $122 billion) went to AD care. AD alone could single-handedly bankrupt Medicare and Medicaid within the next decade if left unchecked.
While the AD research community has traditionally received support from both public and private sources, federal funding for research into the causes of AD has been significantly decreased over the last several years. Over the next decade, an order of magnitude increase in federal funding for studies aimed at elucidating the causes of AD, e.g. five billion dollars per year, will be necessary to develop safe and effective therapies for the treatment and prevention of AD. Moreover, in the current economic climate, it is important to focus on the most direct and highest potential paths to a cure.
Over the next decade, an influx of roughly 50 billion dollars into AD research should allow for the identification of all of the genes involved in AD susceptibility and therapies aimed at treating and preventing AD by 2020. The identification of the complete set of AD genes will enable not only more accurate diagnosis of AD, but also the reliable prediction of risk for AD early in life.
Also, the development of sensitive and specific biomarkers, imaging, and other early detection modalities will be necessary to assess and monitor the disease process prior to the onset of symptoms. Knowledge gained from studies of these genes will guide the development of novel therapies for the treatment and prevention of AD, particularly in those at highest risk, based on their genetics. This pharmacogenomic (personalized medicine) approach to AD could be attained by 2020 with sufficient funding.
Toward this end, we propose a national research strategy that is based on the fact that AD is a highly genetically driven disease. The proposed research strategy is endorsed by the simple fact that over the past two decades, the vast majority of investigation aimed at understanding the causes of AD and developing novel therapies for treatment and prevention has been based first and foremost on studies of the four known AD genes.
The ultimate goal of this strategy is the future eradication of AD based on “early prediction-early prevention”. Our strategy includes the following four steps (Figure 1):
While age is the strongest risk factor for AD, second is family history; up to 80% of AD cases involve a genetic component. Of the four established AD genes, three (APP, PSEN1, PSEN2) can carry any of over 200 mutations that directly cause early-onset (<60), familial AD with virtual certainty when inherited. These mutations account for only ~two percent of AD cases.
A variant (E4) of another gene called APOE increases risk for roughly half of the more common, late-onset cases of AD, but does not guarantee onset. Together, these four genes account for about 30% of the genetic basis of AD. Meanwhile, 70% of AD genetics still remains to be determined.
History has documented that each newly identified AD gene has provided a unique window into the cause of AD thereby leading to new targets for drug discovery. In fact, the vast majority of ongoing AD research and drug discovery would not have been possible without the information garnered from studies of these four AD genes.
Thus, a national AD research strategy should start with intensive studies of these four genes to better understand their role in AD pathology, together with the search for the remaining genes that influence susceptibility for AD.
To identify and validate the remaining AD genes accounting for the other 70% of the genetic basis of AD, labs around the world have been carrying out genome-wide association scans of DNA from AD patients and families.
A major effort in this area is the “Alzheimer’s Genome Project” (AGP)™, which is based at Massachusetts Gen¬eral Hospital under the direction of Dr. Rudy Tanzi, and funded by the Cure Alzheimer’s Fund.
The AGP has recently reported four novel late-onset AD genes based on studies of over 1300 AD families. This discovery was named a “Top Ten Medical Breakthrough of 2008” by Time magazine. In addition, the AGP has identified over 60 additional novel AD gene candidates, currently being validated.
The second step in a national AD research strategy involves “translational” studies aimed at determining how defects in the known and novel AD genes lead to brain pathology. As studies of these genes lead to a better understanding of the molecular mechanisms of neurodegeneration in AD, new targets for drug discovery are made possible. It will be essential to include multiple strategies toward drug discovery including systems neuroscience, biochemical approaches, physical chemistry, the analysis of amyloid and tau and other important opportunities for insights into the mechanism of the disorder.
Based on studies of the four original AD genes, it has become increasingly clear that excessive accumulation in the brain of a peptide (small protein) called the amyloid beta peptide (A-beta), is the key pathological event in the disease process.
The balance between A-beta production versus clearance in the brain determines how much A-beta will accumulate and potentially form toxic beta-amyloid aggregates. Hand in hand with the accumulation of toxic aggregates of beta-amyloid are the neurofibrillary tangles consisting of aggregated tau protein that chokes and kills nerve cells.
Current clinical trials of drugs aimed at retarding disease progression in AD involve therapies that curb the accumulation of A-beta in the brain by either promoting its clearance or turning down its production. Other therapies are aimed at preventing the conversion of tau protein into neurotoxic tangles.
Many of the most promising clinical trials would not have been possible without the identification and characterization of the first four known AD genes. For example, specific protease inhibitors and modulators, e.g. gamma-secretase modulators and beta-secretase inhibitors, which lower cerebral A-beta levels are based on studies of the early-onset familial AD genes.
While there are promising drugs currently in clinical trials, we do not know whether any one of them alone or in combination with others will have a significant effect in stopping, slowing or reversing AD.
Thus, it will be important to have a rich pipeline of as many gene-based targets as possible for additional drug discovery and development. The more shots on goal, the higher the probability of scoring a victory in the treatment and prevention of AD.
As novel AD genes continue to be discovered, “translational” studies will be necessary to determine whether they cause AD in the same manner as the four original AD genes. We expect that many novel AD genes will likewise affect cerebral A-beta levels and tangle formation.
We also expect to identify genes functioning in other biochemical pathways as well as genes that interact with environmental and life-exposure factors to influence susceptibility for AD.
For example, traumatic brain injury (TBI) and stroke are strong risk factors for AD as are cardiovascular risk factors, such as high cholesterol. Physical exercise has also been shown to protect against Alzheimer’s disease.
Thus, translational studies will be required to elucidate the molecular and biochemical basis for how these and other non-genetic risk factors work together with one’s genome to influence risk for AD.
As we gain a clearer understanding of the mechanisms by which the known and novel AD genes cause neural dysfunction and death, we can begin to design platforms for novel drug discovery.
The third step of a national AD research strategy is drug discovery based on the knowledge gained from translational studies of AD genes. This will require close collaboration between academic groups and pharmaceutical and biotechnology companies.
Through translational studies addressing how defects in AD genes lead to aberrations in biochemical activities of proteins and their activities in the brain, we can gain information as to what is “broken” in the AD brain and then devise therapies to “fix” it.
Thus, “translational” studies of AD genes tell us which biochemical pathways in the brain should be targeted in high-throughput drug screens aimed at discovering novel agents (small molecules or biological products) that can be used to effectively treat and prevent AD.
As such, the third step of a national AD research strategy should include taking what is learned from genetic, molecular, and biochemical studies of AD genes (mainly carried out in academia with federal and private foundation funding), and incorporating this information into novel drug screening strategies for therapeutic intervention in AD.
In most cases, translational data will need to be carried over from academia into industry where drug discovery can then be carried out based on that information. However, some drug discovery could also be carried out in drug discovery facilities at academic institutions.
It is worth noting that some of the most recent drug trials in AD that have failed, particularly those targeting beta-amyloid, have not adequately addressed what we now know about the biological and pathological activities of the known AD genes.
As we generate more basic and translational data about the known and novel AD genes, we will be better equipped to design smarter drug screens necessary to effectively treat and prevent AD.
The fourth step in a national AD research strategy will require novel drug candidates to undergo “drug development”. Drug development includes initially a pre-clinical step in which novel therapies are tested in cellular and animal models so that they can be prepared for safe use in humans.
Next, novel drugs and therapies are tested in human clinical trials for safety and efficacy in treating and preventing AD. While clinical trials are generally carried out by pharmaceutical companies, academia can help by concurrently working on the “mechanism of action” by which a novel drug works to treat the disease.
Such information can greatly accelerate the approval of a novel therapeutic. Academia can also facilitate drug trials by generating direly needed data on biomarkers for AD. Biomarkers for disease are helpful at several different levels.
First, they can assist in the accurate diagnosis of AD. This is essential for clinical trials that need to recruit actual AD patients and not those suffering from other forms of dementia.
Second, biomarkers allow additional outcomes to be measured in AD clinical trials beyond improvements in cognition, which can take up to a year to properly assess. In contrast, changes in validated biomarkers for the disease can allow for much earlier assessments, e.g. in two months, as to whether a novel therapy is on track in a clinical trial. The development or identification of key biomarkers is critically needed to identify patients prior to symptom onset as well as to monitor the effects of experimental therapies.
Currently, the most promising biomarkers include measuring A-beta and tau levels in cerebrospinal fluid. Imaging, e.g. for volumetric changes in specific brain regions or for beta-amyloid deposition can also facilitate diagnosis and monitoring of the progress of a novel therapeutic in an AD clinical trial.
Much of the research on biomarkers and imaging In AD is taking place in academic centers, and can greatly facilitate drug development in the pharmaceutical and biotech sectors.
It should also be emphasized that successful clinical trials will require early, pre-symptomatic detection of AD based on imaging, biomarkers, and other early detection diagnostic tools.
In summary, studies of the four known AD genes have already provided an unprecedented window into the molecular underpinnings of AD.
Prior to the discovery of the four known AD genes, the field was limited to merely guessing at the causes of AD with little, if any, success. All four of the known AD genes have pointed to the excessive accumulation of the toxic peptide A-beta in brain as the primary cause of AD, although the route to nerve cell death also involves tangle formation.
Accordingly, most ongoing clinical trials aimed at modifying disease progression (as opposed to just treating the symptoms) are targeted at lowering A-beta and/or tau accumulation in the brain.
Concurrently, firmly establishing the identity of the genes accounting for the remaining 70% of AD genetics, continues around the world.
Every new AD gene identified and validated provides novel targets for drug discovery and unique opportunities to design innovative therapies to treat and prevent AD.
In conclusion, the overarching goal of a national AD research strategy is to reach a cure most efficiently by accelerating studies aimed at identifying and characterizing all of the genes that influence susceptibility to AD, placing highest priority on those that will most readily lead to effective therapeutics for the treatment and prevention of AD.
Over the next decade, the influx of roughly 50 billion dollars into AD research should allow us by 2020 to identify all of the genes involved in AD susceptibility, and to arrive at a cure based largely on prevention.
The identification of the full cadre of AD genes will enable more accurate diagnosis and reliable prediction of risk for AD early in Iife.
As such genetic privacy laws protecting employment, health insurance, life insurance, long-term care, etc. must be in place. As history has already illustrated, the knowledge gained from studies of AD genes will guide the discovery and development of novel therapies for the treatment and prevention of AD.
The combination of reliable prediction and therapies that can stop the disease process will ultimately enable a pharmogenomic (or personalized medicine) approach to AD characterized by “early prediction, early prevention”. With sufficient funding this should be attainable by 2020.
Figure 1. National Alzheimer’s Disease Research Strategy. The “Foundational Research” begins with the identification of dozens of genes influencing susceptibility for AD. A subset of these genes will then be chosen based on strength of the genetic findings and suitability for drug discovery to proceed to “Translational Research”.
Here, the AD genes will be biologically characterized to determine which biochemical pathways are impacted by AD-associated gene defects. This information will then be used for a smaller subset of genes to guide “Drug Discovery” efforts including high-throughput screening of small molecules as well as “biological” therapies, e.g. recombinant proteins.
The most promising therapeutics will then proceed to pre-clinical and ultimately clinical “Drug Development” efforts for a small subset of suitable AD genes. Successful clinical trials will also require early, pre-symptomatic detection of AD based on imaging, biomarkers, and other early detection diagnostic tools.
The identification of the complete set of AD genes will enable not only reliable prediction of AD early in life, but also, the development of therapies that can prevent disease progression, particularly in those at highest risk based on their genetics.
Besides leading to effective treatments for AD, this approach will allow for the future eradication of AD based on a “pharmacogenomic” or “personalized medicine” approach of “early prediction, early prevention” of disease.
